Bio


Dr. Steffner specializes in the evaluation, diagnosis, and treatment of bone and soft tissue tumors in pediatric and adult patients. This includes primary bone and soft tissue sarcomas, locally active conditions such as giant cell tumor, aneurysmal bone cyst, and chondroblastoma, as well as impending and pathologic fractures from metastatic carcinoma, multiple myeloma, and lymphoma. He works closely with the multidisciplinary sarcoma group at the Stanford Cancer Center to provide coordinated, highly specialized treatment strategies.

Research interests include circulating tumor DNA in bone and soft tissue sarcomas, local drug delivery, establishment of a national bone and soft tissue registry, and collaborative clinical studies on imaging and soft tissue management.

Clinical Focus


  • Orthopaedic Surgery
  • Soft Tissue Sarcoma
  • Bone Sarcoma
  • Pediatric Sarcoma

Academic Appointments


Boards, Advisory Committees, Professional Organizations


  • Board Certified, American Board of Orthopaedic Surgery (ABOS) (2015 - Present)
  • Fellow, American Academy of Orthopaedic Surgeons (AAOS) (2015 - Present)
  • Member, Children’s Oncology Group (COG) (2015 - Present)
  • Faculty Member, AO Trauma (2013 - Present)
  • Member, Musculoskeletal Tumor Society (MSTS) (2013 - Present)

Professional Education


  • Board Certification: American Board of Orthopaedic Surgery, Orthopaedic Surgery (2015)
  • Oncology Fellowship, University of Chicago, Chicago IL, Department of Orthopaedic Surgery (2013)
  • Trauma Fellowship, University of California-Davis, Sacramento CA, Department of Orthopaedic Surgery (2012)
  • Residency, University of Chicago, Chicago IL, Department of Orthopaedic Surgery (2011)
  • Doctor of Medicine, Wayne State School of Medicine, Detroit MI, Medicine (2006)

Clinical Trials


  • Phase 1 Study of SQ3370 in Patients With Advanced Solid Tumors Recruiting

    The purpose of this study is to evaluate the safety, tolerability, and preliminary efficacy of SQ3370 in patients with cancer (solid tumors).

    View full details

Graduate and Fellowship Programs


  • Oncology (Fellowship Program)

All Publications


  • Soft tissue pathology for the radiologist: a tumor board primer with 2020 WHO classification update. Skeletal radiology Kuhn, K. J., Cloutier, J. M., Boutin, R. D., Steffner, R., Riley, G. 2020

    Abstract

    Radiologists serve an important role in the diagnosis and staging of soft tissue tumors, often through participation in multidisciplinary tumor board teams. While an important function of the radiologist is to review pertinent imaging and assist in the differential diagnosis, a critical role is to ensure that there is concordance between the imaging and the pathologic diagnosis. This requires a basic understanding of the pathology of soft tissue tumors, particularly in the case of diagnostic dilemmas or incongruent imaging and histologic features. This work is intended to provide an overview of soft tissue pathology for the radiologist to optimize participation in multidisciplinary orthopedic oncology tumor boards, allowing for contribution to management decisions with expertise beyond image interpretation.

    View details for DOI 10.1007/s00256-020-03567-w

    View details for PubMedID 32743671

  • Anti-rotation pins for the compress implant do not increase risk of mechanical failure or impair osseointegration ANNALS OF JOINT Campbell, S. T., Steffner, R. J., Finlay, A., Mohler, D. G., Avedian, R. S. 2019; 4 (8)
  • Motor-sparing high-thoracic erector spinae plane block for proximal humerus surgery and total shoulder arthroplasty surgery: clinical evidence for differential peripheral nerve block? Canadian journal of anaesthesia = Journal canadien d'anesthesie Ma, W., Sun, L., Ngai, L., Costouros, J. G., Steffner, R., Boublik, J., Tsui, B. C. 2019

    View details for DOI 10.1007/s12630-019-01442-4

    View details for PubMedID 31290120

  • The Association of Financial Distress With Disability in Orthopaedic Surgery. The Journal of the American Academy of Orthopaedic Surgeons Mertz, K., Eppler, S. L., Thomas, K., Alokozai, A., Yao, J., Amanatullah, D. F., Chou, L., Wood, K. B., Safran, M., Steffner, R., Gardner, M., Kamal, R. N. 2019; 27 (11): e522–e528

    Abstract

    INTRODUCTION: Increased out-of-pocket costs have led to patients bearing more of the financial burden for their care. Previous work has shown that financial burden and distress can affect outcomes, symptoms, satisfaction, and adherence to treatment. We asked the following questions: (1) Does patients' financial distress correlate with disability in patients with nonacute orthopaedic conditions? (2) Do patient demographic factors affect this correlation?METHODS: We conducted a cross-sectional, observational study of new patients presenting to a multispecialty orthopaedic clinic with a nonacute orthopaedic complication. Patients completed a demographics questionnaire, the InCharge Financial Distress/Financial Well-Being Scale, and the Health Assessment Questionnaire Disability Index. Statistical analysis was done using Pearson's correlation.RESULTS: The mean score for financial distress was 4.10 (SD, 2.09; scale 1 [low distress] to 10 [high distress]; range, 1.13 to 10.0), and the mean disability score was 0.54 (SD, 0.65; scale 0 to 3; range, 0 to 2.75). A moderate positive correlation exists between financial distress and disability (r = 0.43; P < 0.01). Financial distress and disability were highest for poor, uneducated, Medicare patients.CONCLUSIONS: A moderate correlation exists between financial distress and disability in patients with nonacute orthopaedic conditions, particularly in patients with low socioeconomic status. Orthopaedic surgeons may benefit from identifying patients in financial distress and discussing the cost of treatment because of its association with disability and potentially inferior outcomes. Further investigation is needed to test whether decreasing financial distress decreases disability.LEVEL OF EVIDENCE: Level III prospective cohort.

    View details for DOI 10.5435/JAAOS-D-18-00252

    View details for PubMedID 31125323

  • Ferumoxytol Does Not Impact Standardized Uptake Values on PET/MR Scans. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Muehe, A. M., Yerneni, K., Theruvath, A. J., Thakor, A. S., Pribnow, A., Avedian, R., Steffner, R., Rosenberg, J., Hawk, K. E., Daldrup-Link, H. E. 2019

    Abstract

    Tumor response assessments on positron emission tomography (PET)/magnetic resonance imaging (MRI) scans require correct quantification of radiotracer uptake in tumors and normal organs. Historically, MRI scans have been enhanced with gadolinium (Gd)-based contrast agents, which are now controversial due to brain deposition. Recently, ferumoxytol nanoparticles have been identified as an alternative to Gd-based contrast agents because they provide strong tissue enhancement on MR images but are not deposited in the brain. However, it is not known if the strong T1- and T2-contrast obtained with iron oxide nanoparticles such as ferumoxytol could affect MR-based attenuation correction of PET data. The purpose of our study was to investigate if ferumoxytol administration prior to a 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG PET/MR scan would change standardized uptake values (SUV) of normal organs.Thirty pediatric patients (6-18 years) with malignant tumors underwent [18F]FDG-PET/MR scans (dose 3 MBq/kg). Fifteen patients received an intravenous ferumoxytol injection (5 mg Fe/kg) prior to the [18F]FDG-PET/MR scans (group 1). Fifteen additional age- and sex-matched patients received unenhanced [18F]FDG-PET/MR scans (group 2). For attenuation correction of PET data, we used a Dixon-based gradient echo sequence (TR 4.2 ms, TE 1.1, 2.3 ms, FA 5), which accounted for soft tissue, lung, fat, and background air. We used a mixed linear effects model to compare the tissue MRI enhancement, quantified as the signal-to-noise ratio (SNR), as well as tissue radiotracer signal, quantified as SUVmean and SUVmax, between group 1 and group 2. Alpha was assumed at 0.05.The MRI enhancement of the blood and solid extra-cerebral organs, quantified as SNR, was significantly higher on ferumoxytol-enhanced MRI scans compared to unenhanced scans (p < 0.001). However, SUVmean and SUVmax values, corrected based on the patients' body weight or body surface area, were not significantly different between the two groups (p > 0.05).Ferumoxytol administration prior to a [18F]FDG PET/MR scan did not change standardized uptake values (SUV) of solid extra-cerebral organs. This is important, because it allows injection of ferumoxytol contrast prior to a PET/MRI procedure and, thereby, significantly accelerates image acquisition times.

    View details for DOI 10.1007/s11307-019-01409-3

    View details for PubMedID 31325083

  • Outcomes for pediatric patients with osteosarcoma treated with palliative radiotherapy. Pediatric blood & cancer Chen, E. L., Yoo, C. H., Gutkin, P. M., Merriott, D. J., Avedian, R. S., Steffner, R. J., Spunt, S. L., Pribnow, A. K., Million, L., Donaldson, S. S., Hiniker, S. M. 2019: e27967

    Abstract

    Few studies have addressed the efficacy of palliative radiotherapy (RT) for pediatric osteosarcoma (OS), a disease generally considered to be radioresistant. We describe symptom relief, local control, and toxicity associated with palliative RT among children with OS.Patients diagnosed with OS at age 18 and under and treated with RT for palliation of symptomatic metastases or local recurrence at the primary site from 1997 to 2017 were included. We retrospectively reviewed details of RT, symptom improvement, local control, survival, and toxicity.Thirty-two courses of palliative RT were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. The median equivalent dose in 2 Gy fractions (EQD2) was 40.0 Gy (range, 20.0-60.4). The median number of fractions per course was 15 (range, 5-39). Symptom improvement occurred in 24 (75%) courses of RT at a median time of 15.5 days (range, 3-43). In nine courses (37.5%), symptoms recurred after a median duration of symptom relief of 140 days (range, 1-882). Higher EQD2 correlated with longer duration of response (r = 0.39, P = 0.0003). Imaging revealed local failure in 3 of 14 courses followed with surveillance imaging studies (21.4%). The median time to progression was 12.9 months (range, 4.4-21.8). The median follow-up time following the first course of palliative RT was 17.5 months (range, 1.74-102.24), and median time to overall survival was 19.4 months. Toxicity was mild, with grade 2 toxicity occurring in one course (3.1%).RT is an effective method of symptom palliation for patients with recurrent or metastatic OS, with higher delivered dose correlating with longer symptom relief and with little associated toxicity.

    View details for DOI 10.1002/pbc.27967

    View details for PubMedID 31407520

  • Patient Perceptions Correlate Weakly With Observed Patient Involvement in Decision-making in Orthopaedic Surgery CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Mertz, K., Eppler, S., Yao, J., Amanatullah, D. F., Chou, L., Wood, K. B., Safran, M., Steffner, R., Gardner, M., Kamal, R. 2018; 476 (9): 1859–65
  • Staging of Bone and Soft-tissue Sarcomas JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS Steffner, R. J., Jang, E. S. 2018; 26 (13): E269–E278
  • Patient Perceptions Correlate Weakly With Observed Patient Involvement in Decision-making in Orthopaedic Surgery. Clinical orthopaedics and related research Mertz, K., Eppler, S., Yao, J., Amanatullah, D. F., Chou, L., Wood, K. B., Safran, M., Steffner, R., Gardner, M., Kamal, R. 2018

    Abstract

    BACKGROUND: Shared decision-making between patients and physicians involves educating the patient, providing options, eliciting patient preferences, and reaching agreement on a decision. There are different ways to measure shared decision-making, including patient involvement, but there is no consensus on the best approach. In other fields, there have been varying relationships between patient-perceived involvement and observed patient involvement in shared decision-making. The relationship between observed and patient-perceived patient involvement in decision-making has not been studied in orthopaedic surgery.QUESTIONS/PURPOSES: (1) Does patient-perceived involvement correlate with observed measurements of patient involvement in decision-making in orthopaedic surgery? (2) Are patient demographics associated with perceived and observed measurements of patient involvement in decision-making?METHODS: We performed a prospective, observational study to compare observed and perceived patient involvement in new patient consultations for eight orthopaedic surgeons in subspecialties including hand/upper extremity, total joint arthroplasty, spine, sports, trauma, foot and ankle, and tumor. We enrolled 117 English-literate patients 18 years or older over an enrollment period of 2 months. A member of the research team assessed observed patient involvement during a consultation with the Observing Patient Involvement in Decision-Making (OPTION) instrument (scaled 1-100 with higher scores representing greater involvement). After the consultation, we asked patients to complete a questionnaire with demographic information including age, sex, race, education, income, marital status, employment status, and injury type. Patients also completed the Perceived Involvement in Care Scale (PICS), which measures patient-perceived involvement (scaled 1-13 with higher scores representing greater involvement). Both instruments are validated in multiple studies in various specialties and the physicians were blinded to the instruments used. We assessed the correlation between observed and patient-perceived involvement as well as tested the association between patient demographics and patient involvement scores.RESULTS: There was weak correlation between observed involvement (OPTION) and patient-perceived involvement (PICS) (r = 0.37, p < 0.01) in decision-making (mean OPTION, 28.7, SD 7.7; mean PICS, 8.43, SD 2.3). We found a low degree of observed patient involvement despite a moderate to high degree of perceived involvement. No patient demographic factor had a significant association with patient involvement.CONCLUSIONS: Further work is needed to identify the best method for evaluating patient involvement in decision-making in the setting of discordance between observed and patient-perceived measurements. Knowing whether it is necessary for (1) actual observable patient involvement to occur; or (2) a patient to simply believe they are involved in their care can inform physicians on the best way to improve shared decision-making in their practice.LEVEL OF EVIDENCE: Level II, therapeutic study.

    View details for PubMedID 29965894

  • Staging of Bone and Soft-tissue Sarcomas. The Journal of the American Academy of Orthopaedic Surgeons Steffner, R. J., Jang, E. S. 2018

    Abstract

    The purpose of staging in orthopaedic oncology is to provide a framework for classifying tumors based on their risk of local recurrence and distant metastasis to guide treatment decisions. Two separate systems are commonly used to categorize bone and soft-tissue sarcomas. The Musculoskeletal Tumor Society system for bone sarcomas and the Enneking system for soft-tissue sarcomas are the original staging systems developed by orthopaedic surgeons. The American Joint Committee on Cancer staging systems for bone and soft-tissue sarcomas are periodically updated based on new data, and they are currently on their eighth edition.

    View details for PubMedID 29781819

  • LYMPHOMA OF BONE JBJS REVIEWS Steffner, R. J., Jang, E. S., Danford, N. C. 2018; 6 (1): e1

    View details for PubMedID 29298179

  • Conservative management of desmoid tumors is safe and effective. journal of surgical research Park, J. S., Nakache, Y., Katz, J., Boutin, R. D., Steffner, R. J., Monjazeb, A. M., Canter, R. J. 2016; 205 (1): 115-120

    Abstract

    Surgical resection of desmoid tumors has traditionally been the mainstay of therapy, but this is a potentially morbid approach with high rates of recurrence. Given increasing reports of active surveillance in this disease, we sought to evaluate our experience with conservative management hypothesizing this would be an effective strategy.Using a prospectively maintained database of sarcoma patients from 2008 to 2015, we identified 47 patients with a diagnosis of desmoid tumor from all anatomic sites. Data points were abstracted on clinical and pathologic factors, disease stability or progression, and follow-up time. Main outcome measurements were tumor recurrence after surgical resection versus tumor progression with conservative management.In our cohort, 20 patients were managed with surveillance, 24 patients with surgery, and three patients with other approaches. Clinical and tumor characteristics between treatment groups were not significantly different. With a median follow-up of 35.7 mo, there was one complete regression, five partial regressions, and 13 stable diseases among the surveillance group. Only one patient under observation progressed, crossing over to surgical resection. Among 24 patients managed with surgery, 13 patients developed local recurrence. Kaplan-Meier analysis revealed a statistically superior progression-free survival in the surveillance group (P = 0.001).This retrospective analysis adds to the growing body of evidence that observation of desmoid tumors is safe and effective with high rates of stable disease. These data further support an initial conservative approach to desmoid tumors that may spare patients the morbidity and risk of recurrence that accompanies potentially extensive operations.

    View details for DOI 10.1016/j.jss.2016.06.028

    View details for PubMedID 27621007

  • Emerging Concepts in Upper Extremity Trauma Humeral Shaft Fractures ORTHOPEDIC CLINICS OF NORTH AMERICA Steffner, R. J., Lee, M. A. 2013; 44 (1): 21-?

    Abstract

    Fractures of the humeral shaft are common in low-energy and high-energy trauma, and optimal clinical management remains controversial. Nonsurgical management has been supported as the preferred treatment based on high union rates and minimal functional deficit due to a rich vascular supply from overlying muscle and the wide motion available at the glenohumeral joint. Recent studies of nonoperative management have challenged surgeons' understanding of these fractures and the perception of favorable outcomes. Current considerations support expanded operative indications with traditional open-plate fixation and with the use of minimally invasive techniques, implants, and a reconsideration of intramedullary nailing.

    View details for DOI 10.1016/j.ocl.2012.08.005

    View details for Web of Science ID 000313135100004

    View details for PubMedID 23174323

  • Case series of sural island flaps used for soft-tissue defects of the distal-third lower extremity JOURNAL OF WOUND CARE Steffner, R. J., Spiguel, A., Ranieri, J., Suk, M., Yoo, B. J. 2012; 21 (10): 469-475

    Abstract

    To establish the sural island fasciocutaneous flap as an initial consideration for distal third lower-extremity soft tissue coverage and to provide non-plastic surgeons with a procedure they can perform on their own.Literature on reverse sural island fasciocutaneous flaps was reviewed and summarised. We then assessed our care series of sural island flaps from 2008-2011 and looked to provide our operative technique and patient outcomes.Nine patients, aged 12-70 years old, with greater than 1 year follow-up, were reviewed. Five patients had diabetes, peripheral vascular disease, or smoked tobacco. All patients healed their soft tissue coverage with minimal complication and were able to accommodate normal footwear.Reverse sural island flaps are resilient flaps that should be considered as an alternative to free muscle transfer, for distal third lower extremity coverage.There were no external sources of funding for this study. The authors have no conflicts of interest to declare.

    View details for Web of Science ID 000309466600002

    View details for PubMedID 23103480

  • Humeral shaft fractures. Current reviews in musculoskeletal medicine Spiguel, A. R., Steffner, R. J. 2012; 5 (3): 177-183

    Abstract

    Management of humeral shaft fractures has historically been largely conservative. A significant body of literature, dating back to the 1970s, has shown that functional bracing may achieve greater than 90 % union rates and acceptable functional outcomes. More recently, however, with the advent of new surgical techniques and implant options, less tolerance for acceptable deformity and functional deficits, and less patience with conservative management, many treating orthopaedic surgeons are increasingly likely to consider surgical intervention. This article reviews the current recommendations for treatment of humeral shaft fractures, including both nonoperative and operative intervention. It also discusses the current thinking and operative trends in humeral shaft fracture fixation.

    View details for DOI 10.1007/s12178-012-9125-z

    View details for PubMedID 22566083

    View details for PubMedCentralID PMC3535078

  • Surgical Intervention of Nonvertebral Osseous Metastasis CANCER CONTROL Attar, S., Steffner, R. J., Avedian, R., Hussain, W. M. 2012; 19 (2): 113-121

    Abstract

    Nonvertebral osseous metastases can result in pain and disability. The goals of surgical intervention are to reduce pain and to improve function if nonsurgical treatment fails. The indications for proceeding with surgical intervention depend on anatomic location, amount of local destruction, extent of skeletal and visceral disease and, most important, the patient's performance status and life expectancy.This article reviews the evaluation and treatment of metastatic nonvertebral osseous lesions from the perspective of the orthopedic surgeon, based mainly on an assessment of the surgical literature.This article summarizes the approaches to preoperative evaluation, patient selection, and medical optimization. Guidelines for estimating osseous stability and fracture risk are discussed, and surgical implants and their relation to postoperative outcomes are examined. This review also describes less invasive ablative procedures currently available.The surgical management of nonvertebral osseous metastases involves multidisciplinary collaboration. The surgical construct must be a stable, reliable, and durable intervention that is individually tailored and matched to a patient's prognosis and performance status.

    View details for Web of Science ID 000307969100005

    View details for PubMedID 22487973

  • Factors associated with recurrence of primary aneurysmal bone cysts: is argon beam coagulation an effective adjuvant treatment? journal of bone and joint surgery. American volume Steffner, R. J., Liao, C., Stacy, G., Atanda, A., Attar, S., Avedian, R., Peabody, T. D. 2011; 93 (21): e1221-9

    Abstract

    Our goal was to assess the effectiveness and safety of argon beam coagulation as an adjuvant treatment for primary aneurysmal bone cysts, to reevaluate the adjuvant effectiveness of the use of a high-speed burr alone, and, secondarily, to identify predictors of aneurysmal bone cyst recurrence.We retrospectively reviewed the records of ninety-six patients with primary aneurysmal bone cysts who were managed at our institution from January 1, 1983, to December 31, 2008. Forty patients were managed with curettage, a high-speed burr, and argon beam coagulation; thirty-four were managed with curettage and a high-speed burr without argon beam coagulation; and the remaining twenty-two were managed with curettage with argon beam coagulation alone, curettage with no adjuvant treatment, or resection of the entire lesion. Demographic, clinical, and radiographic data were viewed comparatively for possible predictors of recurrence. Kaplan-Meier survival analysis with a log-rank test was performed to measure association and effectiveness.The median age at the time of diagnosis was fifteen years (range, one to sixty-two years). The median duration of follow-up was 29.5 months (range, zero to 300 months). The overall rate of recurrence of aneurysmal bone cyst after surgical treatment was 11.5%. The rate of recurrence was 20.6% after curettage and high-speed-burr treatment alone and 7.5% after curettage and high-speed-burr treatment plus argon beam coagulation. The five-year Kaplan-Meier survival estimate was 92% for patients managed with curettage and adjuvant treatment with a high-speed burr and argon beam coagulation, compared with 73% for patients managed with curettage and a high-speed burr only (p = 0.060).Surgical treatment of aneurysmal bone cyst with curettage and adjuvant argon beam coagulation is effective. Postoperative fracture appears to be a common complication of this treatment and needs to be studied further. Treatment with curettage and high-speed burr alone may not reduce recurrence.

    View details for DOI 10.2106/JBJS.J.01067

    View details for PubMedID 22048101

  • Ascorbic acid recycling by cultured beta cells: Effects of increased glucose metabolism FREE RADICAL BIOLOGY AND MEDICINE Steffner, R. J., Wu, L., Powers, A., May, A. M. 2004; 37 (10): 1612-1621

    Abstract

    Ascorbic acid is necessary for optimal insulin secretion from pancreatic islets. We evaluated ascorbate recycling and whether it is impaired by increased glucose metabolism in the rat beta-cell line INS-1. INS-1 cells, engineered with the potential for overexpression of glucokinase under the control of a tetracycline-inducible gene expression system, took up and reduced dehydroascorbic acid to ascorbate in a concentration-dependent manner that was optimal in the presence of physiologic D-glucose concentrations. Ascorbate uptake did not affect intracellular GSH concentrations. Whereas depletion of GSH in culture to levels about 25% of normal also did not affect the ability of the cells to reduce dehydroascorbic acid, more severe acute GSH depletion to less than 10% of normal levels did impair dehydroascorbic acid reduction. Culture of inducible cells in 11.8 mM D-glucose and doxycycline for 48 h enhanced glucokinase activity, increased glucose utilization, abolished D-glucose-dependent insulin secretion, and increased generation of reactive oxygen species. The latter may have contributed to subsequent decreases in the ability of the cells both to maintain intracellular ascorbate and to recycle it from dehydroascorbic acid. Cultured beta cells have a high capacity to recycle ascorbate, but this is sensitive to oxidant stress generated by increased glucose metabolism due to culture in high glucose concentrations and increased glucokinase expression. Impaired ascorbate recycling as a result of increased glucose metabolism may have implications for the role of ascorbate in insulin secretion in diabetes mellitus and may partially explain glucose toxicity in beta cells.

    View details for DOI 10.1016/j.freeradbiomed.2004.07.032

    View details for Web of Science ID 000224792100010

    View details for PubMedID 15477012

  • Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines JOURNAL OF BIOLOGICAL CHEMISTRY Wu, L., Nicholson, W., Knobel, S. M., Steffner, R. J., May, J. M., Piston, D. W., Powers, A. C. 2004; 279 (13): 12126-12134

    Abstract

    Pancreatic beta cells secrete insulin in response to changes in the extracellular glucose. However, prolonged exposure to elevated glucose exerts toxic effects on beta cells and results in beta cell dysfunction and ultimately beta cell death (glucose toxicity). To investigate the mechanism of how increased extracellular glucose is toxic to beta cells, we used two model systems where glucose metabolism was increased in beta cell lines by enhancing glucokinase (GK) activity and exposing cells to physiologically relevant increases in extracellular glucose (3.3-20 mm). Exposure of cells with enhanced GK activity to 20 mm glucose accelerated glycolysis, but reduced cellular NAD(P)H and ATP, caused accumulation of intracellular reactive oxygen species (ROS) and oxidative damage to mitochondria and DNA, and promoted apoptotic cell death. These changes required both enhanced GK activity and exposure to elevated extracellular glucose. A ROS scavenger partially prevented the toxic effects of increased glucose metabolism. These results indicate that increased glucose metabolism in beta cells generates oxidative stress and impairs cell function and survival; this may be a mechanism of glucose toxicity in beta cells. The level of beta cell GK may also be critical in this process.

    View details for DOI 10.1074/jbc.M307097200

    View details for Web of Science ID 000220334900018

    View details for PubMedID 14688272