Sun Kim, M.D. M.S.

All Publications

• Reframing prediabetes: A call for better risk stratification and intervention. Journal of internal medicine Kim, S. H. 2024

  Abstract

  Prediabetes is an intermediate state of glucose homeostasis whereby plasma glucose concentrations are above normal but below the threshold of diagnosis for diabetes. Over the last several decades, criteria for prediabetes have changed as the cut points for normal glucose concentration and diagnosis of diabetes have shifted. Global consensus does not exist for prediabetes criteria; as a result, the clinical course and risk for type 2 diabetes vary. At present, we can identify individuals with prediabetes based on three glycemic tests (hemoglobin A1c, fasting plasma glucose, and 2-h plasma glucose during an oral glucose tolerance test). The majority of individuals diagnosed with prediabetes meet only one of these criteria. Meeting one, two, or all glycemic criteria changes risk for type 2 diabetes, but this information is not widely known and does not currently guide intervention strategies for individuals with prediabetes. This review summarizes current epidemiology, prognosis, and intervention strategies for individuals diagnosed with prediabetes and suggests a call for more precise risk stratification of individuals with prediabetes as elevated (one prediabetes criterion), high risk (two prediabetes criteria), and very high risk (three prediabetes criteria). In addition, the roles of oral glucose tolerance testing and continuous glucose monitoring in the diagnostic criteria for prediabetes need reassessment. Finally, we must reframe our goals for prediabetes and prioritize intensive interventions for those at high and very high risk for type 2 diabetes.

  View details for DOI 10.1111/joim.13786

  View details for PubMedID 38606904

• Aromatase inhibitor-induced arthralgia ameliorated by Mediterranean diet and active lifestyle guided by continuous glucose monitoring: a case report and review of the literature. Frontiers in oncology Wilson, K. L., Grewelle, R. E., Gupta, T., Kim, S. H., Katsumoto, T. R. 2024; 14: 1189287

  Abstract

  Aromatase inhibitors (AIs) are a cornerstone adjuvant treatment of many hormone receptor-positive breast cancers, and nearly half of women taking aromatase inhibitors suffer from AI-induced arthralgia (AIA), also known as AI-associated musculoskeletal syndrome (AIMSS), for which there are limited evidence-based treatments. Pharmacologic management and complementary methods including supplements, exercise, physical therapy, yoga, acupuncture, and massage have all shown mixed results. Comprehensive diet and lifestyle strategies are understudied in AIA/AIMSS despite their disease-modifying effects across many chronic conditions. Here we report a case of a woman with stage 2 estrogen and progesterone receptor-positive invasive ductal carcinoma on adjuvant anastrozole whose AI-induced arthralgia was durably controlled through a Mediterranean plant-forward diet and daily physical activity guided by continuous glucose monitoring. We posit that diet and a lifestyle inclusive of daily physical activity constitute a low-cost, low-risk, and potentially high-reward strategy for controlling common AI-induced musculoskeletal symptoms and that more investigation in this arena, including well-designed randomized trials, is warranted.

  View details for DOI 10.3389/fonc.2024.1189287

  View details for PubMedID 38361780

  View details for PubMedCentralID PMC10867103

• EXPOSURE TO GLP1RA THERAPY IS ASSOCIATED WITH IMPROVED SURVIVAL IN POST LIVER TRANSPLANT PATIENTS WITH TYPE I I DIABETES MELLITUS Achalu, S., Berry, R., Manikat, R., Yeoh, A., Gombar, S., Kim, S. H., Ghaziani, T., Dronamraju, D., Dhanasekaran, R., Kwong, A. J., Torok, N. J., Goel, A., Kim, W., Kwo, P. LIPPINCOTT WILLIAMS & WILKINS. 2023: S311-S312

  View details for Web of Science ID 001094865400315

• EMPAGLIFLOZIN IN DIURETIC REFRACTORY ASCITES (DRAIN-EM): RESULTS OF A SINGLE-CENTER FEASIBILITY STUDY Goel, A., Tarlow, B. D., Kwong, A. J., Hu, K., Cheng, X., Kim, S. H., Charu, V., Dronamraju, D., Kim, W., Kwo, P. LIPPINCOTT WILLIAMS & WILKINS. 2023: S1337-S1338

  View details for Web of Science ID 001094865403171

• WE ARE GOING DOWN THE WRONG PATH! THE CURRENT AASLD GUIDANCE MISCLASSIFIES MAJORITY OF PATIENTS WITH MASLD AND SIGNIFICANT FIBROSIS Kim, W., Chung, N. L., Mannalithara, A., Charu, V., Torok, N. J., Kwo, P., Kwong, A. J., Kim, S. H. LIPPINCOTT WILLIAMS & WILKINS. 2023: S167

  View details for Web of Science ID 001094865400159

• Glycemic and metabolic sub-classification of prediabetes and risk factors for cardiovascular disease in the D2d cohort. American journal of preventive cardiology Kashyap, S. R., Desouza, C., Aroda, V. R., Kim, S. H., Neff, L. M., Wu, S. S., Raskin, P., Pratley, R. 2023; 15: 100525

  Abstract

  Prediabetes represents a spectrum of metabolic abnormalities, including insulin resistance and secretory impairment, that carries increased cardiovascular disease (CVD) risk. It is unclear whether specific glycemic and metabolic sub-classifications are associated with CVD risk. This cross-sectional analysis of 3946 participants from the Vitamin D and Type 2 Diabetes (D2d) study cohort aimed to determine the associations between various baseline CVD risk factors, glycemic sub-classifications of prediabetes (FPG, 2hPG, and HbA1c), and measures of insulin sensitivity and secretion from an OGTT.The metabolic syndrome and atherosclerotic cardiovascular disease (ASCVD) risk scores were determined for tertiles of insulin sensitivity (HOMA2S) and insulinogenic index (IGI). Unadjusted analyses showed elevated CVD risk factors in the lowest tertile for both IGI and HOMA2S.After adjustment for age, gender, race, obesity, and smoking status, the association remained between HOMA2S and ASCVD score (r = -0.11, p< 0.001) but not for IGI. Those who met at least 2 diagnosic criteria for prediabetes had the largest proportion (> 40%) of participants with high ASCVD risk score >20. A higher percentage of individuals that met all 3 criteria for prediabetes had metabolic syndrome and ASCVD risk score >20 (87.2% and 15.3%, respectively) than those who only met 1 prediabetes criterion (51.6% and 7.1%, respectively).In conclusion, multiple metabolic (HOMA2S, IGI) and glycemic criteria of prediabetes (FPG, 2hPG, & HbA1c) are needed to fully recognize the elevated CVD risk profile that can manifest in prediabetes.

  View details for DOI 10.1016/j.ajpc.2023.100525

  View details for PubMedID 37650052

  View details for PubMedCentralID PMC10462804

• Effect of Vitamin D on Regression to Normal Glucose Regulation and Individual Glycemic Measures: A secondary analysis among participants adherent to the trial protocol in the randomized clinical trial vitamin D and type 2 diabetes (D2d) study. Diabetes research and clinical practice Hsia, D. S., Nelson, J., Vickery, E. M., Rasouli, N., LeBlanc, E. S., Kim, S., Brodsky, I., Pratley, R., Dawson-Hughes, B., Pittas, A. G., D2d Research Group 2023: 110792

  Abstract

  AIMS: To examine the effect of vitamin D on regression to normal glucose regulation (NGR) and individual glycemic measures in the D2d study.METHODS: In per-protocol analyses, we examined time to new-onset diabetes; time to new-onset NGR defined as first occurrence of: 2-or-3 glycemic criteria in the normal range (NGR-1) or fasting plasma glucose (FPG) and 2-hour post-load-glucose (2hPG) in the normal range (NGR-2); proportion meeting NGR at the last study visit; and change in FPG, 2hPG, and HbA1c.RESULTS: Among 2423 participants, hazard ratio [HR] for diabetes was 0.84 [95%CI, 0.71, 0.99]). HR (95%CI) was 1.16 (0.99, 1.36) for new-onset NGR-1 and 1.06 (0.87, 1.30) for NGR-2. At the last visit, NGR-1 occurred in 12.4% vs. 9.5% participants in the vitamin D vs. placebo group (rate ratio for vitamin D 1.31 [1.02, 1.70]); whereas, NGR-2 occurred in 8.7% vs. 6.0% (rate ratio for vitamin D 1.45 [1.05, 2.00]). During follow-up, FPG, HbA1c, and 2hPG increased in both groups. Mean difference in FPG favored vitamin D (-0.80 mg/dL; 95%CI, -1.26, -0.33).CONCLUSIONS: In secondary analyses among participants adherent to the trial protocol, vitamin D lowered risk of developing diabetes and increased likelihood of NGR at the end of the study.

  View details for DOI 10.1016/j.diabres.2023.110792

  View details for PubMedID 37343726

• New-Onset Diabetes after COVID-19. The Journal of clinical endocrinology and metabolism Kim, S. H., Arora, I., Hsia, D. S., Knowler, W. C., LeBlanc, E., Mylonakis, E., Pratley, R., Pittas, A. G. 2023

  Abstract

  There is evidence suggesting that infection with SARS-CoV-2 can lead to several long-term sequelae including diabetes. This mini-review examines the rapidly evolving and conflicting literature on new-onset diabetes after COVID-19, which we term NODAC. We searched PubMed, MEDLINE, and medRxiv from inception until December 1, 2022 using both MeSH terms and free text words including "COVID-19," "SARS-CoV-2," "diabetes," "hyperglycemia," "insulin resistance," and "pancreatic β-cell." We also supplemented searches by examining reference lists from retrieved articles. Current evidence suggests that COVID-19 increases the risk of developing diabetes, but the attributable risk is uncertain due to limitations of study designs and the evolving nature of the pandemic, including new variants, widespread population exposure to the virus, diagnostic options for COVID-19 and vaccination status. The etiology of diabetes after COVID-19 is likely multifactorial and includes factors associated with host characteristics (e.g., age), social determinants of health (e.g., deprivation index), and pandemic-related effects both at the personal (e.g., psychosocial stress) and the societal-community level (e.g., containment measures). COVID-19 may have direct and indirect effects on pancreatic β-cell function and insulin sensitivity related to: the acute infection and its treatment (e.g., glucocorticoids); autoimmunity; persistent viral residency in multiple organs including adipose tissue; endothelial dysfunction; and hyperinflammatory state. While our understanding of NODAC continues to evolve, consideration should be given for diabetes to be classified as a post-COVID syndrome, in addition to traditional classifications of diabetes (e.g., type 1 or type 2), so that the pathophysiology, natural history and optimal management can be studied.

  View details for DOI 10.1210/clinem/dgad284

  View details for PubMedID 37207448

• Indices of hepatic steatosis and fibrosis in prediabetes and association with diabetes development in the vitamin D and type 2 diabetes study. Journal of diabetes and its complications Corbin, K. D., Pittas, A. G., Desouza, C., Grdinovac, K. K., Herzig, K. H., Kashyap, S. R., Kim, S. H., Nelson, J., Rasouli, N., Vickery, E. M., Knowler, W. C., Pratley, R. E. 2023; 37 (6): 108475

  Abstract

  Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity that leads to poor outcomes in people at high risk for development of type 2 diabetes (T2D). Vitamin D is a possible mediator. In the vitamin D and type 2 diabetes study (D2d), we investigated the relationship of baseline indices of NAFLD with incident T2D and whether the effect of vitamin D on diabetes was modified by NAFLD.Cross-sectional associations of indices of NAFLD with glycemia and vitamin D status were assessed in 3972 individuals screened for the D2d study. In those with prediabetes randomized to vitamin D or placebo (n = 2423), we examined longitudinal associations of NAFLD indices with incident T2D. We used validated non-invasive scores to assess steatosis [(hepatic steatosis index (HSI); NAFLD-liver fat score (NAFLD-LFS)] and advanced fibrosis [fibrosis-4 (FIB-4) index; AST to Platelet Ratio Index (APRI)].Eighty-five percent of screened participants had likely steatosis by HSI and 71 % by NAFLD-LFS; 3 % were likely to have advanced fibrosis by FIB-4 and 1.2 % by APRI. FIB-4 indicated that 20.4 % of individuals require further follow up to assess liver health. Steatosis and fibrosis scores were higher among participants with worse glycemia. The NAFLD-LFS and APRI predicted development of diabetes (hazard ratios [95%CI] 1.35 [1.07, 1.70]; P = 0.012) and 2.36 (1.23, 4.54; P = 0.010), respectively). The effect of vitamin D on diabetes risk was not modified by baseline NAFLD indices. Individuals with likely steatosis had a smaller increase in serum 25-hydroxyvitamin D level in response to vitamin D than those without steatosis.The predicted high prevalence of steatosis, the need for further fibrosis workup, and the relationship between liver health and incident T2D suggest that routine screening with clinically accessible scores may be an important strategy to reduce disease burden.

  View details for DOI 10.1016/j.jdiacomp.2023.108475

  View details for PubMedID 37104979

• Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial. American journal of kidney diseases : the official journal of the National Kidney Foundation Yi, T. W., Smyth, B., Di Tanna, G. L., Arnott, C., Cardoza, K., Kang, A., Pollock, C., Agarwal, R., Bakris, G., Charytan, D. M., de Zeeuw, D., Heerspink, H. J., Neal, B., Wheeler, D. C., Cannon, C. P., Zhang, H., Zinman, B., Perkovic, V., Levin, A., Mahaffey, K. W., Jardine, M. 2023

  Abstract

  It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the CREDENCE study.Secondary analysis of a randomized controlled trial.Participants in the CREDENCE trial.Participants were randomly assigned to canagliflozin 100 mg daily or placebo.Primary composite outcome of kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease. Pre-specified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention-to-treat population using Cox regression models.The mean age of the cohort was 63.0±9.2 years and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of the serum creatinine, or death from kidney or cardiovascular causes) differed between age groups (HR 0.67, 95% CI 0.52 to 0.87; HR 0.63, 95% CI 0.48 to 0.82; and HR 0.89, 95% CI 0.61 to 1.29; for the <60, 60-69, and ≥70 year groups, respectively; Pinteraction=0.3); or among females and males (HR 0.71, 95% CI 0.54 to 0.95; and HR 0.69, 95% CI 0.56 to 0.84, respectively; Pinteraction=0.8). No differences in safety outcomes by age group or sex were observed.This was a post hoc analysis with multiple comparisons.Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. Owing to higher background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.

  View details for DOI 10.1053/j.ajkd.2022.12.015

  View details for PubMedID 36889425

• Teprotumumab-related hyperglycemia. The Journal of clinical endocrinology and metabolism Amarikwa, L., Mohamed, A., Kim, S. H., Kossler, A. L., Dosiou, C. 2022

  Abstract

  CONTEXT: Graves orbitopathy (GO) or thyroid eye disease is a potentially sight-threatening and disfiguring autoimmune disease. Teprotumumab is a monoclonal antibody against the insulin-like growth factor-I receptor that was recently approved for GO treatment. Hyperglycemia is a recognized adverse event of teprotumumab, occurring in 10% of patients in two recent randomized controlled trials.OBJECTIVE: Our study aimed to report the incidence, severity, management, and longitudinal glycemic changes in patients treated with teprotumumab in an academic practice cohort.METHODS: This longitudinal, observational study included all consecutive patients treated with teprotumumab between March 2020 and May 2022 at one institution. Hemoglobin A1c was measured every 3-months.RESULTS: Forty-two patients with baseline normoglycemia (n=22), pre-diabetes (n=10), and diabetes (n=10) were followed for a mean of 47.5 weeks. Overall, HbA1c increased by 0.5% at 3-months. Least-square mean changes in HbA1c at 3 months were 1.3 (p<0.001), 0.7 (p=0.01), and 0.1 (p=0.41) in patients with diabetes, pre-diabetes, and normoglycemia, respectively. Twenty-two patients (52%) had hyperglycemia which was graded as mild, moderate, and life-threatening in 55%(12/22), 41%(9/22), and 5%(1/22) of cases, respectively. Age, pre-existing diabetes, and Hispanic and Asian race/ethnicity were significant risk factors for hyperglycemia. Among patients with hyperglycemia, 36.4% (8/22) returned to baseline glycemic status at last follow-up.CONCLUSIONS: While effective, teprotumumab carries a significant risk of hyperglycemia, especially in patients with diabetes. Hyperglycemia may persist after stopping teprotumumab. These findings underscore the importance of guidelines for screening and management of teprotumumab-related hyperglycemia.

  View details for DOI 10.1210/clinem/dgac627

  View details for PubMedID 36300333

• THE WAIST-TO-HIP RATIO ADDS LITTLE TO THE STEATOSIS-ASSOCIATED FIBROSIS ESTIMATOR (SAFE) SCORE IN PREDICTING SIGNIFICANT FIBROSIS AMONG PATIENTS WITH NAFLD Sripongpun, P., Charu, V., Kim, S. H., Kim, W. WILEY. 2022: S792-S793

  View details for Web of Science ID 000870796602258

• Reply to T Kalayjian and EC Westman. The American journal of clinical nutrition Gardner, C. D., Landry, M. J., Aronica, L., Cunanan, K. M., Kim, S. H. 2022

  View details for DOI 10.1093/ajcn/nqac201

  View details for PubMedID 35883212

• Effect of a Ketogenic Diet versus Mediterranean Diet on HbA1c in Individuals with Prediabetes and Type 2 Diabetes Mellitus: the Interventional Keto-Med Randomized Crossover Trial. The American journal of clinical nutrition Gardner, C. D., Landry, M. J., Perelman, D., Petlura, C., Durand, L. R., Aronica, L., Crimarco, A., Cunanan, K. M., Chang, A., Dant, C. C., Robinson, J. L., Kim, S. H. 2022

  Abstract

  Consensus has not been reached on what constitutes an optimal diet in individuals with prediabetes and type 2 diabetes (T2DM), especially between low-carbohydrate options.To compare two low-carbohydrate diets with 3 key similarities (incorporate non-starchy vegetables and avoid added sugars and refined grains) and 3 key differences (incorporate vs avoid legumes, fruits, and whole intact grains), for their effects on glucose control and cardiometabolic risk factors in individuals with prediabetes and T2DM.Keto-Med was a randomized, crossover, interventional trial. Forty participants aged ≥ 18 years with prediabetes or T2DM followed a Well Formulated Ketogenic Diet (WFKD) and Mediterranean-Plus diet (Med-Plus) for 12-weeks each, in random order. Diets shared 3 key similarities noted above. Med-Plus incorporated legumes, fruits, and whole intact grains while WFKD avoided them. Primary outcome was % change in HbA1c after 12-weeks on each diet. Secondary and exploratory outcomes included % change in body weight, fasting insulin, glucose, and blood lipids, glucose (continuous glucose monitor), and nutrient intake.Primary analysis had n = 33 with complete data. HbA1c did not differ between diets at 12-weeks. Triglycerides decreased more for WFKD (% change(SEM)): -16%(4%) vs -5%(6%), p = 0.02) and LDL-C was higher for WFKD (+10%(4%) vs -5%(5%), p = 0.01). Weight decreased 8%(1%) vs 7%(1%) and HDL-C increased 11%(2%) vs 7%(3%) for WFKD vs Med-Plus, respectively; however, there was a significant interaction of diet by order for both. Participants had lower intakes of fiber and 3 nutrients on WFKD vs Med-Plus. Twelve-week follow-up data suggested Med-Plus diet was more sustainable.HbA1c was not different between diet phases after 12-weeks, but improved from baseline on both diets, likely due to several shared dietary aspects. WFKD was beneficial for greater decrease in triglycerides, but also had potential untoward risks from elevated LDL-C, and lower nutrient intakes from avoiding legumes, fruits, and whole intact grains, as well as being less sustainable.clinicaltrials.gov NCT03810378.

  View details for DOI 10.1093/ajcn/nqac154

  View details for PubMedID 35641199

• The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk non-alcoholic fatty liver disease in primary care. Hepatology (Baltimore, Md.) Sripongpun, P., Kim, W. R., Mannalithara, A., Charu, V., Vidovszky, A., Asch, S., Desai, M., Kim, S. H., Kwong, A. J. 2022

  Abstract

  Non-alcoholic fatty liver disease (NAFLD) is common in primary care. Liver fibrosis stage 2 or higher (≥F2) increases future risk of morbidity and mortality. We developed and validated a score to aid in the initial assessment of liver fibrosis for NAFLD in primary care.Biopsy-proven NAFLD patients' data were extracted from the 'NASH CRN' observational study (n = 676). Using logistic regression and machine-learning methods, we constructed prediction models to distinguish ≥F2 from F0/1. The models were tested in participants in a trial ('FLINT', n = 280) and local NAFLD patients with magnetic resonance elastography data (n = 130). The final model was applied to examinees in the National Health and Nutrition Examination Survey III (NHANES, n = 11,953) to correlate with longterm mortality.A multivariable logistic regression model was selected as the Steatosis-Associated Fibrosis Estimator (SAFE) score, which consists of age, body mass index, diabetes, platelets, aspartate and alanine aminotransferases and globulins (total serum protein minus albumin). The model yielded areas under receiver operating characteristic curves ≥0.80 in distinguishing F0/1 from ≥F2 in testing datasets, consistently higher than those of FIB-4 and NAFLD Fibrosis Scores. The negative predictive values in ruling out ≥F2 at SAFE of 0 were 88% and 92% in the two testing sets. In the NHANES III set, survival up to 25 years of subjects with SAFE <0 was comparable to that of those without steatosis (p = 0.34), while increasing SAFE scores correlated with shorter survival with an adjusted hazard ratio of 1.54 (p < 0.01) for subjects with SAFE>100.The SAFE score, which uses widely available variables to estimate liver fibrosis in patients diagnosed with NAFLD, may be used in primary care to recognize low-risk NAFLD.

  View details for DOI 10.1002/hep.32545

  View details for PubMedID 35477908

• Cardiovascular outcomes associated with prescription of SGLT-2 inhibitors versus DPP-4 inhibitors in patients with diabetes mellitus and chronic kidney disease. Diabetes, obesity & metabolism Rhee, J. J., Han, J., Montez-Rath, M. E., Kim, S. H., Cullen, M. R., Stafford, R. S., Winkelmayer, W. C., Chertow, G. M. 1800

  Abstract

  AIMS: To determine the association with cardiovascular (CV) outcomes of sodium glucose cotransporter-2 (SGLT-2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).MATERIALS AND METHODS: We conducted a population-based cohort study of new users of SGLT-2 inhibitors and DPP-4 inhibitors with T2DM and CKD using data from Optum Clinformatics DataMart. We assembled three cohorts: T2DM/no CKD, T2DM/CKD 1-2, and T2DM/ CKD 3a. Study outcomes were 1) time to first heart failure (HF) hospitalization; and 2) time to a composite CV endpoint comprised of non-fatal myocardial infarction (MI) or stroke. After inverse probability of treatment weighting, we used proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI).RESULTS: New users of SGLT-2 inhibitors versus of DPP-4 inhibitors had lower risks of HF hospitalization in the T2DM/no CKD (HR, 0.76; 95% CI, 0.70, 0.82) and T2DM/CKD 1-2 (HR, 0.63; 95% CI, 0.48, 0.84), but no significant association was present in the T2DM/CKD 3a cohort. Compared with prescription of DPP-4 inhibitors, SGLT-2 inhibitors were associated with lower risks of non-fatal MI or stroke of 23% (HR, 0.77; 95% CI, 0.70, 0.85) in the T2DM/no CKD cohort, but no significant associations were present in the T2DM/CKD 1-2 and T2DM/CKD 3a cohorts.CONCLUSIONS: Incident prescription of SGLT-2 inhibitors was associated with lower risks of HF hospitalization but not with non-fatal MI or stroke despite suggesting benefit, relative to prescription of DPP-4 inhibitor across different stages of CKD. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/dom.14657

  View details for PubMedID 35118793

• Effects of vitamin D supplementation on insulin sensitivity and secretion in prediabetes. The Journal of clinical endocrinology and metabolism Rasouli, N., Brodsky, I. G., Chatterjee, R., Kim, S. H., Pratley, R. E., Staten, M. A., Pittas, A. G. 2021

  Abstract

  CONTEXT: Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on insulin sensitivity and beta-cell function remain unclear.OBJECTIVE: To investigate the effects of vitamin D3 supplementation on insulin sensitivity and beta-cell function.METHODS: This is a pre-specified secondary analysis of the Vitamin D and type 2 diabetes (D2d) study. Overweight/obese adults at high risk for type 2 diabetes were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months.MAIN OUTCOME: Disposition index (DI), as an estimate of beta-cell function, was calculated as the product of HOMA2%Scpep and C-peptide response during the first 30 minutes of a 75-gram oral glucose tolerance test (OGTT).RESULTS: Mean age was 60.5±9.8 years and BMI was 31.9±4.4kg/m 2. Mean serum 25(OH)D level increased from 27.9±10.3ng/mL at baseline to 54.9ng/mL at two years in the vitamin D group and was unchanged (28.5±10.0ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the two groups. Among participants with baseline 25(OH)D level <12ng/mL, the mean percent differences for DI between the vitamin D and placebo groups was 8.5% (95%CI 0.2-16.8).CONCLUSIONS: Supplementation with vitamin D3 for 24 months did not improve an OGTT-derived index of beta-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status.

  View details for DOI 10.1210/clinem/dgab649

  View details for PubMedID 34473295

• Statins Are Associated With Increased Insulin Resistance and Secretion. Arteriosclerosis, thrombosis, and vascular biology Abbasi, F., Lamendola, C., Harris, C. S., Harris, V., Tsai, M., Tripathi, P., Abbas, F., Reaven, G., Reaven, P., Snyder, M. P., Kim, S. H., Knowles, J. W. 2021: ATVBAHA121316159

  Abstract

  OBJECTIVE: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01).CONCLUSIONS: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02437084.

  View details for DOI 10.1161/ATVBAHA.121.316159

  View details for PubMedID 34433298

• Effect of Vitamin D Supplementation on Kidney Function in Adults with Prediabetes: A Secondary Analysis of a Randomized Trial. Clinical journal of the American Society of Nephrology : CJASN Kim, S. H., Brodsky, I. G., Chatterjee, R., Kashyap, S. R., Knowler, W. C., Liao, E., Nelson, J., Pratley, R., Rasouli, N., Vickery, E. M., Sarnak, M., Pittas, A. G., D2d Research Group, D2d Research Group collaborators, Pittas, A. G., Brodsky, I., Ceglia, L., Chadha, C., Chatterjee, R., Dawson-Hughes, B., Desouza, C., Dolor, R., Foreyt, J., Ghazi, A., Hsia, D. S., Johnson, K. C., Kashyap, S. R., Kim, S., LeBlanc, E. S., Lewis, M. R., Liao, E., Malozowski, S., Neff, L. M., O'Neil, P., Park, J., Peters, A., Phillips, L. S., Pratley, R., Raskin, P., Rasouli, N., Robbins, D., Rosen, C., Aroda, V. R., Sheehan, P., Staten, M. A., Knowler, W. C. 2021; 16 (8): 1201-1209

  Abstract

  BACKGROUND AND OBJECTIVES: Low serum 25-hydroxyvitamin D (25[OH]D) concentration has been associated with higher levels of proteinuria and lower levels of eGFR in observational studies. In the Vitamin D and Type 2 Diabetes (D2d) study, we investigated the effect of vitamin D supplementation on kidney outcomes in a population with prediabetes.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Overweight/obese adults with high risk for type 2 diabetes (defined by meeting two of three glycemic criteria for prediabetes) were randomized to vitamin D3 4000 IU per day versus placebo. Median duration of treatment was 2.9 years (interquartile range 2.0-3.5 years). Kidney outcomes included (1) worsening in Kidney Disease: Improving Global Outcomes (KDIGO ) risk score (low, moderate, high, very high) on two consecutive follow-up visits after the baseline visit and (2) mean changes in eGFR and urine albumin-to-creatinine ratio (UACR).RESULTS: Among 2166 participants (mean age 60 years, body mass index 32 kg/m2, serum 25(OH)D 28 ng/ml, eGFR 87 ml/min per 1.73 m2, UACR 11 mg/g, 79% with hypertension), 10% had moderate, high, or very high KDIGO risk score. Over a median follow-up of 2.9 years, there were 28 cases of KDIGO worsening in the vitamin D group and 30 in the placebo group (hazard ratio, 0.89; 95% confidence interval [95% CI], 0.52 to 1.52]). Mean difference in eGFR from baseline was -1.0 ml/min per 1.73 m2 (95% CI, -1.3 to -0.7) in the vitamin D group and -0.1 ml/min per 1.73 m2 (95% CI, -0.4 to 0.2) in the placebo group; between-group difference was -1.0 ml/min per 1.73 m2 (95% CI, -1.4 to -0.6). Mean difference in UACR was 2.7 mg/g (95% CI, 1.2 to 4.3) in the vitamin D group and 2.0 (95% CI, 0.5 to 3.6) in the placebo group; between-group difference was 0.7 mg/g (95% CI, -1.5 to 2.9).CONCLUSIONS: Among persons with prediabetes, who were not preselected on the basis of serum 25(OH)D concentration, vitamin D supplementation did not affect progression of KDIGO risk scores and did not have a meaningful effect on change in UACR or eGFR.

  View details for DOI 10.2215/CJN.00420121

  View details for PubMedID 34362787

• Association of pericardial adipose tissue with left ventricular structure and function: a region-specific effect? Cardiovascular diabetology Kim, J., Kim, S. W., Lee, J. S., Lee, S. K., Abbott, R., Lee, K. Y., Lim, H. E., Sung, K., Cho, G., Koh, K. K., Kim, S. H., Shin, C., Kim, S. H. 2021; 20 (1): 26

  Abstract

  BACKGROUND: The independent role of pericardial adipose tissue (PAT) as an ectopic fat associated with cardiovascular disease (CVD) remains controversial. This study aimed to determine whether PAT is associated with left ventricular (LV) structure and function independent of other markers of general obesity.METHODS: We studied 2471 participants (50.9% women) without known CVD from the Korean Genome Epidemiology Study, who underwent 2D-echocardiography with tissue Doppler imaging (TDI) and computed tomography measurement for PAT.RESULTS: Study participants with more PAT were more likely to be men and had higher cardiometabolic indices, including blood pressure, glucose, and cholesterol levels (all P<0.001). Greater pericardial fat levels across quartiles of PAT were associated with increased LV mass index and left atrial volume index (all P<0.001) and decreased systolic (P=0.015) and early diastolic (P<0.001) TDI velocities, except for LV ejection fraction. These associations remained after a multivariable-adjusted model for traditional CV risk factors and persisted even after additional adjustment for general adiposity measures, such as waist circumference and body mass index. PAT was also the only obesity index independently associated with systolic TDI velocity (P<0.001).CONCLUSIONS: PAT was associated with subclinical LV structural and functional deterioration, and these associations were independent of and stronger than with general and abdominal obesity measures.

  View details for DOI 10.1186/s12933-021-01219-4

  View details for PubMedID 33494780

• Adherence to Ketogenic and Mediterranean Study Diets in a Crossover Trial: The Keto-Med Randomized Trial. Nutrients Landry, M. J., Crimarco, A. n., Perelman, D. n., Durand, L. R., Petlura, C. n., Aronica, L. n., Robinson, J. L., Kim, S. H., Gardner, C. D. 2021; 13 (3)

  Abstract

  Adherence is a critical factor to consider when interpreting study results from randomized clinical trials (RCTs) comparing one diet to another, but it is frequently not reported by researchers. The purpose of this secondary analysis of the Keto-Med randomized trial was to provide a detailed examination and comparison of the adherence to the two study diets (Well Formulated Ketogenic Diet (WFKD) and Mediterranean Plus (Med-Plus)) under the two conditions: all food being provided (delivered) and all food being obtained by individual participants (self-provided). Diet was assessed at six time points including baseline (×1), week 4 of each phase when participants were receiving food deliveries (×2), week 12 of each phase when participants were preparing and providing food on their own (×2), and 12 weeks after participants completed both diet phases and were free to choose their own diet pattern (×1). The adherence scores for WFKD and Med-Plus were developed specifically for this study. Average adherence to the two diet patterns was very similar during both on-study time points of the intervention. Throughout the study, a wide range of adherence was observed among participants-for both diet types and during both the delivery phase and self-provided phase. Insight from this assessment of adherence may aid other researchers when answering the important question of how to improve behavioral adherence during dietary trials. This study is registered at clinicaltrials.gov NCT03810378.

  View details for DOI 10.3390/nu13030967

  View details for PubMedID 33802709

• Effect of liraglutide vs. placebo treatment on circulating proglucagon-derived peptides that mediate improvements in body weight, insulin secretion and action: a randomized controlled trial. Diabetes, obesity & metabolism Kim, S. H., Abbasi, F., Nachmanoff, C., Stefanakis, K., Kumar, A., Kalra, B., Savjani, G., Mantzoros, C. S. 2020

  Abstract

  AIMS: To examine how circulating GLP-1 concentrations during liraglutide treatment relate to its therapeutic actions on glucose and weight, and to study the effects of liraglutide on other proglucagon-derived peptides (PGDPs), including endogenous GLP-1, GLP-2, glucagon, oxyntomodulin, glicentin, and major proglucagon fragment, which also regulate metabolic and weight control.MATERIALS AND METHODS: Adults who were overweight/obese (BMI 27-40 kg/m2 ) with prediabetes were randomized to liraglutide (1.8mg/day) vs placebo for 14weeks. We used specific assays to measure exogenous (liraglutide, GLP-1 agonist (GLP-1A)) and endogenous (GLP-1E) GLP-1, alongside 5 other PGDP concentrations during a mixed-meal tolerance test (MMTT) completed at baseline and at week 14 (liraglutide, n=16; placebo, n=19). Glucose during MMTT, steady-state plasma glucose (SSPG) concentration for insulin resistance, and insulin secretion rate (ISR) were previously measured. MMTT area-under-the-curve (AUC) was calculated for ISR, glucose, and levels of PGDPs.RESULTS: Participants on liraglutide vs placebo had significantly (p≤0.004) decreased weight (mean -3.6%, 95% CI [-5.2, -2.1]), SSPG (-32% [-43, -22]) and glucose AUC (-7.0% [-11.5, -2.5]), and increased ISR AUC (30%, [16, 44]). Treatment with liraglutide significantly (p≤0.005) increased exogenous GLP-1A AUC (median 310 vs 262 pg/mL X 8h at baseline but decreased endogenous GLP-1E AUC (13.1 vs 24.2 pmol/L x 8h at baseline)), as well as the 5 other PGDPs. Only glucagon AUC decreased in the placebo group (471 vs 594 pg/mL x 8h at baseline). GLP-1A AUC at study end was significantly (p≤0.04) linearly associated with % decrease in weight (r=-0.54) and SSPG (r=-0.59) and increase in ISR AUC (r=0.51) in the liraglutide group.CONCLUSIONS: Circulating GLP-1A concentrations, reflecting liraglutide levels, predict improvement in weight, insulin action, and secretion in a linear manner. Importantly, liraglutide also downregulates all other PGDPs, normalization of the levels of which may provide additional metabolic benefits in the future. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/dom.14242

  View details for PubMedID 33140542

• A Call for a New Paradigm for Diabetes Care in the Era of Sodium-Glucose Cotransporter2 Inhibitors (SGLT2i). Cardiology and therapy Kim, S. H., Chang, T. I., Mahaffey, K. W. 2020

  Abstract

  In 2013, canagliflozin was the first sodium-glucose cotransporter2 inhibitor (SGLT2i) approved by the US Food and Drug Administration for the treatment of type2 diabetes (T2DM). Today, there are four SGLT2i approved for T2DM, and some SGLT2i have been approved for indications beyond glucose control. For example, SGLT2i reduce major adverse clinical events (MACE) including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (canagliflozin); cardiovascular death (empagliflozin, dapagliflozin); diabetic kidney disease progression (canagliflozin); and heart failure hospitalization (canagliflozin, dapagliflozin). However, despite the potential benefits of SGLT2i in reducing adverse clinical events, providers underprescribe SGLT2i for eligible patients. Thus, we propose the CKD-PCP framework which allows multiple providers to utilize the benefits of SGLT2i. CKD-PCP has dual meaning: it applies to providers who most often care for patients with T2DM (Cardiologists, Kidney specialists, Diabetologists, and Primary Care Physicians) and it refers to the benefits of SGLT2i (treatment of Cardiovascular disease, Kidney disease, Diabetes, and reduction of blood Pressure, Calories, and Plasma volume). This article is based on previously conducted studies and the authors disclosetheir roles in relevant trialsin the Acknowledgements.

  View details for DOI 10.1007/s40119-020-00190-7

  View details for PubMedID 32661684

• A RETROSPECTIVE STUDY EXAMINING PHENTERMINE ON PRECONCEPTION WEIGHT LOSS AND PREGNANCY OUTCOMES. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists Chang, J. J., Lathi, R. B., Kim, S. H. 2020

  Abstract

  Background: Obesity is a well-known risk factor for infertility. However, use of weight loss medications prior to conception is underutilized. The objectives of our study are to describe weight loss, pregnancy rates, and live birth rates after short-term phentermine use in women with obesity and infertility. Methods: This was a retrospective analysis of 55 women (18-45 years old) who were overweight or obese, diagnosed with infertility, and prescribed phentermine for weight loss in an ambulatory endocrinology clinic at a single, tertiary level academic medical center. Main outcome measures were mean percent weight change at 3 months after starting phentermine and pregnancy and live birth rates from start of phentermine to June 30, 2017. Results: Median duration of phentermine use was 70 days (Q1, Q3 [33, 129]). Mean ± SD percent weight change at 3 months after starting phentermine was -5.3 ± 4.1% (p < 0.001). The pregnancy rate was 60% and live birth rate was 49%. There was no significant difference in pregnancy rates (52% vs. 68%, p = 0.23) or live birth rates (44% vs. 54%, p = 0.50) in women who lost ≥5% vs. <5% of their baseline weight. Number of metabolic comorbidities was negatively associated with pregnancy rate. Phentermine was generally well tolerated with no serious adverse events. Conclusions: Phentermine can produce clinically significant weight loss in women with obesity during the preconception period. Higher pregnancy or live birth rates were not observed with greater degree of weight loss with phentermine.

  View details for DOI 10.4158/EP-2019-0609

  View details for PubMedID 32407664

• A nuanced relationship between prediabetes and chronic kidney disease. The Journal of clinical endocrinology and metabolism Kim, S. H. 2020

  View details for DOI 10.1210/clinem/dgaa079

  View details for PubMedID 32086934

• Antidiabetic medication use in patients with type 2 diabetes and chronic kidney disease JOURNAL OF DIABETES AND ITS COMPLICATIONS Rhee, J. J., Han, J., Montez-Rath, M. E., Kim, S. H., Cullen, M. R., Stafford, R. S., Winkelmayer, W. C., Chertow, G. M. 2019; 33 (11)

  View details for DOI 10.1016/j.jdiacomp2019.107423

  View details for Web of Science ID 000497890000003

• Longitudinal changes in left ventricular structure and function in patients with type 2 diabetes: Normal weight versus overweight/obesity DIABETES & VASCULAR DISEASE RESEARCH Kim, S., Sung, K., Lee, S., Park, J., Kim, N., Kim, S. H., Shin, C. 2019; 16 (5): 450–57

  View details for DOI 10.1177/1479164119843760

  View details for Web of Science ID 000481478400006

• Natural course of fatty liver in 36,195 South Korean adults. Scientific reports Sung, K., Lee, M., Lee, J., Lee, S., Kim, Y., Song, W., Huh, J., Park, J., Shin, J., Seo, M. H., Kim, S., Kim, S. H. 2019; 9 (1): 9062

  Abstract

  Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, and yet the natural course remains unclear. Study population included 36,195 individuals who participated in a health-screening program and diagnosed with fatty liver by abdominal ultrasound. Participants were provided written information regarding fatty liver and advised to make lifestyle changes. Ultrasound was repeated after at least 6 months. After a mean follow up of 4.9 years (±3.4), 19.6% resolved their fatty liver. Individuals who resolved were more likely female (22.9% vs. 12.3%), thinner (body mass index [BMI], 25.2±2.7 vs. 26±2.7), and with lower HOMA-IR (1.4 vs. 1.7) (P.70.001). Decrease in BMI predicted resolution of fatty liver with 42% of those in the top quartile of BMI decline resolving compared with 5.7% in the lowest quartile (odds ratio [OR] (95% confidence interval [CI]) 15.65 (14.13-17.34), P<0.001)). Baseline HOMA-IR also predicted resolution with those in the top quartile (most insulin resistant) being least likely to resolve (12%) vs. those in the lowest quartile (25%) (OR 0.36 [0.31-0.42], P<0.001). Fatty liver disease is persistent. Individuals with higher degree of insulin resistance are also the most likely to have persistent steatosis at follow up.

  View details for DOI 10.1038/s41598-019-44738-7

  View details for PubMedID 31308382

• Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017 DIABETOLOGIA Kim, D., Li, A. A., Cholankeril, G., Kim, S. H., Ingelsson, E., Knowles, J. W., Harrington, R. A., Ahmed, A. 2019; 62 (7): 1185–94

  View details for DOI 10.1007/s00125-019-4870-9

  View details for Web of Science ID 000471176200009

• Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy NEW ENGLAND JOURNAL OF MEDICINE Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., CREDENCE Trial Investigators 2019; 380 (24): 2295–2306

  View details for DOI 10.1056/NEJMoa1811744

  View details for Web of Science ID 000471299100008

• Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017. Diabetologia Kim, D., Li, A. A., Cholankeril, G., Kim, S. H., Ingelsson, E., Knowles, J. W., Harrington, R. A., Ahmed, A. 2019

  Abstract

  AIMS/HYPOTHESIS: The determination of diabetes as underlying cause of death by using the death certificate may result in inaccurate estimation of national mortality attributed to diabetes, because individuals who die with diabetes generally have other conditions that may contribute to their death. We investigated the trends in age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from cardiovascular disease (CVD), complications of diabetes and cancer among individuals with diabetes listed on death certificates in the USA from 2007 to 2017.METHODS: Using the US Census and national mortality database, we calculated age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality rates among adults over 20years with diabetes listed on death certificates. A total of 2,686,590 deaths where diabetes was underlying or contributing cause of death were analysed. We determined temporal mortality rate patterns by joinpoint regression analysis with estimates of annual percentage change (APC).RESULTS: Age-standardised diabetes mortality rates compared among underlying cause of death, contributing cause of death and all-cause mortality were 32.2 vs 75.7 vs 105.1 per 100,000 individuals during the study period. The age-standardised mortality rates due to diabetes as underlying or contributing cause of death declined from 112.2 per 100,000 individuals in 2007 to 104.3 per 100,000 individuals in 2017 with the most pronounced decline noted from 2007 to 2014 (APC -1.4%; 95% CI -1.9%, -1.0%) and stabilisation in decline from 2014 to 2017 (APC 1.1%; 95% CI -0.6%, 2.8%). In terms of cause-specific mortality among individuals with diabetes listed on death certificates, the age-standardised mortality rates for CVD declined at an annual rate of 1.2% with a marked decline of 2.3% between 2007 and 2014. Age-standardised diabetes-specific mortality rates as underlying cause of death decreased from 2007 to 2009 (APC -4.5%) and remained stable from 2009 to 2017. Age-standardised mortality rates for cancer steadily decreased with an average APC of -1.4% (95% CI -1.8%, -1.0%) during the 11-year period. Mortality in the subcategory of CVD demonstrated significant differences.CONCLUSIONS/INTERPRETATION: Current national estimates capture about 30% of all-cause mortality among individuals with diabetes listed as underlying or contributing cause of death on death certificates. The age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from CVD in individuals with diabetes listed as underlying or contributing cause of death plateaued from 2014 onwards except for hypertensive heart disease and heart failure.

  View details for PubMedID 31011776

• Utility of ALT Concentration in Men and Women with Nonalcoholic Fatty Liver Disease: Cohort Study. Journal of clinical medicine Sung, K., Lee, M., Lee, J., Lee, S., Kim, S., Kim, S. H. 2019; 8 (4)

  Abstract

  Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated alanine aminotransferase (ALT), but the clinical utility of ALT in detecting and following individuals with NAFLD remains unclear. We conducted a retrospective analysis of 30,988 men and 5204 women with NAFLD diagnosed by ultrasound and stratified them according to sex-specific ALT quartiles. We compared metabolic variables at baseline and repeated ultrasound after at least 6 months among ALT quartiles (Q) in men (Q1 5-24, Q2 25-33, Q3 34-48, Q4 ≥ 49 IU/L) and women (Q1 5-14, Q2 15-20, Q3 21-28, Q4 ≥ 29 IU/L). Prevalence of obesity (BMI ≥ 25 kg/m) and metabolic abnormalities (glucose intolerance, hypertension) significantly (p < 0.001) increased from ALT Q1 to Q4 in both men and women at baseline. After a mean follow-up of 4.93 years, 17.6% of men and 31.1% of women resolved their NAFLD. The odds ratio (OR) of resolving significantly (p < 0.001) decreased by quartiles even after multiple adjustments. The adjusted OR for resolution in Q4 was 0.20 (0.18-0.23) in men and 0.35 (0.26-0.47) in women compared with Q1. Individuals with NAFLD span the full range of ALT concentrations, but those with the highest ALT have the worst metabolic profile and persistent NAFLD.

  View details for PubMedID 30987010

• Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia DIABETES & VASCULAR DISEASE RESEARCH Raygor, V., Abbasi, F., Lazzeroni, L. C., Kim, S., Ingelsson, E., Reaven, G. M., Knowles, J. W. 2019; 16 (2): 153–59

  View details for DOI 10.1177/1479164118813890

  View details for Web of Science ID 000465592900007

• Myths about Insulin Resistance: Tribute to Gerald Reaven. Endocrinology and metabolism (Seoul, Korea) Kim, S. H., Abbasi, F. 2019; 34 (1): 47–52

  Abstract

  Gerald Reaven was often called the "father of insulin resistance." On the 1-year anniversary of his death in 2018, we challenge three myths associated with insulin resistance: metformin improves insulin resistance; measurement of waist circumference predicts insulin resistance better than body mass index; and insulin resistance causes weight gain. In this review, we highlight Reaven's relevant research that helped to dispel these myths associated with insulin resistance.

  View details for PubMedID 30912338

• Myths about Insulin Resistance: Tribute to Gerald Reaven ENDOCRINOLOGY AND METABOLISM Kim, S. H., Abbasi, F. 2019; 34 (1): 47–52

  View details for DOI 10.3803/EnM.2019.34.1.47

  View details for Web of Science ID 000462184200006

• Vitamin D Supplementation and Prevention of Type 2 Diabetes. The New England journal of medicine Pittas, A. G., Dawson-Hughes, B. n., Sheehan, P. n., Ware, J. H., Knowler, W. C., Aroda, V. R., Brodsky, I. n., Ceglia, L. n., Chadha, C. n., Chatterjee, R. n., Desouza, C. n., Dolor, R. n., Foreyt, J. n., Fuss, P. n., Ghazi, A. n., Hsia, D. S., Johnson, K. C., Kashyap, S. R., Kim, S. n., LeBlanc, E. S., Lewis, M. R., Liao, E. n., Neff, L. M., Nelson, J. n., O'Neil, P. n., Park, J. n., Peters, A. n., Phillips, L. S., Pratley, R. n., Raskin, P. n., Rasouli, N. n., Robbins, D. n., Rosen, C. n., Vickery, E. M., Staten, M. n. 2019

  Abstract

  Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown.We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508.A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (0.95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups.Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

  View details for DOI 10.1056/NEJMoa1900906

  View details for PubMedID 31173679

• Antidiabetic medication use in patients with type 2 diabetes and chronic kidney disease. Journal of diabetes and its complications Rhee, J. J., Han, J. n., Montez-Rath, M. E., Kim, S. H., Cullen, M. R., Stafford, R. S., Winkelmayer, W. C., Chertow, G. M. 2019: 107423

  Abstract

  To quantify patterns of conventional and newer antidiabetic medication use in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).We used data from a large claims and integrated dataset that includes employed and commercially insured patients in the US to select patients who had T2DM and CKD with information on laboratory values and prescriptions for antidiabetic medications from January 1, 2014 to January 1, 2015. We stratified the analyses by sociodemographic variables.In a cohort of 38,577 patients with T2DM and CKD, we found wide variation in the treatment of T2DM by CKD stage as well as by several sociodemographic factors. Although metformin was the most commonly prescribed medication, only about half of patients in the cohort and fewer than two-thirds of patients with early stage CKD were prescribed metformin. Approximately 10.6% of patients with CKD stage 4 and 2.1% of the patients with CKD stage 5 were prescribed metformin. Sulfonylureas with active metabolites that accumulate with impaired kidney function were prescribed in more than one-third of patients with CKD stages 3b, 4, and 5. Only 3.4% and 12.3% of patients were prescribed GLP-1 and DPP-4 respectively.Prescriptions for metformin were lower than expected among patients with mild to moderate CKD. Prescriptions for newer antidiabetic medications with known safety and efficacy across the spectrum of CKD remained low. Prescriptions for agents contraindicated in advanced CKD continued to be written in a sizeable fraction of patients.

  View details for DOI 10.1016/j.jdiacomp.2019.107423

  View details for PubMedID 31537413

• Longitudinal changes in left ventricular structure and function in patients with type 2 diabetes: Normal weight versus overweight/obesity. Diabetes & vascular disease research Kim, S. H., Sung, K. C., Lee, S. K., Park, J. n., Kim, N. H., Kim, S. H., Shin, C. n. 2019: 1479164119843760

  Abstract

  Although reported to be independent of obesity, the longitudinal changes of left ventricular structure and function have not been well characterized in normal-weight individuals with type 2 diabetes compared with overweight/obese individuals with type 2 diabetes.A total of 558 participants in the Korean Genome and Epidemiology Study who underwent tissue Doppler echocardiography at baseline (cycle 4) and after 8 years (cycle 8) were classified into three groups based on body mass index and diabetes status: (1) normal-weight individuals without type 2 diabetes, (2) normal-weight individuals with type 2 diabetes and (3) overweight/obese individuals with type 2 diabetes.Only overweight/obese individuals with type 2 diabetes group had higher adjusted left ventricular mass index and lower tissue Doppler imaging early diastolic velocity and E/Em ratio compared with the normal-weight individuals without type 2 diabetes group at baseline and after 8 years. Participants in overweight/obese individuals with type 2 diabetes group also showed the higher prevalence and odds of left ventricular hypertrophy (16.0%; adjusted odds ratio: 2.24; 95% confidence interval: 1.22-5.06) and left ventricular diastolic dysfunction (49.1%; 3.45; 1.01-4.32). Among participants with normal left ventricular structure and function at baseline, only overweight/obese individuals with type 2 diabetes group was associated with greater incidence of left ventricular hypertrophy (relative risk: 2.28; 1.04-4.98) over 8 years but not diastolic dysfunction.Cross-sectional and longitudinal observations suggest that increasing body mass index category and its associated metabolic abnormalities at baseline are associated with an increased risk for left ventricular hypertrophy and greater impairment in left ventricular diastolic parameters.

  View details for PubMedID 31081361

• Increasing Mortality Among Patients With Diabetes and Chronic Liver Disease From 2007 Through 2017. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Kim, D. n., Cholankeril, G. n., Kim, S. H., Abbasi, F. n., Knowles, J. W., Ahmed, A. n. 2019

  View details for DOI 10.1016/j.cgh.2019.06.011

  View details for PubMedID 31220638

• Baseline Characteristics of the Vitamin D and Type 2 Diabetes (D2d) Study: A Contemporary Prediabetes Cohort That Will Inform Diabetes Prevention Efforts DIABETES CARE LeBlanc, E. S., Pratley, R. E., Dawson-Hughes, B., Staten, M. A., Sheehan, P. R., Lewis, M. R., Peters, A., Kim, S. H., Chatterjee, R., Aroda, V. R., Chadha, C., Neff, L. M., Brodsky, I. G., Rosen, C., Desouza, C. V., Foreyt, J. P., Hsia, D. S., Johnson, K. C., Raskin, P., Kashyap, S. R., O'Neil, P., Phillips, L. S., Rasouli, N., Liao, E. P., Robbins, D. C., Pittas, A. G., D2d Res Grp 2018; 41 (8): 1590–99

  Abstract

  To describe baseline characteristics of the Vitamin D and Type 2 Diabetes (D2d) study, the first large U.S. diabetes prevention clinical trial to apply current American Diabetes Association (ADA) criteria for prediabetes.This is a multicenter (n = 22 sites), randomized, double-blind, placebo-controlled, primary prevention clinical trial testing effects of oral daily 4,000 IU cholecalciferol (D3) compared with placebo on incident diabetes in U.S. adults at risk for diabetes. Eligible participants were at risk for diabetes, defined as not meeting criteria for diabetes but meeting at least two 2010 ADA glycemic criteria for prediabetes: fasting plasma glucose (FPG) 100-125 mg/dL, 2-h postload glucose (2hPG) after a 75-g oral glucose load 140-199 mg/dL, and/or a hemoglobin A1c (HbA1c) 5.7-6.4% (39-46 mmol/mol).A total of 2,423 participants (45% of whom were women and 33% nonwhite) were randomized to cholecalciferol or placebo. Mean (SD) age was 59 (9.9) years and BMI 32 (4.5) kg/m2. Thirty-five percent met all three prediabetes criteria, 49% met the FPG/HbA1c criteria only, 9.5% met the 2hPG/FPG criteria only, and 6.3% met the 2hPG/HbA1c criteria only. Black participants had the highest mean HbA1c and lowest FPG concentration compared with white, Asian, and other races (P < 0.01); 2hPG concentration did not differ among racial groups. When compared with previous prediabetes cohorts, the D2d cohort had lower mean 2hPG concentration but similar HbA1c and FPG concentrations.D2d will establish whether vitamin D supplementation lowers risk of diabetes and will inform about the natural history of prediabetes per contemporary ADA criteria.

  View details for DOI 10.2337/dc18-0240

  View details for Web of Science ID 000439288600008

  View details for PubMedID 29941495

• Racial Differences in Insulin Resistance, Secretion, and Clearance Kim, S. H. AMER DIABETES ASSOC. 2018

  View details for DOI 10.2337/db18-2099-P

  View details for Web of Science ID 000462825104331

• Adapting to insulin resistance in obesity: role of insulin secretion and clearance DIABETOLOGIA Jung, S., Jung, C., Reaven, G. M., Kim, S. H. 2018; 61 (3): 681–87

  Abstract

  The aim of this study was to quantify the relative contributions of increased insulin secretion rate (ISR) and decreased insulin clearance rate (ICR) in the compensatory hyperinsulinaemia characteristic of insulin-resistant individuals without diabetes.Obese (BMI ≥30 kg/m2) individuals without diabetes (n = 91) were identified from a registry of volunteers. Volunteers underwent the following measurements: oral glucose tolerance; insulin resistance (steady-state plasma glucose [SSPG] concentration during the insulin suppression test [IST]); ISR (using the graded glucose infusion test [GGIT]); and ICR (using the IST and GGIT). Participants were stratified into tertiles based on SSPG concentration: SSPG-1(insulin-sensitive); SSPG-2 (intermediate); and SSPG-3 (insulin-resistant).There were no differences in BMI and waist circumference among the SSPG tertiles. Serum alanine aminotransferase concentrations were higher in the SSPG-2 and SSPG-3 groups compared with the SSPG-1 group (p = 0.02). Following an oral glucose challenge, there was a progressive increase in the total integrated insulin response from the most insulin-sensitive to the most insulin-resistant tertiles (p < 0.001). Following intravenous glucose, the SSPG-3 group had significantly greater integrated glucose (median [interquartile range], 32.9 [30.8-36.3] mmol/l × h) and insulin responses (1711 [1476-2223] mmol/l × h) compared with the SSPG-1 group (30.3 [28.8-32.9] mmol/l × h, p = 0.04, and 851 [600-1057] pmol/l × h, p < 0.001, respectively). Furthermore, only the SSPG-3 group had significant changes in both ISR and ICR (p < 0.001). In the SSPG-2 group, only the ICR was significantly decreased compared with the SSPG-1 group. Therefore, ICR progressively declined during the IST with increasing insulin resistance (SSPG-1, 0.48 [0.41-0.59]; SSPG-2, 0.43 [0.39-0.50]; SSPG-3, 0.34 [0.31-0.40]).While both increases in ISR and decreases in ICR compensate for insulin resistance, decreases in ICR may provide the first adaptation to decreased insulin sensitivity.

  View details for PubMedID 29196782

• Inflammation in the Prediction of Type 2 Diabetes and Hypertension in Healthy Adults ARCHIVES OF MEDICAL RESEARCH Sung, K., Ryu, S., Sung, J., Kim, Y., Won, Y., Cho, D., Kim, S. H., Liu, A. 2017; 48 (6): 535–45

  Abstract

  While inflammation is associated with obesity and insulin resistance, their inter-relationships in the development of type 2 diabetes or hypertension are not clear.To evaluate inflammatory markers in prediction of type 2 diabetes and hypertension.The study population of this retrospective cohort study consisted of individuals who participated in a comprehensive health screening program with measurement of white blood cell count and C-reactive protein from 2002-2010 (N = 96,606) in nondiabetic and normotensive Koreans. Median follow up time were 3.7 years for incident type 2 diabetes and 3.3 years for hypertension. Multivariate Cox proportional hazards models were performed to assess risk for type 2 diabetes or hypertension by white blood cell or C-reactive protein quartiles with adjustment of various possible confounding factors including insulin resistance.During the follow-up period, 1448 (1.5%) developed type 2 diabetes and 10,405 (10.8%) developed hypertension. Among men, comparison of adjusted hazard ratios (HR) for incident type 2 diabetes in the highest versus lowest white blood cell or C-reactive protein quartiles were 1.48 [95% confidence interval (CI), 1.20-1.83] and 1.30 (95% CI, 1.07-1.57), respectively. Among women, white blood cell but not C-reactive protein was significantly associated with type 2 diabetes [HR 1.79 (95% CI 1.24-2.57)]. White blood cell and C-reactive protein quartiles were also modestly associated with incident hypertension in both sexes.Although white blood cell and C-reactive protein are associated with adiposity and insulin resistance, these inflammatory markers also independently predict type 2 diabetes and/or hypertension.

  View details for PubMedID 29221802

• Adapting to Insulin Resistance in Obesity: Role of Insulin Secretion and Clearance Kim, S. H., Reaven, G. M. AMER DIABETES ASSOC. 2017: LB75

  View details for Web of Science ID 000463087200280

• Relationship among age, insulin resistance, and blood pressure. Journal of the American Society of Hypertension Jung, C., Jung, S. H., Lee, B., Rosenberg, M., Reaven, G. M., Kim, S. H. 2017

  Abstract

  The effect of age to modify the relationship between insulin resistance and hypertension is unclear. In this retrospective, cross-sectional study, median age was used to create two age groups (<52 vs. ≥52 years), and comparisons were made of metabolic characteristics, including steady-state plasma glucose (SSPG) concentrations measured during the insulin suppression test to quantify insulin resistance. Individuals were stratified into SSPG tertiles and categorized as having normal blood pressure (BP), prehypertension, or hypertension. SSPG concentrations were similar in the two age groups (161 vs. 164 mg/dL). In the most insulin-resistant tertile, distribution of normal BP, prehypertension, and hypertension was equal in those aged <52 years, whereas in those aged ≥52 years, prevalence of hypertension was increased approximately fivefold compared with those with normal BP. Multivariate regression analysis demonstrated significant interaction between age and SSPG in predicting systolic BP (P = .023). In stratified analysis, SSPG, but not age, was an independent predictor of systolic BP and diastolic BP in ≥52 years group, whereas the reverse was true in the younger group. The adverse impact of insulin resistance on BP was accentuated in older individuals and may have a greater impact than further aging.

  View details for DOI 10.1016/j.jash.2017.04.005

  View details for PubMedID 28558951

• Dissecting the relationship between obesity and hyperinsulinemia: Role of insulin secretion and insulin clearance. Obesity Kim, M. K., Reaven, G. M., Kim, S. H. 2017; 25 (2): 378-383

  Abstract

  The aim of this study was to better delineate the complex interrelationship among insulin resistance (IR), secretion rate (ISR), and clearance rate (ICR) to increase plasma insulin concentrations in obesity.Healthy volunteers (92 nondiabetic individuals) had an insulin suppression test to measure IR and graded-glucose infusion test to measure ISR and ICR. Obesity was defined as a body mass index (BMI) ≥30 kg/m(2) , and IR was defined as steady-state plasma glucose (SSPG) ≥10 mmol/L during the insulin suppression test. Plasma glucose and insulin concentrations, ISR, and ICR were compared in three groups: insulin sensitive/overweight; insulin sensitive/obesity; and insulin resistant/obesity.Compared with the insulin-sensitive/overweight group, the insulin-sensitive/obesity had significantly higher insulin area under the curve (AUC) and ISR AUC during the graded-glucose infusion test (P < 0.001). Glucose AUC and ICR were similar. The insulin-resistant/obesity group had higher insulin AUC and ISR AUC compared with the insulin-sensitive/obesity but also had higher glucose AUC and decreased ICR (P < 0.01). In multivariate analysis, both BMI and SSPG were significantly associated with ISR.Plasma insulin concentration and ISR are increased in individuals with obesity, irrespective of degree of IR, but a decrease in ICR is confined to the subset of individuals with IR.

  View details for DOI 10.1002/oby.21699

  View details for PubMedID 28000428

  View details for PubMedCentralID PMC5269435

• Effect of Pioglitazone on Cardiometabolic Risk in Patients With Obstructive Sleep Apnea. American journal of cardiology Liu, A., Abbasi, F., Kim, S. H., Ariel, D., Lamendola, C., Cardell, J., Xu, S., Patel, S., Tomasso, V., Mojaddidi, H., Grove, K., Tsao, P. S., Kushida, C. A., Reaven, G. M. 2017

  Abstract

  Prevalence of insulin resistance is increased in patients with obstructive sleep apnea (OSA). Because insulin resistance is an independent predictor of cardiovascular disease (CVD), this study was initiated to see if pioglitazone administration would improve insulin sensitivity and thereby decrease risk of CVD in overweight/obese, nondiabetic, insulin-resistant patients with untreated OSA. Patients (n = 30) were administered pioglitazone (45 mg/day) for 8 weeks, and measurements were made before and after intervention of insulin action (insulin-mediated glucose uptake by the insulin suppression test), C-reactive protein, lipid/lipoprotein profile, and gene expression profile of periumbilical subcutaneous fat tissue. Insulin sensitivity increased 31% (p <0.001) among pioglitazone-treated subjects, associated with a decrease in C-reactive protein concentration (p ≤0.001), a decrease in plasma triglyceride, and increase in high-density lipoprotein cholesterol concentrations (p ≤0.001), accompanied by significant changes in apolipoprotein A1 and B concentrations and lipoprotein subclasses known to decrease CVD risk. In addition, subcutaneous adipose tissue gene expression profile showed a 1.6-fold (p <0.01) increase in GLUT4 expression and decreased expression in 5 of 9 inflammatory genes (p <0.05). In conclusion, enhanced insulin sensitivity can significantly decrease multiple cardiometabolic risk factors in patients with untreated OSA, consistent with the view that coexisting insulin resistance plays an important role in the association between OSA and increased risk of CVD.

  View details for DOI 10.1016/j.amjcard.2016.12.034

  View details for PubMedID 28219664

• Salsalate treatment for prediabetes: a therapeutic alternative? Diabetic medicine Kim, S. H., Reaven, G. 2016

  View details for DOI 10.1111/dme.13293

  View details for PubMedID 27885717

• Insulin clearance: an underappreciated modulator of plasma insulin concentration. Journal of investigative medicine Kim, S. H., Reaven, G. M. 2016; 64 (7): 1162-1165

  Abstract

  Plasma glucose concentrations are tightly regulated and maintained within a narrow range in non-diabetic individuals. Maintenance of this physiological state is primarily a function of the ability of the pancreatic β-cells to modify insulin secretion rate (ISR), thus preventing wide-swings in plasma glucose concentrations. As a consequence, and in contrast to plasma glucose concentrations, plasma insulin concentrations vary substantially in non-diabetic individuals. Although differences in ISR are primarily responsible for the variability in plasma insulin concentration, there is increasing evidence that differences in insulin clearance rate (ICR) also play a role in regulation of plasma insulin concentration. The goal of this mini-review is to highlight situations that demonstrate the important role of ICR in both insulin and glucose homeostasis.

  View details for DOI 10.1136/jim-2016-000149

  View details for PubMedID 27229887

• Relationship between insulin sensitivity and insulin secretion rate: not necessarily hyperbolic DIABETIC MEDICINE Kim, S. H., Silvers, A., Viren, J., Reaven, G. M. 2016; 33 (7): 961-967

  Abstract

  There is general acceptance that the physiological relationship between insulin sensitivity and insulin secretion is hyperbolic. This conclusion has evolved from studies in which one test assessed both variables, and changes in plasma insulin concentration were used as a surrogate measure for insulin secretion rate. The aim of this study was to see if a hyperbolic relationship would also emerge when separate and direct measures were used to quantify both insulin sensitivity and insulin secretion rate.Steady-state plasma glucose (SSPG) was determined in 146 individuals without diabetes using the insulin suppression test, with 1/SSPG used to quantify insulin sensitivity. The graded-glucose infusion test was used to quantify insulin secretion rate. Plasma glucose and insulin concentrations obtained during an oral glucose tolerance test (OGTT) were used to calculate surrogate estimates of insulin action and insulin secretion rate. A hyperbolic relationship was assumed if the β coefficient was near -1 using the following model: log (insulin secretion measure) = constant + β × log (insulin sensitivity measure).OGTT calculations of insulin sensitivity (Matsuda) and plasma insulin response [ratio of insulin/glucose area-under-the-curve (AUC) or insulin total AUC] provided the expected hyperbolic relationship [β = -0.95, 95% CI (-1.09, -0.82); -1.06 (-1.14, -0.98)]. Direct measurements of insulin sensitivity and insulin secretion rate did not yield the same curvilinear relationship [β = -1.97 (-3.19, -1.36)].These findings demonstrate that the physiological relationship between insulin sensitivity and insulin secretion rate is not necessarily hyperbolic, but will vary with the method(s) by which it is determined.

  View details for DOI 10.1111/dme.13055

  View details for Web of Science ID 000379930900014

  View details for PubMedID 26670479

  View details for PubMedCentralID PMC4911331

• Does enhanced insulin sensitivity improve sleep measures in patients with obstructive sleep apnea: a randomized, placebo-controlled pilot study. Sleep medicine Liu, A., Kim, S. H., Ariel, D., Abbasi, F., Lamendola, C., Cardell, J., Xu, S., Patel, S., Tomasso, V., Mojaddidi, H., Grove, K., Tsao, P. S., Kushida, C. A., Reaven, G. M. 2016; 22: 57-60

  Abstract

  High fasting insulin levels have been reported to predict development of observed apneas, suggesting that insulin resistance may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to determine whether enhancing insulin sensitivity in individuals with OSA would improve sleep measures.Insulin-resistant, nondiabetic individuals with untreated OSA were randomized (2:1) to pioglitazone (45 mg/day) or placebo for eight weeks in this single-blind study. All individuals had repeat measurements pertaining to sleep (overnight polysomnography and functional outcomes of sleep questionnaire) and insulin action (insulin suppression test).A total of 45 overweight/obese men and women with moderate/severe OSA were randomized to pioglitazone (n = 30) or placebo (n = 15). Although insulin sensitivity increased 31% among pioglitazone-treated compared with no change among individuals receiving placebo (p <0.001 for between-group difference), no improvement in quantitative or qualitative sleep measurements was observed.Pioglitazone administration increased insulin sensitivity in otherwise untreated individuals with OSA, without any change in polysomnographic sleep measures over an eight-week period. These findings do not support a causal role for insulin resistance in the pathogenesis of OSA.

  View details for DOI 10.1016/j.sleep.2016.06.005

  View details for PubMedID 27544837

• Cardiometabolic Effects of Glucagon-Like Peptide-1 Agonists. Current atherosclerosis reports Sarraju, A., Kim, S. H., Knowles, J. W. 2016; 18 (2): 7-?

  Abstract

  Cardiovascular disease is the leading cause of death among adults in the USA. Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are known risk factors for cardiovascular disease. Despite the development of numerous effective anti-glycemic therapies, we have been unable to completely mitigate cardiovascular risk with glucose lowering alone, and prevention of cardiovascular disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. Glucagon-like peptide-1 (GLP-1) is a key hormone in the pathophysiology of diabetes. GLP-1 agonists have been recently approved for the treatment of T2DM as well as for chronic weight management. In this review, we aim to explore the effects of GLP-1 agonists on cardiovascular health with a focus on cardiometabolic variables and cardiac function.

  View details for DOI 10.1007/s11883-016-0558-5

  View details for PubMedID 26782825

• Second-Line Agents for the Treatment of Type 2 Diabetes and Prevention of CKD. Clinical journal of the American Society of Nephrology : CJASN Yu, M. K., Kim, S. H. 2016; 11 (12): 2104–6

  View details for PubMedID 27827307

  View details for PubMedCentralID PMC5142075

• Hyperinsulinemia in Individuals with Obesity: Role of Insulin Clearance OBESITY Kim, M. K., Reaven, G. M., Chen, Y. I., Kim, E., Kim, S. H. 2015; 23 (12): 2430-2434

  Abstract

  Several studies have shown decreased insulin clearance rate (ICR) in individuals with obesity, but it remains unclear whether this is predominately due to obesity-associated insulin resistance (IR) or obesity itself. This study aimed to clarify the complex interrelationship that exists between obesity, IR, and ICR.Healthy volunteers (n = 277) had measurement of IR and ICR using the insulin suppression test (IST). IR was quantified by determining the steady-state plasma glucose (SSPG) during the IST. ICR was estimated by dividing the insulin infusion rate by the steady-state plasma insulin concentration. We performed our analysis by stratifying the experimental population into four dichotomous categories, varying in obesity and IR. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m(2) , and IR was defined as SSPG ≥ 150 mg/dL.Individuals with obesity had higher fasting insulin compared with individuals without obesity, regardless of IR. ICR was similar between individuals with and without obesity but was higher in insulin resistant individuals compared with insulin-sensitive individuals. In multivariate analysis, both fasting insulin and SSPG were significantly associated with ICR. No significant relationships were observed between BMI and ICR.Reduced ICR in obesity is secondary to IR, not excess adiposity.

  View details for DOI 10.1002/oby.21256

  View details for Web of Science ID 000367189300023

  View details for PubMedCentralID PMC4701635

• Hyperinsulinemia in individuals with obesity: Role of insulin clearance. Obesity (Silver Spring, Md.) Kim, M. K., Reaven, G. M., Chen, Y. I., Kim, E., Kim, S. H. 2015; 23 (12): 2430-4

  Abstract

  Several studies have shown decreased insulin clearance rate (ICR) in individuals with obesity, but it remains unclear whether this is predominately due to obesity-associated insulin resistance (IR) or obesity itself. This study aimed to clarify the complex interrelationship that exists between obesity, IR, and ICR.Healthy volunteers (n = 277) had measurement of IR and ICR using the insulin suppression test (IST). IR was quantified by determining the steady-state plasma glucose (SSPG) during the IST. ICR was estimated by dividing the insulin infusion rate by the steady-state plasma insulin concentration. We performed our analysis by stratifying the experimental population into four dichotomous categories, varying in obesity and IR. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m(2) , and IR was defined as SSPG ≥ 150 mg/dL.Individuals with obesity had higher fasting insulin compared with individuals without obesity, regardless of IR. ICR was similar between individuals with and without obesity but was higher in insulin resistant individuals compared with insulin-sensitive individuals. In multivariate analysis, both fasting insulin and SSPG were significantly associated with ICR. No significant relationships were observed between BMI and ICR.Reduced ICR in obesity is secondary to IR, not excess adiposity.

  View details for DOI 10.1002/oby.21256

  View details for PubMedID 26524351

  View details for PubMedCentralID PMC4701635

• Comparison of the association with sleep apnoea of obesity versus insulin resistance EUROPEAN RESPIRATORY JOURNAL Liu, A., Ariel, D., Lamendola, C., Kim, S. H., Abbasi, F., Cardell, J., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 46 (6): 1829–32

  View details for PubMedID 26405296

• Salsalate-induced changes in lipid, lipoprotein, and apoprotein concentrations in overweight or obese, insulin-resistant, nondiabetic individuals. Journal of clinical lipidology Ariel, D., Kim, S. H., Liu, A., Abbasi, F., Lamendola, C. A., Grove, K., Tomasso, V., Reaven, G. M. 2015; 9 (5): 658-663

  Abstract

  Although salsalate administration consistently lowers plasma triglyceride concentrations in patients with type II diabetes, prediabetes, and/or insulin resistance, changes in low-density lipoprotein cholesterol (LDL-C) concentrations have been inconsistent; varying from no change to a significant increase. To evaluate the clinical relevance of this discordance in more detail, we directly measured LDL-C and obtained a comprehensive assessment of changes in lipid, lipoprotein, and apoprotein concentrations associated with salsalate use in insulin-resistant individuals, overweight or obese, but without diabetes, using vertical auto profile method.A single-blind, randomized, placebo-controlled study was performed in volunteers who were overweight or obese, without diabetes, and insulin resistant on the basis of their steady-state plasma glucose concentration during an insulin suppression test. Participants were randomized 2:1 to receive salsalate 3.5 g/d (n = 27) or placebo (n = 14) for 4 weeks. Comprehensive lipid, lipoprotein, and apoprotein analysis by vertical auto profile was obtained after an overnight fast, before and after study intervention.There was no change in directly measured LDL-C concentration in salsalate-treated individuals. However, salsalate administration was associated with various changes considered to decrease atherogenicity; including decreases in triglyceride and total very low-density lipoprotein cholesterol (VLDL-C) concentrations, a shift from small denser LDL lipoproteins toward larger, more buoyant LDL particles, decreases in VLDL1+2-C and LDL4-C, and nonsignificant decreases in non-high-density lipoprotein cholesterol and apolipoprotein B. No significant changes occurred in the placebo-treated group.Atherogenicity of the lipid, lipoprotein, and apoprotein profile of insulin-resistant individuals who were overweight or obese improved significantly in association with salsalate treatment. The clinical importance of this finding awaits further study.

  View details for DOI 10.1016/j.jacl.2015.06.009

  View details for PubMedID 26350812

• Salsalate-induced changes in lipid, lipoprotein, and apoprotein concentrations in overweight or obese, insulin-resistant, nondiabetic individuals. Journal of clinical lipidology Ariel, D., Kim, S. H., Liu, A., Abbasi, F., Lamendola, C. A., Grove, K., Tomasso, V., Reaven, G. M. 2015; 9 (5): 658-663

  View details for DOI 10.1016/j.jacl.2015.06.009

  View details for PubMedID 26350812

• Increased body mass index negatively impacts blastocyst formation rate in normal responders undergoing in vitro fertilization JOURNAL OF ASSISTED REPRODUCTION AND GENETICS Comstock, I. A., Kim, S., Behr, B., Lathi, R. B. 2015; 32 (9): 1299-1304

  Abstract

  The aim of this study is to investigate the effect of female BMI and metabolic dysfunction on blastocyst formation rate.This was a retrospective cohort study that was performed in an academic center for reproductive medicine. Patients who were normal weight, overweight with metabolic dysfunction, or obese who had ≥6 oocytes retrieved in a fresh IVF cycle were included in the study. The blastocyst formation rate was calculated from the number of ≥5 cell embryos on day 3 observed in culture until day 5 or day 6. Only good quality blastocysts were included in the calculation as defined by a morphologic grade of 3BB or better.The blastocyst formation rate was significantly better in the normal-weight controls versus overweight/obese patients (57.2 versus 43.6 %, p < 0.007). There was no difference in blastocyst formation between the patients with a BMI 25-29.9 kg/m(2) with metabolic dysfunction and those with a BMI ≥30 kg/m(2).The maternal metabolic environment has a significant impact on embryo quality as measured by blastocyst formation. A decreased blastocyst formation rate is likely a significant contributor to poorer reproductive outcomes in overweight and obese women with infertility.

  View details for DOI 10.1007/s10815-015-0515-1

  View details for Web of Science ID 000362519600002

  View details for PubMedID 26109331

  View details for PubMedCentralID PMC4595387

• Usefulness of Fetuin-A to Predict Risk for Cardiovascular Disease Among Patients With Obstructive Sleep Apnea. American journal of cardiology Liu, A., Lamendola, C., Ariel, D., Abbasi, F., Kim, S. H., Cardell, J., Tomasso, V., Xu, S., Patel, S., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 116 (2): 219-224

  Abstract

  Patients with obstructive sleep apnea (OSA) are at increased risk for cardiovascular diseases (CVDs). Fetuin-A, a novel hepatokine, has been associated with the metabolic syndrome (MetS), insulin resistance, and type 2 diabetes mellitus, all of which are highly prevalent in patients with OSA and associated with increased CVD risk. The goal of this study was to determine whether fetuin-A could be involved in the pathogenesis of CVD risk in patients with OSA, through relations of fetuin-A with MetS components and/or insulin resistance. Overweight or obese, nondiabetic volunteers (n = 120) were diagnosed with OSA by in-laboratory nocturnal polysomnography. Steady-state plasma glucose concentrations derived during the insulin suppression test were used to quantify insulin-mediated glucose uptake; higher steady-state plasma glucose concentrations indicated greater insulin resistance. Fasting plasma fetuin-A and lipoprotein concentrations were measured. Whereas neither the prevalence of MetS nor the number of MetS components was associated with tertiles of fetuin-A concentrations, the lipoprotein components of MetS, triglycerides and high-density lipoprotein cholesterol, increased (p <0.01) and decreased (p <0.05), respectively, across fetuin-A tertiles. Additionally, comprehensive lipoprotein analysis revealed that very low density lipoprotein (VLDL) particles and VLDL subfractions (VLDL1+2 and VLDL3) were increased across fetuin-A tertiles. In contrast, neither insulin resistance nor sleep measurements related to OSA were found to be modified by fetuin-A concentrations. In conclusion, abnormalities of lipoprotein metabolism, but not MetS or insulin resistance per se, may represent a mechanism by which fetuin-A contributes to increased CVD risk in patients with OSA.

  View details for DOI 10.1016/j.amjcard.2015.04.014

  View details for PubMedID 25960379

• Abnormalities of lipoprotein concentrations in obstructive sleep apnea are related to insulin resistance. Sleep Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Holmes, T. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 38 (5): 793-799

  Abstract

  Prevalence of cardiovascular disease (CVD) is increased in patients with obstructive sleep apnea (OSA), possibly related to dyslipidemia in these individuals. Insulin resistance is also common in OSA, but its contribution to dyslipidemia of OSA is unclear. The study’s aim was to define the relationships among abnormalities of lipoprotein metabolism, clinical measures of OSA, and insulin resistance.Cross-sectional study. OSA severity was defined by the apnea-hypopnea index (AHI) during polysomnography. Hypoxia measures were expressed as minimum and mean oxygen saturation, and the oxygen desaturation index. Insulin resistance was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Fasting plasma lipid/ lipoprotein evaluation was performed by vertical auto profile methodology.Academic medical center.107 nondiabetic, overweight/ obese adults.Lipoprotein particles did not correlate with AHI or any hypoxia measures, nor were there differences noted by categories of OSA severity. By contrast, even after adjustment for age, sex, and BMI, SSPG was positively correlated with triglycerides (r = 0.30, P < 0.01), very low density lipoprotein (VLDL) and its subclasses (VLDL1+2) (r = 0.21-0.23, P < 0.05), and low density lipoprotein subclass 4 (LDL4) (r = 0.30, P < 0.01). SSPG was negatively correlated with high density lipoprotein (HDL) (r = -0.38, P < 0.001) and its subclasses (HDL2 and HDL3) (r = -0.32, -0.43, P < 0.01), and apolipoprotein A1 (r = -0.33, P < 0.01). Linear trends of these lipoprotein concentrations across SSPG tertiles were also significant.Pro-atherogenic lipoprotein abnormalities in OSA are related to insulin resistance, but not to OSA severity or degree of hypoxia. Insulin resistance may represent the link between OSA-related dyslipidemia and increased CVD risk.

  View details for DOI 10.5665/sleep.4678

  View details for PubMedID 25348129

• Abnormalities of Lipoprotein Concentrations in Obstructive Sleep Apnea Are Related to Insulin Resistance SLEEP Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Holmes, T. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 38 (5): 793-?

  Abstract

  Prevalence of cardiovascular disease (CVD) is increased in patients with obstructive sleep apnea (OSA), possibly related to dyslipidemia in these individuals. Insulin resistance is also common in OSA, but its contribution to dyslipidemia of OSA is unclear. The study’s aim was to define the relationships among abnormalities of lipoprotein metabolism, clinical measures of OSA, and insulin resistance.Cross-sectional study. OSA severity was defined by the apnea-hypopnea index (AHI) during polysomnography. Hypoxia measures were expressed as minimum and mean oxygen saturation, and the oxygen desaturation index. Insulin resistance was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Fasting plasma lipid/ lipoprotein evaluation was performed by vertical auto profile methodology.Academic medical center.107 nondiabetic, overweight/ obese adults.Lipoprotein particles did not correlate with AHI or any hypoxia measures, nor were there differences noted by categories of OSA severity. By contrast, even after adjustment for age, sex, and BMI, SSPG was positively correlated with triglycerides (r = 0.30, P < 0.01), very low density lipoprotein (VLDL) and its subclasses (VLDL1+2) (r = 0.21-0.23, P < 0.05), and low density lipoprotein subclass 4 (LDL4) (r = 0.30, P < 0.01). SSPG was negatively correlated with high density lipoprotein (HDL) (r = -0.38, P < 0.001) and its subclasses (HDL2 and HDL3) (r = -0.32, -0.43, P < 0.01), and apolipoprotein A1 (r = -0.33, P < 0.01). Linear trends of these lipoprotein concentrations across SSPG tertiles were also significant.Pro-atherogenic lipoprotein abnormalities in OSA are related to insulin resistance, but not to OSA severity or degree of hypoxia. Insulin resistance may represent the link between OSA-related dyslipidemia and increased CVD risk.

  View details for DOI 10.5665/sleep.4678

  View details for Web of Science ID 000353876600017

  View details for PubMedID 25348129

• Relationship between insulin resistance and amino acids in women and men. Physiological reports Seibert, R., Abbasi, F., Hantash, F. M., Caulfield, M. P., Reaven, G., Kim, S. H. 2015; 3 (5)

  Abstract

  Insulin resistance has been associated with higher plasma amino acid (AA) concentrations, but majority of studies have used indirect measures of insulin resistance. Our main objective was to define the relationship between plasma AA concentrations and a direct measure of insulin resistance in women and men. This was a cross-sectional study of 182 nondiabetic individuals (118 women and 64 men) who had measurement of 24 AAs and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test. Fourteen out of 24 AA concentrations were significantly (P < 0.05) higher in men than women; only glycine was lower in men. Majority of these AAs were positively associated with SSPG; only glycine concentration was negatively associated. Glutamic acid, isoleucine, leucine, and tyrosine concentrations had the strongest correlation with SSPG (r ≥ 0.4, P < 0.001). The degree of association was similar in women and men, independent of obesity, and similar to traditional markers of insulin resistance (e.g., glucose, triglyceride, high-density lipoprotein cholesterol). Compared with women, men tended to have a more unfavorable AA profile with higher concentration of AAs associated with insulin resistance and less glycine. However, the strength of association between a direct measurement of insulin resistance and AA concentrations were similar between sexes and equivalent to several traditional markers of insulin resistance.

  View details for DOI 10.14814/phy2.12392

  View details for PubMedID 25952934

  View details for PubMedCentralID PMC4463823

• Effect of liraglutide administration and a calorie-restricted diet on lipoprotein profile in overweight/obese persons with prediabetes. Nutrition, metabolism, and cardiovascular diseases : NMCD Ariel, D., Kim, S. H., Abbasi, F., Lamendola, C. A., Liu, A., Reaven, G. M. 2014; 24 (12): 1317-1322

  Abstract

  To evaluate the effects of 14 weeks of liraglutide plus modest caloric restriction on lipid/lipoprotein metabolism in overweight/obese persons with prediabetes.Volunteers with prediabetes followed a calorie-restricted diet (-500 Kcal/day) plus liraglutide (n = 23) or placebo (n = 27) for 14 weeks. The groups were similar in age (58 ± 7 vs. 58 ± 8 years) and body mass index (31.9 ± 2.8 vs. 31.9 ± 3.5 kg/m(2)). A comprehensive lipid/lipoprotein profile was obtained before and after intervention using vertical auto profile (VAP). Weight loss was greater in the liraglutide group than in the placebo group (6.9 vs. 3.3 kg, p < 0.001), as was the fall in fasting plasma glucose concentration (9.9 mg/dL vs. 0.3 mg/dL, p < 0.001). VAP analysis revealed multiple improvements in lipid/lipoprotein metabolism in liraglutide-treated compared with placebo-treated volunteers, including decreases in concentrations of total cholesterol, low-density lipoprotein cholesterol and several of its subclasses, triglyceride, and non-high-density cholesterol. The liraglutide-treated group also had a significant shift away from small, dense low-density lipoprotein-particles, as well as decreases in apolipoprotein B concentration and ratio of apolipoprotein B/apolipoprotein A-1. There were no significant changes in the lipoprotein profile in the placebo-treated group.Treatment with liraglutide plus modest calorie restriction led to enhanced weight loss, a decrease in fasting plasma glucose concentration, and improvement in multiple aspects of lipid/lipoprotein metabolism associated with increased cardiovascular disease (CVD) risk. The significant clinical benefit associated with liraglutide-assisted weight loss in a group at high risk for CVD - obese/overweight individuals with prediabetes - as seen in our pilot study, suggests that this approach deserves further study.

  View details for DOI 10.1016/j.numecd.2014.06.010

  View details for PubMedID 25280957

• Effect of Salsalate on Insulin Action, Secretion, and Clearance in Nondiabetic, Insulin-Resistant Individuals: A Randomized, Placebo-Controlled Study DIABETES CARE Kim, S. H., Liu, A., Ariel, D., Abbasi, F., Lamendola, C., Grove, K., Tomasso, V., Ochoa, H., Reaven, G. 2014; 37 (7): 1944-1950

  Abstract

  Salsalate treatment has been shown to improve glucose homeostasis, but the mechanism remains unclear. The aim of this study was to evaluate the effect of salsalate treatment on insulin action, secretion, and clearance rate in nondiabetic individuals with insulin resistance.This was a randomized (2:1), single-blind, placebo-controlled study of salsalate (3.5 g daily for 4 weeks) in nondiabetic individuals with insulin resistance. All individuals had measurement of glucose tolerance (75-g oral glucose tolerance test), steady-state plasma glucose (SSPG; insulin suppression test), and insulin secretion and clearance rate (graded-glucose infusion test) before and after treatment.Forty-one individuals were randomized to salsalate (n = 27) and placebo (n = 14). One individual from each group discontinued the study. Salsalate improved fasting (% mean change -7% [95% CI -10 to -14] vs. 1% [-3 to 5], P = 0.005) but not postprandial glucose concentration compared with placebo. Salsalate also lowered fasting triglyceride concentration (-25% [-34 to -15] vs. -6% [-26 to 14], P = 0.04). Salsalate had no effect on SSPG concentration or insulin secretion rate but significantly decreased insulin clearance rate compared with placebo (-23% [-30 to -16] vs. 3% [-10 to 15], P < 0.001). Salsalate was well tolerated, but four individuals needed a dose reduction due to symptoms.Salsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentration. These improvements were associated with a decrease in insulin clearance rate without change in insulin action or insulin secretion.

  View details for DOI 10.2337/dc13-2977

  View details for Web of Science ID 000338020400030

  View details for PubMedCentralID PMC4067392

• Effect of salsalate on insulin action, secretion, and clearance in nondiabetic, insulin-resistant individuals: a randomized, placebo-controlled study. Diabetes care Kim, S. H., Liu, A., Ariel, D., Abbasi, F., Lamendola, C., Grove, K., Tomasso, V., Ochoa, H., Reaven, G. 2014; 37 (7): 1944-1950

  Abstract

  Salsalate treatment has been shown to improve glucose homeostasis, but the mechanism remains unclear. The aim of this study was to evaluate the effect of salsalate treatment on insulin action, secretion, and clearance rate in nondiabetic individuals with insulin resistance.This was a randomized (2:1), single-blind, placebo-controlled study of salsalate (3.5 g daily for 4 weeks) in nondiabetic individuals with insulin resistance. All individuals had measurement of glucose tolerance (75-g oral glucose tolerance test), steady-state plasma glucose (SSPG; insulin suppression test), and insulin secretion and clearance rate (graded-glucose infusion test) before and after treatment.Forty-one individuals were randomized to salsalate (n = 27) and placebo (n = 14). One individual from each group discontinued the study. Salsalate improved fasting (% mean change -7% [95% CI -10 to -14] vs. 1% [-3 to 5], P = 0.005) but not postprandial glucose concentration compared with placebo. Salsalate also lowered fasting triglyceride concentration (-25% [-34 to -15] vs. -6% [-26 to 14], P = 0.04). Salsalate had no effect on SSPG concentration or insulin secretion rate but significantly decreased insulin clearance rate compared with placebo (-23% [-30 to -16] vs. 3% [-10 to 15], P < 0.001). Salsalate was well tolerated, but four individuals needed a dose reduction due to symptoms.Salsalate treatment in nondiabetic, insulin-resistant individuals improved fasting, but not postprandial, glucose and triglyceride concentration. These improvements were associated with a decrease in insulin clearance rate without change in insulin action or insulin secretion.

  View details for DOI 10.2337/dc13-2977

  View details for PubMedID 24963111

• C-reactive protein and risk of cardiovascular and all-cause mortality in 268 803 East Asians EUROPEAN HEART JOURNAL Sung, K., Ryu, S., Chang, Y., Byrne, C. D., Kim, S. H. 2014; 35 (27): 1809-1816

  Abstract

  C-reactive protein concentrations are decreased in Asians compared with people of white European ethnicity. It is uncertain whether C-reactive protein is a robust biomarker of cardiovascular disease (CVD) in Asians. This study aimed to determine the association between C-reactive protein and CVD and all-cause mortality in a large population of Koreans.Mortality outcomes for 268 803 Koreans enrolled in a health screening programme with measurements of C-reactive protein at baseline and median follow-up of 4.49 years (1 155 930 person-years) were analysed. A subset (48%) of subjects had a repeat C-reactive protein measurement during follow-up. The median (interquartile) baseline C-reactive protein values were higher in men than in women [0.6 (0.3-1.3) vs. 0.4 (0.1-1.1), P < 0.001]. Only 8.6% of men and 6.2% of women met the standard cut point for C-reactive protein >3 mg/L, which represents the top tertile in white populations. During a median follow-up of 4.49 years (1 155 930 person-years), 1047 died; 187 died of CVD causes. In men but not women, baseline C-reactive protein quartiles were linearly associated with both CVD and all-cause mortality (P < 0.001), even after adjustment for known CVD risk factors. Regardless of baseline C-reactive protein concentration, any increase or decrease in C-reactive protein over time did not affect the HR for all-cause, or CVD mortality. Models with C-reactive protein yielded a net reclassification improvement for CVD mortality of 24.9% (P = 0.04) for individuals with intermediate risk.C-reactive protein concentrations are substantially lower in Koreans than reported for whites populations. Nonetheless, C-reactive protein levels are associated with CVD and all-cause mortality in Korean men. Standard cut points for C-reactive protein may under-represent Asians at risk for CVD.

  View details for DOI 10.1093/eurheartj/ehu059

  View details for Web of Science ID 000340067200014

  View details for PubMedID 24569028

• Ability of the plasma concentration ratio of triglyceride/high-density lipoprotein cholesterol to identify increased cardio-metabolic risk in an east Asian population DIABETES RESEARCH AND CLINICAL PRACTICE Sung, K., Reaven, G., Kim, S. 2014; 105 (1): 96-101

  Abstract

  The plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) has identified increased cardio-metabolic risk and outcome in European populations. The goal of this study was to see if this ratio would also have clinical utility in identifying cardio-metabolic risk in an East Asian population.Measurements of various cardio-metabolic risk factors, including coronary calcium scores, were available on 12,166 apparently healthy Korean adults. Approximately 25% of men and women with the highest TG/HDL-C ratios were classified as being at high cardio-metabolic risk, and their risk factor profiles compared to the remainder of the population, as well as to individuals with the metabolic syndrome (MetS).High cardio-metabolic risk (upper 25%) was defined as a TG/HDL-C ratio ≥3.5 (men) or ≥2.0 (women), and all cardio-metabolic risk factors measured, including coronary calcium scores, were significantly more adverse when compared to individuals beneath these cut-points. Although cardio-metabolic risk profiles appeared reasonably comparable in subjects identified by either a high TG/HDL-C or a diagnosis of MetS, use of the TG/HDL-C increased the numbers at high risk.Evidence that determination of the plasma TG/HDL-C concentration ratio provides a simple way to identify individual at increased cardio-metabolic risk has been extended to an East Asian population. The ability of an elevated TG/HDL-C ratio to accomplish this goal is comparable to that achieved using the more complicated MetS criteria.

  View details for DOI 10.1016/j.diabres.2014.04.021

  View details for Web of Science ID 000338715400014

• Sex Differences Modulate Relationships among Obesity, Insulin Resistance, and Obstructive Sleep Apnea Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C., Reaven, G. M. AMER DIABETES ASSOC. 2014: A446

  View details for Web of Science ID 000359481602402

• Effect of Salsalate on Insulin Action, Secretion, and Clearance in Non-Diabetic, Insulin-Resistant Individuals: A Randomized, Placebo-Controlled Study Kim, S., Liu, A., Ariel, D., Abbasi, F., Lamendola, C., Grove, K., Tomasso, V., Ochoa, H., Reaven, G. M. AMER DIABETES ASSOC. 2014: A32

  View details for Web of Science ID 000359481600122

• A retrospective cohort study to evaluate the impact of meaningful weight loss on fertility outcomes in an overweight population with infertility FERTILITY AND STERILITY Kort, J. D., Winget, C., Kim, S. H., Lathi, R. B. 2014; 101 (5): 1400-1403

  Abstract

  To determine if meaningful weight loss (≥10%) improved conception and live birth rates of overweight patients with infertility.A retrospective cohort study.Academic medical center.Overweight patients (body mass index ≥25 kg/m(2); n = 52) being treated for infertility and referred for weight loss counseling.Patients were given a "meaningful" weight loss goal of 10%. They were followed by an endocrinologist who provided diet and exercise recommendations, metabolic screening, and pharmacologic intervention when indicated.Pregnancy rate, live birth rate, weight loss.Thirty-two percent of the patients achieved meaningful weight loss. Patients achieving meaningful weight loss had significantly higher conception (88% vs. 54%) and live birth rates (71% vs. 37%) than those who did not.Weight loss improves live birth rates in overweight patients with infertility. Health care providers should incorporate weight loss counseling when caring for overweight patients who plan to conceive.

  View details for DOI 10.1016/j.fertnstert.2014.01.036

  View details for Web of Science ID 000335504600043

  View details for PubMedID 24581574

• Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study. Diabetologia Kim, S. H., Liu, A., Ariel, D., Abbasi, F., Lamendola, C., Grove, K., Tomasso, V., Reaven, G. 2014; 57 (3): 455-462

  Abstract

  Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (-7.7% vs -3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40-70 years old, overweight (BMI 27-40 kg/m(2)) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n = 35) or matching placebo (n = 33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.Liraglutide treatment (n = 24) significantly (p ≤ 0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs -4% [-11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs -0.5% (-15, 14]), and decreased insulin clearance rate (-3.5% [-11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n = 25). The liraglutide-treated group also had significantly (p ≤ 0.03) lower day-long glucose (-8.2% [-11, -6] vs -0.1 [-3, 2]) and NEFA concentrations (-14 [-20, -8] vs -2.1 [-10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p ≤ 0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.ClinicalTrials.gov NCT01784965 FUNDING: The study was funded by the ADA.

  View details for DOI 10.1007/s00125-013-3134-3

  View details for PubMedID 24326527

• Sex differences in insulin resistance and cardiovascular disease risk. journal of clinical endocrinology and metabolism Kim, S. H., Reaven, G. 2013; 98 (11): E1716-21

  Abstract

  The possibility that differences in insulin sensitivity explain why women, especially younger women, have a lower cardiovascular disease (CVD) risk than men remains an unsettled issue.The objective of this study was to evaluate whether sex disparities in CVD risk are associated with differences in insulin resistance.This was a cross-sectional study of women (n = 468) and men (n = 354) who had the measurement of CVD risk factors and steady-state plasma glucose (SSPG) concentration (insulin resistance) using the insulin suppression test. The population was also divided by median age (51 y) to evaluate the effect of age on sex differences. MAIN OUTCOME MEASURES/RESULTS: In general, the SSPG concentration was similar between sexes. At higher BMI (≥30 kg/m(2)), women had significantly lower SSPG concentration than men (sex × BMI interaction, P = .001). However, sex differences in CVD risk factors were not due to differences in SSPG but accentuated by a higher degree of insulin resistance in younger (age < 51 y) but not older (≥ 51 y) individuals. In younger individuals, women had significantly (P ≤ .007) lower diastolic blood pressure and fasting glucose and triglyceride concentration compared with men in SSPG tertile 3 (most insulin resistant) but not in tertile 1 (least insulin resistant). Older women had lower diastolic blood pressure compared with men, regardless of SSPG. High-density lipoprotein cholesterol remained higher in women, regardless of age or SSPG.The female advantage is not due to a difference in insulin action but results from an attenuation of the relationship between insulin resistance and CVD risk, especially in younger individuals.

  View details for DOI 10.1210/jc.2013-1166

  View details for PubMedID 24064694

  View details for PubMedCentralID PMC3816264

• Benefits of liraglutide treatment in overweight and obese older individuals with prediabetes. Diabetes care Kim, S. H., Abbasi, F., Lamendola, C., Liu, A., Ariel, D., Schaaf, P., Grove, K., Tomasso, V., Ochoa, H., Liu, Y. V., Chen, Y. I., Reaven, G. 2013; 36 (10): 3276-3282

  Abstract

  OBJECTIVEThe aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD.RESEARCH DESIGN AND METHODSWe randomized 68 older individuals (mean age, 58 ± 8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed.RESULTSEleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P = 0.26). Subjects who continued to use liraglutide (n = 24) lost twice as much weight as those using placebo (n = 27; 6.8 vs. 3.3 kg; P < 0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (-3.2 vs. 0.2 mmol/L; P < 0.001) and significantly (P ≤ 0.04) greater lowering of systolic blood pressure (-8.1 vs. -2.6 mmHg), fasting glucose (-0.5 vs. 0 mmol/L), and triglyceride (-0.4 vs. -0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. -0.9 bpm; P = 0.001).CONCLUSIONSThe addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.

  View details for DOI 10.2337/dc13-0354

  View details for PubMedID 23835684

• Beyond fasting plasma glucose: The association between coronary heart disease risk and postprandial glucose, postprandial insulin and insulin resistance in healthy, nondiabetic adults. Metabolism: clinical and experimental Bhat, S. L., Abbasi, F. A., Blasey, C., Reaven, G. M., Kim, S. H. 2013; 62 (9): 1223-1226

  Abstract

  Prediabetes is defined by elevations of plasma glucose concentration, and is aimed at identifying individuals at increased risk of type 2 diabetes and coronary heart disease (CHD). However, since these individuals are also insulin resistant and hyperinsulinemic, we evaluated the association between several facets of carbohydrate metabolism and CHD risk profile in apparently healthy, nondiabetic individuals.Plasma glucose and insulin concentrations were measured before and at hourly intervals for eight hours after two test meals in 281 nondiabetic individuals. Insulin action was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. CHD risk was assessed by measurements of blood pressure and fasting lipoprotein profile.For purposes of analysis, the population was divided into tertiles, and the results demonstrated that the greater the 1) fasting plasma glucose (FPG) concentration, 2) incremental plasma insulin response to meals, and 3) SSPG concentration, the more adverse the CHD risk profile (p<0.05). In contrast, the CHD risk profile did not significantly worsen with increases in the incremental plasma glucose response to meals.In nondiabetic individuals, higher FPG concentrations, accentuated daylong incremental insulin responses to meals, and greater degrees of insulin resistance are each associated with worse CHD risk profile (higher blood pressures, higher triglycerides, and lower high density lipoprotein cholesterol concentrations). Interventional efforts aimed at decreasing CHD in such individuals should take these abnormalities into consideration.

  View details for DOI 10.1016/j.metabol.2013.04.012

  View details for PubMedID 23809477

• Liraglutide for Overweight, Older Individuals With Prediabetes Kim, S., Abbasi, F., Lamendola, C., Liu, A., Ariel, D., Schaaf, P., Grove, K., Reaven, G. AMER DIABETES ASSOC. 2013: A260

  View details for Web of Science ID 000209473601328

• Relationship between Insulin Resistance and Coronary Artery Calcium in Young Men and Women PLOS ONE Sung, K., Choi, J., Gwon, H., Choi, S., Kim, B., Kwag, H. J., Kim, S. H. 2013; 8 (1)

  Abstract

  The gender disparity in cardiovascular disease (CVD) risk is greatest between young men and women. However, the causes of that are not fully understood. The objective of this study was to evaluate the relationship between insulin resistance and the presence of coronary artery calcium (CAC) to identify risk factors that may predispose young men and women to CVD.Insulin resistance and CVD risk factors were examined in 8682 Korean men and 1829 women aged 30-45 years old. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR), and CAC was measured using computed tomography. Women were less likely to be insulin resistant (upper quartile of HOMA-IR, 18% vs. 27%, p<0.001) and had a lower prevalence of CAC (1.6% vs. 6.4%, p<0.001). Even when equally insulin resistant men and women were compared, women continued to have lower prevalence of CAC (3.1% vs. 7.2%, p = 0.004) and a more favorable CVD risk profile. Finally, after adjustment for traditional CVD risk factors, insulin resistance remained an independent predictor of CAC only in men (p = 0.03).Young women have a lower risk for CVD and a lower CAC prevalence compared with men. This favorable CVD risk profile in women appears to occur regardless of insulin sensitivity. Unlike men, insulin resistance was not a predictor of CAC in women in this cohort. Therefore, insulin resistance has less impact on CVD risk and CAC in young women compared with men, and insulin resistance alone does not explain the gender disparity in CVD risk that is observed at an early age.

  View details for DOI 10.1371/journal.pone.0053316

  View details for Web of Science ID 000313682700025

  View details for PubMedID 23341938

  View details for PubMedCentralID PMC3547016

• Metabolic syndrome, insulin resistance and kidney function in non-diabetic individuals NEPHROLOGY DIALYSIS TRANSPLANTATION Johns, B. R., Pao, A. C., Kim, S. H. 2012; 27 (4): 1410-1415

  Abstract

  Metabolic syndrome has been recently identified as a risk factor for chronic kidney disease (CKD). Since the five individual components of the metabolic syndrome have also been identified as risk factors for CKD, the metabolic syndrome diagnosis may represent an aggregate of CKD risk factors. On the other hand, the components of the metabolic syndrome are also associated with insulin resistance, which may directly mediate the increased CKD risk.This study was a cross-sectional evaluation of the relationship between metabolic syndrome, insulin resistance and estimated glomerular filtration rate (eGFR) in 574 non-diabetic individuals. Insulin resistance was directly quantified using the insulin suppression test, and the metabolic syndrome components were measured. eGFR was calculated using the three validated estimation equations: the Chronic Kidney Disease Epidemiology Collaboration equation, the Mayo quadratic equation and the Modification of Diet in Renal Disease study equation.While CKD prevalence was higher and mean eGFR was lower in individuals who met the metabolic syndrome criteria compared with those who did not, we did not observe a significant relationship between insulin resistance and eGFR. Of all of the components of the metabolic syndrome, only hypertension was significantly associated with CKD prevalence [odds ratio (95% confidence interval), 3.5 (1.2-10.1), P=0.02].Although CKD is more common among individuals with the metabolic syndrome, insulin resistance is not a common factor.

  View details for DOI 10.1093/ndt/gfr498

  View details for Web of Science ID 000302310700022

  View details for PubMedID 21908415

  View details for PubMedCentralID PMC3315670

• Measurement of insulin action: a tribute to Sir Harold Himsworth DIABETIC MEDICINE Kim, S. H. 2011; 28 (12): 1487-1493

  Abstract

  Sir Harold Himsworth was a renowned clinician and researcher. Among his myriad of accomplishments, he was the first to differentiate diabetes mellitus into 'insulin-sensitive' and 'insulin-insensitive' forms. To help distinguish these two types, he developed the first test to measure insulin sensitivity, the insulin-glucose test. This article reviews Himsworth's pioneer methods and subsequent advances in the measurement of insulin action. The advantages and limitations of commonly used methods to assess insulin sensitivity are also examined.

  View details for DOI 10.1111/j.1464-5491.2011.03409.x

  View details for Web of Science ID 000297118400009

  View details for PubMedID 21838770

• Plasma glucose and insulin responses to mixed meals: Impaired fasting glucose re-visited DIABETES & VASCULAR DISEASE RESEARCH BHAT, S. L., Abbasi, F., Blasey, C., Reaven, G. M., Kim, S. H. 2011; 8 (4): 271-275

  Abstract

  In individuals with varying glucose tolerance, glucose and insulin comparisons are usually made based on response to oral glucose challenge. However, an oral glucose tolerance test may not reflect daylong glucose and insulin excursions in response to meals. To better understand individuals with impaired fasting glucose (IFG), we compared insulin action as well as plasma glucose and insulin responses to mixed meals in individuals with normal fasting glucose (NFG; n = 141) and IFG (n = 148) concentrations.Insulin action was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Plasma glucose and insulin concentrations were measured before and hourly after two mixed meals.SSPG concentrations were significantly higher in the IFG group (11.8 ± 3.6 vs. 9.1 ± 3.8 mmol/l). Mean hourly daylong glucose (6.4 ± 0.07 vs. 5.5 ± 0.04 mmol/l) and insulin (390 ± 20 vs. 279 ± 15 pmol/l) concentrations were also higher in those with IFG (p < 0.001). Daylong incremental meal-stimulated glucose response, however, was comparable (p = 0.77) in the two groups, whereas the incremental insulin response was 44% higher in the IFG group.Although individuals are currently defined as having IFG based on fasting plasma glucose concentration, our data show that these individuals with IFG also are insulin resistant and have higher daylong insulin concentrations.

  View details for DOI 10.1177/1479164111421036

  View details for Web of Science ID 000296976700004

  View details for PubMedID 21933842

• Interrelationship between Fatty Liver and Insulin Resistance in the Development of Type 2 Diabetes JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Sung, K., Kim, S. H. 2011; 96 (4): 1093-1097

  Abstract

  Although fatty liver and insulin resistance are known to be associated, the relationship between the two in the development of type 2 diabetes mellitus (T2DM) is unclear.We investigated the 5-yr risk of developing T2DM in individuals diagnosed with fatty liver using ultrasound and stratified by insulin sensitivity using quartiles of fasting insulin concentration.We examined the clinical and laboratory data of 11,091 Koreans who had a medical evaluation including fasting insulin concentration and abdominal ultrasound at baseline and had a follow-up after 5 yr.At baseline, 27% of the population had fatty liver. Almost half (47%) of the individuals with fatty liver had baseline insulin concentration in the highest quartile compared with 17% in those without fatty liver (P < 0.001). Regardless of baseline insulin concentration, individuals with fatty liver had significantly (P < 0.001) more baseline clinical and metabolic abnormalities, including higher glucose and triglyceride concentration and lower high-density lipoprotein cholesterol concentration. In addition, regardless of baseline insulin concentration, individuals with fatty liver had a significantly increased risk for incident T2DM compared with those without fatty liver [crude odds ratio, 5.05 (95% confidence interval, 2.08-12.29) in the lowest insulin quartile and 6.34 (3.58-11.21) in the highest quartile]. In individuals in the highest insulin quartile, the odds ratio for developing T2DM remained significant even after multivariate adjustment including baseline glucose concentration [2.42 (1.23-4.75)].Although associated with insulin resistance, fatty liver diagnosed by ultrasound appears to independently increase the risk of T2DM.

  View details for DOI 10.1210/jc.2010-2190

  View details for Web of Science ID 000289242800053

  View details for PubMedID 21252243

  View details for PubMedCentralID PMC3070249

• METABOLIC SYNDROME, INSULIN RESISTANCE, AND KIDNEY FUNCTION IN NONDIABETIC INDIVIDUALS Johns, B., Pao, A., Kim, S. W B SAUNDERS CO-ELSEVIER INC. 2011: A76

  View details for Web of Science ID 000288657100239

• Relationship between insulin resistance and C-reactive protein in a patient population treated with second generation antipsychotic medications INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY Kim, S. H., Reaven, G., Lindley, S. 2011; 26 (1): 43-47

  Abstract

  C-reactive protein (CRP) is an inflammatory marker associated with obesity, insulin resistance, and cardiovascular disease. A recent study found CRP levels to be higher in individuals treated with certain antipsychotic medications such as olanzapine; however, it is not clear whether this is associated directly with drug intake or indirectly with drug-associated weight gain and insulin resistance. The objective of this study was to explore the potential predictors of CRP including insulin resistance, components of the metabolic syndrome, psychiatric diagnosis, and antipsychotic medication in patients treated with antipsychotics. Sixty-four outpatients without diabetes being treated with a single second generation antipsychotic medication had direct measurements of insulin resistance at the end of a 180-min infusion of glucose, insulin, and octreotide (insulin suppression test) as well as components of the metabolic syndrome. Insulin resistance was the strongest predictor of CRP (r=0.52, P<0.001). When adjusted for insulin resistance, there was no significant relationship between CRP and any of the components of the metabolic syndrome criteria, specific drug treatment or psychiatric diagnoses. In conclusion, insulin resistance is strongly associated with CRP levels and likely contributes to earlier associations between CRP and certain antipsychotic treatments.

  View details for DOI 10.1097/YIC.0b013e3283400cd3

  View details for Web of Science ID 000285083700005

  View details for PubMedID 20861740

• Obesity and Insulin Resistance: An Ongoing Saga DIABETES Kim, S. H., Reaven, G. 2010; 59 (9): 2105-2106

  View details for DOI 10.2337/db10-0766

  View details for Web of Science ID 000281612000004

  View details for PubMedID 20805385

  View details for PubMedCentralID PMC2927930

• Glucose-Stimulated Insulin Secretion in Gastric Bypass Patients with Hypoglycemic Syndrome: No Evidence for Inappropriate Pancreatic beta-cell Function OBESITY SURGERY Kim, S. H., Abbasi, F., Lamendola, C., Reaven, G. M., McLaughlin, T. 2010; 20 (8): 1110-1116

  Abstract

  Roux-en-Y gastric bypass surgery (RYGB) has been associated with a hypoglycemic syndrome characterized by postprandial hypoglycemia and hyperinsulinemia. The syndrome is believed to occur due to insulin hypersecretion from either pancreatic beta-cell hyperplasia or hyperfunction.Eight RYGB patients with hypoglycemic syndrome had insulin secretion rates determined during a 240-min graded intravenous glucose infusion. They were compared to 34 nondiabetic, nonsurgical individuals who were divided based on their insulin sensitivity status as measured by the insulin suppression test: insulin-sensitive (n = 8), insulin intermediate (n = 7), and insulin-resistant (n = 19).RYGB patients had insulin concentrations and HOMA-IR similar to the insulin-sensitive reference group. In addition, integrated insulin secretion rates were comparable to the insulin-sensitive group and significantly lower than the insulin intermediate (p

  View details for DOI 10.1007/s11695-010-0183-2

  View details for Web of Science ID 000280746100304

  View details for PubMedID 20665189

• Relationship between body mass index and insulin resistance in patients treated with second generation antipsychotic agents JOURNAL OF PSYCHIATRIC RESEARCH Kim, S. H., Nikolics, L., Abbasi, F., Lamendola, C., Link, J., Reaven, G. M., Lindley, S. 2010; 44 (8): 493-498

  Abstract

  Second generation antipsychotics (SGAs) can increase weight gain and weight-induced insulin resistance. Recent studies have suggested weight-independent effects of certain SGAs on insulin resistance; however the magnitude of these effects and the relationship between BMI and insulin resistance in patients on SGAs are not established. To evaluate, the relationship between body mass index (BMI) and insulin resistance in 54 patients being stably treated with olanzapine (n=19), risperidone (n=16), or aripiprazole (n=19) was compared with data from a large reference population (n=201) not on SGAs. Insulin resistance was directly quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. The relationship between BMI and SSPG was similar between the SGA (r=0.58) and the reference population (r=0.50). When SSPG was standardized based on expected values for the reference population, patients on olanzapine had a higher degree of insulin resistance (mean z-score+/-SD, 0.68+/-0.9) than expected for level of BMI compared with those on aripiprazole (-0.25+/-1) and risperidone (-0.3+/-0.9), F(2,51)=6.28 (p=0.004). Thus, olanzapine group was 0.76 SD above the reference population or in the 78 percentile for insulin resistance. SSPG was correlated with fasting plasma insulin concentration (0.78 (0.64-0.87), p<0.001) but not fasting glucose concentration (0.15 (-0.13-0.40), p=0.29). In conclusion, BMI contributes a quarter to a third of the variance in insulin resistance in the SGA population similar to the reference population. Olanzapine also appears to have an independent effect on insulin resistance that is above and beyond obesity.

  View details for DOI 10.1016/j.jpsychires.2009.11.007

  View details for Web of Science ID 000278653500002

  View details for PubMedID 19962157

  View details for PubMedCentralID PMC2873096

• Utility of Homeostasis Model Assessment of beta-Cell Function in Predicting Diabetes in 12,924 Healthy Koreans Response DIABETES CARE Kim, S. H., Sung, K., Reaven, G. M. 2010; 33 (5): E72-E72

  View details for DOI 10.2337/dc10-0283

  View details for Web of Science ID 000208521200008

• Utility of Homeostasis Model Assessment of beta-Cell Function in Predicting Diabetes in 12,924 Healthy Koreans DIABETES CARE Sung, K., Reaven, G. M., Kim, S. H. 2010; 33 (1): 200-202

  Abstract

  It is unclear how well homeostasis model assessment of beta-cell function (HOMA-beta) predicts diabetes development beyond its components, especially glucose.We identified 12,924 nondiabetic Koreans who had fasting plasma glucose and insulin concentrations measured in 2003 and again in 2008. To minimize the impact of differences in baseline glucose concentration, individuals were divided into three glucose categories: normal fasting glucose (NFG, glucose <5.6 mmol/l), impaired fasting glucose (IFG-100) (5.6-6.0 mmol/l), and IFG-110 (6.1-6.9 mmol/l).Diabetes developed in 29% of individuals in the IFG-110 group, compared with 5% in IFG-100 and 0.3% in NFG groups. Within each glucose category, those who progressed to diabetes had higher baseline glucose concentrations (P < or = 0.04). Baseline HOMA-beta, however, was not lower but higher in individuals who developed diabetes in the NFG group (P = 0.009) and similar in the IFG-100 and IFG-110 groups.These data question the utility of using HOMA-beta to predict the development of diabetes.

  View details for DOI 10.2337/dc09-1070

  View details for Web of Science ID 000273622200040

  View details for PubMedID 19808927

  View details for PubMedCentralID PMC2797973

• Plasma Glucose and Insulin Regulation Is Abnormal Following Gastric Bypass Surgery with or Without Neuroglycopenia OBESITY SURGERY Kim, S. H., Liu, T. C., Abbasi, F., Lamendola, C., Morton, J. M., Reaven, G. M., McLaughlin, T. L. 2009; 19 (11): 1550-1556

  Abstract

  Enhanced insulin sensitivity is commonly seen following Roux-en-Y gastric bypass surgery (RYGB) whereas symptomatic hypoglycemia post-RYGB seems to occur infrequently. It is unclear how different plasma glucose and insulin responses are in patients with symptomatic hypoglycemia (SX-RYGB) versus those who remain asymptomatic (ASX-RYGB), nor when compared with non-surgical controls with varying degrees of insulin sensitivity.Plasma glucose and insulin concentrations were determined following a 75-g oral glucose challenge in five groups: symptomatic and asymptomatic patients following RYGB (n = 9 each) and overweight/obese controls, divided into three subgroups (n = 30 each) on the basis of degree of insulin sensitivity measured by the insulin suppression test.SX-RYGB group had higher 30-min glucose after oral glucose compared with the ASX-RYGB group (p = 0.04). The two groups did not differ in peak glucose and insulin concentrations, nadir glucose concentration, or insulin-to-glucose ratio 30 min after oral glucose. These values were significantly different from the three control groups, and peak insulin concentrations post-RYGB were increased at every degree of insulin sensitivity as compared with the control groups.Plasma glucose and insulin responses to oral glucose in patients with symptomatic hypoglycemia post-RYGB are minimally different when compared to individuals who remain asymptomatic, and both groups demonstrate hyperinsulinemia out of proportion to their degree of insulin sensitivity.

  View details for DOI 10.1007/s11695-009-9893-8

  View details for Web of Science ID 000271282900014

  View details for PubMedID 19557485

• FACTORS ASSOCIATED WITH IMPAIRMENT OF INSULIN SECRETION IN HCV INFECTION: IMPACT OF LATINO ETHNICITY Kim, S. H., Ayala, C., Maher, J. J., Khalili, M. JOHN WILEY & SONS INC. 2009: 921A

  View details for Web of Science ID 000270456001334

• Plasma Glucose and Insulin Regulation Is Abnormal Following Gastric Bypass Surgery with or without Neuroglycopenia Kim, S. H., Liu, T. C., Abbasi, F., Lamendola, C., Morton, J. M., Reaven, G. M., McLaughlin, T. AMER DIABETES ASSOC. 2009: A10

  View details for Web of Science ID 000266352600037

• Effect of moderate alcoholic beverage consumption on insulin sensitivity in insulin-resistant, nondiabetic individuals METABOLISM-CLINICAL AND EXPERIMENTAL Kim, S. H., Abbasi, F., Lamendola, C., Reaven, G. M. 2009; 58 (3): 387-392

  Abstract

  Although moderate alcohol consumption has been associated with a decrease in plasma insulin concentrations, relatively few studies have been conducted to evaluate the effect of alcohol on insulin sensitivity, particularly in nondiabetic, insulin-resistant individuals. Because enhanced insulin sensitivity could contribute to the reported association between moderate alcohol consumption and reduced risk of heart disease and diabetes, we believed it is important to address this issue. Consequently, we evaluated the ability of moderate alcohol consumption to improve insulin sensitivity, as measured by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test, in 20 nondiabetic, insulin-resistant individuals. Measurements were made of SSPG, glucose, insulin, and lipoprotein concentrations before and after consuming 30 g of alcohol for 8 weeks, either as vodka (n = 9) or red wine (n = 11). The SSPG concentrations (insulin resistance) decreased by approximately 8% in the total group (P = .08), and high-density lipoprotein cholesterol concentration increased by a mean of 0.09 mmol/L (P = .02). Trends were similar in individuals who consumed vodka or red wine. Men tended to have greater decline in SSPG and increase in high-density lipoprotein cholesterol compared with women. There were no other metabolic changes in fasting plasma glucose, insulin, and triglyceride concentrations. These data demonstrate that 8 weeks of moderate alcohol consumption had minimal impact on enhancing insulin sensitivity in nondiabetic, insulin-resistant individuals, raising questions as to the role, if any, of improved insulin sensitivity in the purported clinical benefits associated with moderate alcohol consumption.

  View details for DOI 10.1016/j.metabol.2008.10.013

  View details for Web of Science ID 000263882400019

  View details for PubMedID 19217456

  View details for PubMedCentralID PMC2676844

• Insulin resistance and hyperinsulinemia - You can't have one without the other DIABETES CARE Kim, S. H., Reaven, G. M. 2008; 31 (7): 1433-1438

  Abstract

  Recently, it has been suggested that insulin resistance and hyperinsulinemia can exist in isolation and have differential impacts on cardiovascular disease (CVD). To evaluate this suggestion, we assessed the degree of discordance between insulin sensitivity and insulin response in a healthy, nondiabetic population.Insulin sensitivity was quantified by determining the steady-state plasma glucose (SSPG) concentration during an insulin suppression test in 446 individuals. The integrated insulin response was calculated after a 75-g oral glucose challenge. We analyzed the correlation between insulin resistance and insulin response in addition to quantifying the proportion in quartiles of insulin response by quartiles of insulin sensitivity. Then we compared CVD risk factors between individuals within the same insulin sensitivity quartile but within different insulin response quartiles to evaluate the differential clinical impact of insulin resistance and hyperinsulinemia.Insulin resistance and insulin response were highly correlated (r = 0.76, P < 0.001). A majority (95%) of the most insulin-resistant individuals (top SSPG quartile) were either in the highest insulin response quartile (71%) or second highest (24%). Similarly, 92% of the most insulin-sensitive individuals (lowest SSPG quartile) were in the lowest two insulin response quartiles. There were minimal differences in CVD risk factors between individuals with different insulin responses but within the same insulin sensitivity quartile.Although not perfectly related, insulin resistance and hyperinsulinemia rarely exist in isolation in a nondiabetic population. It is difficult to discern an independent impact of hyperinsulinemia on CVD risk factors associated with insulin resistance.

  View details for DOI 10.2337/dc08-0045

  View details for Web of Science ID 000257421000032

  View details for PubMedID 18594063

  View details for PubMedCentralID PMC2453638

• Insulin resistance and hyperinsulinemia: You can't have one without the other Kim, S. H., Reaven, G. M. AMER DIABETES ASSOC. 2008: A368

  View details for Web of Science ID 000256612001568

• Effect of 8 weeks of red wine and vodka on insulin sensitivity in insulin resistant individuals Kim, S. H., Reaven, G. M. AMER DIABETES ASSOC. 2008: A102

  View details for Web of Science ID 000256612000343

• Isolated Impaired Fasting Glucose and Peripheral Insulin Sensitivity Not a simple relationship DIABETES CARE Kim, S. H., Reaven, G. M. 2008; 31 (2): 347-352

  Abstract

  In a recent consensus statement, the American Diabetes Association (ADA) concluded that individuals with impaired fasting glucose (IFG) have "normal muscle insulin sensitivity." To subject this conclusion to further validation, we evaluated the relationship between glucose tolerance categories and peripheral insulin sensitivity in a large nondiabetic population.Insulin sensitivity was directly quantified by determining the steady-state plasma glucose (SSPG) concentration during an insulin suppression test in 446 nondiabetic individuals divided into four groups: normal glucose tolerance (NGT, n = 318), isolated IFG (n = 63), isolated impaired glucose tolerance (IGT, n = 33), and combined IFG and IGT (IFG/IGT, n = 32).Insulin sensitivity was significantly different in all three groups with pre-diabetes (IFG, IGT, IFG/IGT) as compared with NGT (P < 0.05). Using tertiles of SSPG concentration in the NGT group as operational definitions of insulin resistance (highest tertile) and insulin sensitivity (lowest tertile), there was considerable heterogeneity within the pre-diabetic groups. Thus, 57% of IFG individuals were insulin resistant, and 13% were insulin sensitive. The IFG/IGT group was most homogeneous, with 94% classified as insulin resistant and only 3% as insulin sensitive.Peripheral insulin sensitivity varies considerably in nondiabetic individuals, with IFG individuals showing the most heterogeneity within the pre-diabetes group. We believe that this heterogeneity in insulin sensitivity, and the relatively few patients in whom insulin sensitivity has been measured directly in the past, explain the discrepancy between our findings and those of the recent ADA consensus statement.

  View details for DOI 10.2337/dc07-1574

  View details for Web of Science ID 000266563300033

  View details for PubMedID 18000184

• Relationship among alcohol, body weight, and cardiovascular risk factors in 27,030 Korean men DIABETES CARE Sung, K., Kim, S. H., Reaven, G. M. 2007; 30 (10): 2690-2694

  Abstract

  Recent studies suggest a lower risk for overweight/obesity in moderate alcohol drinkers. However, the validity of this relationship and its impact on the putative benefits of alcohol consumption on cardiovascular disease (CVD) risk has not been well evaluated.We assessed the impact of BMI on the relationship between alcohol consumption and CVD risk factors (blood pressure, lipid panel, and glucose and insulin concentrations) in 27,030 healthy Korean men with no major comorbidities or medication intake seen in a large urban Korean hospital.BMI and overweight prevalence increased linearly with alcohol intake (P < 0.001). Alcohol intake was also positively associated with blood pressure and triglyceride, HDL, and fasting glucose concentrations (P < 0.001) and negatively associated with LDL and insulin concentrations (P < 0.001). With nondrinkers as the reference group, the odds ratio for having insulin in the top quartile also declined linearly when adjusted for age, BMI, smoking, and exercise, with the heaviest drinkers (>40 g/day) having an odds ratio of 0.71 (95% CI 0.62-0.82) (P < 0.001). The relationship between alcohol and CVD risk factors was similar in normal-weight and overweight individuals.Alcohol intake is associated with increasing BMI and several metabolic abnormalities, including higher fasting glucose. Paradoxically, it is also associated with lower insulin concentrations. The clinical significance of these findings needs further investigation.

  View details for DOI 10.2337/dc07-0315

  View details for Web of Science ID 000250223400056

  View details for PubMedID 17623829

• Metabolic impact of switching antipsychotic therapy to aripiprazole after weight gain - A pilot study JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY Kim, S. H., Ivanova, O., Abbasi, F. A., Lamendola, C. A., Reaven, G. M., Glick, I. D. 2007; 27 (4): 365-368

  Abstract

  Switching antipsychotic regimen to agents with low weight gain potential has been suggested in patients who gain excessive weight on their antipsychotic therapy. In an open-label pilot study, we evaluated the metabolic and psychiatric efficacy of switching to aripiprazole in 15 (9 men, 6 women) outpatients with schizophrenia who had gained at least 10 kg on their previous antipsychotic regimen. Individuals had evaluation of glucose tolerance, insulin resistance (insulin suppression test), lipid concentrations, and psychiatric status before and after switching to aripiprazole for 4 months. A third of the individuals could not psychiatrically tolerate switching to aripiprazole. In the remaining individuals, psychiatric symptoms significantly improved with decline in Clinical Global Impression Scale (by 26%, P = 0.015) and Positive and Negative Syndrome Scale (by 22%, P = 0.023). Switching to aripiprazole did not alter weight or metabolic outcomes (fasting glucose, insulin resistance, and lipid concentrations) in the patients of whom 73% were insulin resistant and 47% had impaired or diabetic glucose tolerance at baseline. In conclusion, switching to aripiprazole alone does not ameliorate the highly prevalent metabolic abnormalities in the schizophrenia population who have gained weight on other second generation antipsychotic medications.

  View details for DOI 10.1097/JCP.0b013e3180a9076c

  View details for Web of Science ID 000248062400007

  View details for PubMedID 17632220

• The relationship between insulin resistance and dyslipidaemia in cigarette smokers DIABETES OBESITY & METABOLISM Farin, H. M., Abbasi, F., Kim, S. H., Lamendola, C., McLaughlin, T., Reaven, G. M. 2007; 9 (1): 65-69

  Abstract

  Considerable evidence shows that cigarette smokers tend to have the dyslipidemic pattern of high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations, a highly atherogenic lipoprotein profile also typical of the insulin-resistant state even in the absence of cigarette smoking. However, because cigarette smokers are frequently insulin resistant, it is unclear if this dyslipidaemia is secondary to smoking, per se, or simply to the fact that smokers tend to be insulin resistant. The present study was initiated to determine whether this dyslipidaemia prevalent in cigarette smokers and characteristic of insulin-resistant individuals is a function of cigarette smoking or of insulin resistance.As measured using vertical auto profile-II methodology, the lipid and lipoprotein concentrations were compared in 34 cigarette smokers divided into insulin-sensitive and insulin-resistant subgroups. The two groups were similar in age and body mass index, differing only in their insulin-mediated glucose uptake as quantified by the steady-state plasma glucose concentration determined during the insulin suppression test.While levels of TG and very low-density lipoprotein cholesterol (VLDL-C) were significantly elevated in insulin-resistant cigarette smokers, total cholesterol (C), low-density lipoprotein cholesterol (LDL-C), narrow-density (ND) LDL-C, intermediate-density lipoprotein-C (IDL-C), HDL-C and non-HDL-C were not different in the two groups. The insulin-resistant smokers also had a preponderance of small, dense LDL particles, while the reverse was true of the insulin-sensitive cigarette smokers.These data suggest that the dyslipidaemia previously attributed to smoking occurs primarily in those smokers who are also insulin resistant.

  View details for DOI 10.1111/j.1463-1326.2006.00574.x

  View details for Web of Science ID 000242781700008

  View details for PubMedID 17199720

• Comparison of the 1997 and 2003 American Diabetes Association classification of impaired fasting glucose - Impact on prevalence of impaired fasting glucose, coronary heart disease risk factors, and coronary heart disease in a community-based medical practice JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kim, S. H., Chunawala, L., Linde, R., Reaven, G. M. 2006; 48 (2): 293-297

  Abstract

  The goals of this study were to assess the effect of the 2003 American Diabetes Association definition of impaired fasting glucose (IFG) on prevalence of IFG, coronary heart disease (CHD) risk factors, and CHD compared with the 1997 IFG definition.Although IFG is viewed as increasing CHD risk, this association is unclear and has not been well studied after changing the IFG criterion, especially in a clinical practice setting.This was a cross-sectional evaluation of 8,295 members (3,763 men and 4,532 women) of a community medical center who were between the ages of 30 and 69 years, without a history of diabetes mellitus, and who had available measurements of fasting plasma glucose and lipid concentrations within the past 2 years. The prevalence of IFG, CHD risk factors, and CHD with the 1997 and 2003 IFG definition was compared.The prevalence of IFG increased from 8% to 35% with the 2003 criterion. Individuals with glucose of 100 to 109 mg/dl had lower prevalence of most CHD risk factors (hypertension, triglyceride > or =150 mg/dl, high-density lipoprotein cholesterol <40 mg/dl, meeting 2 components of the metabolic syndrome criteria, CHD risk > or =10% by Framingham score) compared with individuals with glucose 110 to 125 mg/dl. Individuals identified with the 2003 IFG definition did not have an increase in known CHD when adjusted for covariates (odds ratio 1.4 [95% confidence interval (CI) 0.7 to 2.3] vs. 3.2 [95% CI 1.8 to 5.9]).One-third of the population has IFG with the 2003 definition, yet many of these individuals do not have increased prevalence of CHD risk factors or CHD.

  View details for DOI 10.1016/j.jacc.2006.03.043

  View details for Web of Science ID 000239080000011

  View details for PubMedID 16843178

• Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals DIABETES Kim, S. H., Abbasi, F., Chu, J. W., McLaughlin, T. L., Lamendola, C., Polonsky, K. S., Reaven, G. M. 2005; 54 (8): 2447-2452

  Abstract

  Compensatory hyperinsulinemia permitting insulin-resistant individuals to maintain normal glucose tolerance is associated with a left shift in the glucose-stimulated insulin secretion rate (GS-ISR) dose-response curve and decrease in the insulin metabolic clearance rate (I-MCR). To see whether these changes would reverse with improvement in insulin sensitivity, 14 nondiabetic insulin-resistant subjects received rosiglitazone for 12 weeks (4 mg daily for 4 weeks and then 8 mg daily for 8 weeks). Insulin-mediated glucose uptake was quantified by measuring the steady-state plasma glucose concentration during the insulin suppression test. GS-ISR and I-MCR were determined during a 240-min graded intravenous glucose infusion. I-MCR was also calculated during the insulin suppression test. After rosiglitazone treatment, insulin sensitivity improved with significant fall in steady-state plasma glucose (means +/- SE from 13.5 +/- 0.62 to 9.8 +/- 1.02 mmol/l, P < 0.001). In response, the integrated GS-ISR decreased by 21% (P < 0.001), with a right shift in the dose-response curve. Calculated I-MCR increased by 34% (P = 0.008) during the insulin suppression test and by 21% (P = 0.03) during the graded glucose infusion. In conclusion, enhanced insulin sensitivity in rosiglitazone-treated nondiabetic insulin-resistant individuals was associated with a shift to the right in the GS-ISR dose-response curve and an increase in I-MCR.

  View details for Web of Science ID 000230869500023

  View details for PubMedID 16046313

• The metabolic syndrome: one step forward, two steps back. Diabetes & vascular disease research Kim, S. H., Reaven, G. M. 2004; 1 (2): 68-75

  Abstract

  Individuals with insulin resistance are at increased risk of glucose intolerance, dyslipidaemia and essential hypertension. In 1988, it was proposed that this cluster of abnormalities associated with insulin resistance identifies individuals at increased risk for cardiovascular disease. Recently, in an effort to raise awareness of this problem, both the World Health Organisation (WHO) and the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program have suggested a set of clinical criteria to diagnose individuals with what they both refer to as the metabolic syndrome. Although using the same term, the two groups have different goals for creating this diagnosis and different criteria to identify individuals, which relate to their different institutional goals. This review critically evaluates the similarities and differences between the two groups' concepts of the metabolic syndrome and questions the clinical utility of making the diagnosis with either set of definitions.

  View details for PubMedID 16304726

• Impact of degree of obesity on surrogate estimates of insulin resistance DIABETES CARE Kim, S. H., Abbasi, F., Reaven, G. M. 2004; 27 (8): 1998-2002

  Abstract

  To evaluate the role of adiposity in the relationship between specific and surrogate estimates of insulin-mediated glucose uptake (IMGU) in a large nondiabetic population.Healthy volunteers were classified by BMI into normal weight (<25.0 kg/m(2), n = 208), overweight (25.0-29.9 kg/m(2), n = 168), and obese (>or=30.0 kg/m(2), n = 109) groups. We then assessed how differences in BMI affect the correlation between steady-state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide, glucose, and insulin (a specific measure of IMGU) and five surrogate estimates: fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and area under the curve for insulin in response to oral glucose (I-AUC).Correlation coefficients (r values) between SSPG and surrogate measures of IMGU were all significant (P < 0.05), but the magnitude varied between BMI groups: normal weight: fasting plasma glucose 0.20, fasting plasma insulin 0.33, HOMA-IR 0.36, QUICKI -0.33, and I-AUC 0.69; overweight: fasting plasma glucose 0.19, fasting plasma insulin 0.55, HOMA-IR 0.55, QUICKI -0.54, and I-AUC 0.72; and obese: fasting plasma glucose 0.40, fasting plasma insulin 0.56, HOMA-IR 0.60, QUICKI -0.61, and I-AUC 0.69.The relationship between direct and surrogate estimates of IMGU varies with BMI, with the weakest correlations seen in the normal-weight group and the strongest in the obese group. In general, I-AUC is the most useful surrogate estimate of IMGU in all weight groups. Fasting plasma insulin, HOMA-IR, and QUICKI provide comparable information about IMGU. Surrogate estimates of IMGU based on fasting insulin and glucose account for no more than 13% of the variability in insulin action in the normal-weight group, 30% in the overweight group, and 37% in the obese group.

  View details for Web of Science ID 000223026200023

  View details for PubMedID 15277430

• Carbonated beverage consumption and bone mineral density among older women: The Rancho Bernardo study AMERICAN JOURNAL OF PUBLIC HEALTH Kim, S. H., Morton, D. J., BARRETTCONNOR, E. L. 1997; 87 (2): 276-279

  Abstract

  The association between carbonated beverage consumption and bone mineral density was examined in a community-based cohort of older White women.One thousand women 44 to 98 years of age had bone mineral density measured at four sites and provided medical and behavioral histories, including type and quantity of carbonated beverages consumed.Bone mineral density levels were not associated with intake of any type of carbonated beverage after adjustment for age, obesity, calcium intake, exercise, and current use of tobacco and alcohol, thiazides, estrogen, or thyroid hormone.Modest intake of carbonated beverages does not appear to have adverse effects on bone mineral density in older women.

  View details for Web of Science ID A1997WN49300026

  View details for PubMedID 9103110

  View details for PubMedCentralID PMC1380807