Academic Appointments

Honors & Awards

  • Glenn Foundation for Medical Research Postdoctoral Fellowships in Aging Research, American Federation for Aging Research (AFAR) (2021-22)
  • Young Investigator Scientific Achievement Award, Rachmiel Levine-Arthur Riggs Diabetes Symposium (2019)
  • NIH T32 Endocrinology Training Grant, Stanford School of Medicine (2018-2020)
  • SDRC Best Poster Award, Stanford Frontiers in Diabetes Research (2018)
  • College of Medicine Dean Award, Penn State College of Medicine (2016)
  • D. Eugene Rannels Award for Outstanding Doctoral Dissertation in Physiology, Pennsylvania State University (2016)
  • Cell and Molecular Physiology Robert Gunn Award, The American Physiological Society (2016)
  • ASN Emerging Leaders in Science Award, American Society for Nutrition (2016)
  • Endocrinology and Metabolism Campbell Award, The American Physiological Society (2015)
  • ASN Emerging Leaders in Science Award, American Society for Nutrition (2015)
  • Epithelial Transport Meritorious Travel Award, The American Physiological Society (2015)
  • Howard Morgan Travel Award, Penn State College of Medicine (2015)
  • Selected Student Presentation Award, International Society for Zinc Biology (2014)
  • Huck Institute Graduate Enrichment Fund, Pennsylvania State University (2014-2016)
  • Vitamins & Minerals RIS Poster Competition Award, Experimental Biology Boston, MA (2013)
  • Graham Robert Endowed Fellowship, Pennsylvania State University (2011-2013)

Boards, Advisory Committees, Professional Organizations

  • Member, American Society for Nutrition (2014 - Present)
  • Member, American Physiological Society (2013 - Present)

All Publications

  • beta-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes. Diabetes Lee, S., Xu, H., Van Vleck, A., Mawla, A. M., Li, A. M., Ye, J., Huising, M. O., Annes, J. P. 2022


    Mitochondrial dysfunction plays a central role in Type 2 Diabetes (T2D); however, the pathogenic mechanisms in pancreatic beta-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is a key mitochondrial enzyme with dual functions in the TCA cycle and electron transport chain (ETC). Using human diabetic samples and a mouse model of beta-cell-specific SDH ablation (SDHBbetaKO), we define SDH deficiency as a driver of mitochondrial dysfunction in beta-cell failure and insulinopenic diabetes. beta-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential (DeltaPsim) collapse, thereby compromising glucose-stimulated ATP production, insulin secretion and beta-cell growth. Mechanistically, metabolomic and transcriptomic studies reveal that the loss of SDH causes excess succinate accumulation, which inappropriately activates mTORC1-regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, which mirror diabetes-associated human beta-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive beta-cell failure of diabetes and identify mTORC1 inhibition as a potential mitigation strategy.

    View details for DOI 10.2337/db21-0834

    View details for PubMedID 35472723

  • Novel Pathogenic de novo INS p.T97P Variant Presenting with Severe Neonatal DKA. Endocrinology Lal, R. A., Moeller, H. P., Thomson, E. A., Horton, T. M., Lee, S., Freeman, R., Prahalad, P., Poon, A. S., Annes, J. P. 2021


    Pathogenic INS gene mutations are causative for Mutant INS-gene-induced Diabetes of Youth (MIDY). We characterize a novel de novo heterozygous INS gene mutation (c.289A>C, p.T97P) that presented in an autoantibody-negative 5-month-old male infant with severe diabetic ketoacidosis. In silico pathogenicity prediction tools provided contradictory interpretations, while structural modeling indicated a deleterious effect on proinsulin folding. Transfection of wildtype and INS p.T97P expression and luciferase reporter constructs demonstrated elevated intracellular mutant proinsulin levels and dramatically impaired proinsulin/insulin and luciferase secretion. Notably, proteasome inhibition partially and selectively rescued INS p.T97P-derived luciferase secretion. Additionally, expression of INS p.T97P caused increased intracellular proinsulin aggregate formation and XBP-1s protein levels, consistent with induction of endoplasmic reticulum stress. We conclude that INS p.T97P is a newly identified pathogenic A-chain variant that is causative for MIDY via disruption of proinsulin folding and processing with induction of the endoplasmic reticulum stress response.

    View details for DOI 10.1210/endocr/bqab246

    View details for PubMedID 34888628

  • A genetic variant in SLC30A2 causes breast dysfunction during lactation by inducing ER stress, oxidative stress and epithelial barrier defects SCIENTIFIC REPORTS Lee, S., Zhou, Y., Gill, D. L., Kelleher, S. L. 2018; 8: 3542


    SLC30A2 encodes a zinc (Zn) transporter (ZnT2) that imports Zn into vesicles in highly-specialized secretory cells. Numerous mutations and non-synonymous variants in ZnT2 have been reported in humans and in breastfeeding women; ZnT2 variants are associated with abnormally low milk Zn levels and can lead to severe infantile Zn deficiency. However, ZnT2-null mice have profound defects in mammary epithelial cell (MEC) polarity and vesicle secretion, indicating that normal ZnT2 function is critical for MEC function. Here we report that women who harbor a common ZnT2 variant (T288S) present with elevated levels of several oxidative and endoplasmic reticulum (ER) stress markers in their breast milk. Functional studies in vitro suggest that substitution of threonine for serine at amino acid 288 leads to hyperphosphorylation retaining ZnT2 in the ER and lysosomes, increasing ER and lysosomal Zn accumulation, ER stress, the generation of reactive oxygen species, and STAT3 activation. These changes were associated with decreased abundance of zona occludens-1 and increased tight junction permeability. This study confirms that ZnT2 is important for normal breast function in women during lactation, and suggests that women who harbor defective variants in ZnT2 may be at-risk for poor lactation performance.

    View details for PubMedID 29476070

  • CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition. Endocrinology Abdolazimi, Y. n., Lee, S. n., Xu, H. n., Allegretti, P. n., Horton, T. M., Yeh, B. n., Moeller, H. P., Nichols, R. J., McCutcheon, D. n., Shalizi, A. n., Smith, M. n., Armstrong, N. A., Annes, J. P. 2018


    Pharmacologic expansion of endogenous β-cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2,400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase (JNK) inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual specificity tyrosine-phosphorylation-regulated kinases (DYRK1A/B) inhibition. In contrast to rat β-cells, which were broadly growth responsive to compound treatment, human β-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3β (GSK-3β) or transforming growth factor-β (ALK5/TGF-β) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T-cells (NFAT) as the primary mechanism of human β-cell replication induction. However, inhibition of NFAT activity had limited impact on CC-401-induced β-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the β-cell replication-inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control β-cell replication and leverage a novel DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control β-cell growth.

    View details for PubMedID 29514186

  • Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells. Cell chemical biology Horton, T. M., Allegretti, P. A., Lee, S. n., Moeller, H. P., Smith, M. n., Annes, J. P. 2018


    Diabetes is a hyperglycemic condition characterized by pancreatic β-cell dysfunction and depletion. Whereas methods for monitoring β-cell function in vivo exist, methods to deliver therapeutics to β cells are lacking. We leveraged the rare ability of β cells to concentrate zinc to preferentially trap zinc-binding molecules within β cells, resulting in β-cell-targeted compound delivery. We determined that zinc-rich β cells and islets preferentially accumulated TSQ (6-methoxy-8-p-toluenesulfonamido-quinoline) in a zinc-dependent manner compared with exocrine pancreas. Next, we asked whether appending a zinc-chelating moiety onto a β-cell replication-inducing compound was sufficient to confer preferential β-cell accumulation and activity. Indeed, the hybrid compound preferentially accumulated within rodent and human islets in a zinc-dependent manner and increased the selectivity of replication-promoting activity toward β cells. These data resolve the fundamental question of whether intracellular accumulation of zinc-chelating compounds is influenced by zinc content. Furthermore, application of this principle yielded a proof-of-concept method for β-cell-targeted drug delivery and bioactivity.

    View details for PubMedID 30527998

  • Genetic Disruption of Adenosine Kinase in Mouse Pancreatic ß-Cells Protects Against High Fat Diet-Induced Glucose Intolerance. Diabetes Navarro, G., Abdolazami, Y., Zhao, Z., Xu, H., Lee, S., Armstrong, N. A., Annes, J. P. 2017


    Islet β-cells adapt to insulin resistance through increased insulin secretion and expansion. Type 2 diabetes typically occurs when prolonged insulin resistance exceeds the adaptive capacity of β-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate β-cell replication. Here, we evaluated whether ADK disruption in mouse β-cells affects β-cell mass and/or protects against high-fat diet (HFD)-induced glucose dysregulation. Mice targeted at the Adk locus were bred to Rip-Cre and Ins1-Cre/ERT(1Lphi) mice to enable constitutive (βADKO) and conditional (iβADKO) disruption of ADK expression in β-cells, respectively. Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion (GSIS) were longitudinally monitored in normal chow (NC)-fed and HFD-fed mice. In addition, β-cell mass and replication were measured by immunofluorescence-based islet morphometry. NC-fed adult βADKO and iβADKO mice displayed glucose tolerance, insulin tolerance and β-cell mass comparable to control animals. By contrast, HFD-fed βADKO and iβADKO animals had improved glucose tolerance and increased in vivo GSIS. Improved glucose handling was associated with increased β-cell replication and mass. We conclude that ADK expression negatively regulates the adaptive β-cell response to HFD challenge. Therefore, modulation of ADK activity is a potential strategy for enhancing the adaptive β-cell response.

    View details for DOI 10.2337/db16-0816

    View details for PubMedID 28468960

  • Zinc transporter 2 interacts with vacuolar ATPase and is required for polarization, vesicle acidification, and secretion in mammary epithelial cells. The Journal of biological chemistry Lee, S. n., Rivera, O. C., Kelleher, S. L. 2017; 292 (52): 21598–613


    An important feature of the mammary gland is its ability to undergo profound morphological, physiological, and intracellular changes to establish and maintain secretory function. During this process, key polarity proteins and receptors are recruited to the surface of mammary epithelial cells (MECs), and the vesicle transport system develops and matures. However, the intracellular mechanisms responsible for the development of secretory function in these cells are unclear. The vesicular zinc (Zn2+) transporter ZnT2 is critical for appropriate mammary gland architecture, and ZnT2 deletion is associated with cytoplasmic Zn2+ accumulation, loss of secretory function and lactation failure. The underlying mechanisms are important to understand as numerous mutations and non-synonymous genetic variation in ZnT2 have been detected in women that result in severe Zn2+ deficiency in exclusively breastfed infants. Here we found that ZnT2 deletion in lactating mice and cultured MECs resulted in Zn2+-mediated degradation of phosphatase and tensin homolog (PTEN), which impaired intercellular junction formation, prolactin receptor trafficking, and alveolar lumen development. Moreover, ZnT2 directly interacted with vacuolar H+-ATPase (V-ATPase), and ZnT2 deletion impaired vesicle biogenesis, acidification, trafficking, and secretion. In summary, our findings indicate that ZnT2 and V-ATPase interact and that this interaction critically mediates polarity establishment, alveolar development, and secretory function in the lactating mammary gland. Our observations implicate disruption in ZnT2 function as a modifier of secretory capacity and lactation performance.

    View details for DOI 10.1074/jbc.M117.794461

    View details for PubMedID 29114036

    View details for PubMedCentralID PMC5766956

  • Biological underpinnings of breastfeeding challenges: the role of genetics, diet, and environment on lactation physiology. American journal of physiology. Endocrinology and metabolism Lee, S., Kelleher, S. L. 2016; 311 (2): E405-22


    Lactation is a dynamic process that has evolved to produce a complex biological fluid that provides nutritive and nonnutritive factors to the nursing offspring. It has long been assumed that once lactation is successfully initiated, the primary factor regulating milk production is infant demand. Thus, most interventions have focused on improving breastfeeding education and early lactation support. However, in addition to infant demand, increasing evidence from studies conducted in experimental animal models, production animals, and breastfeeding women suggests that a diverse array of maternal factors may also affect milk production and composition. In this review, we provide an overview of our current understanding of the role of maternal genetics and modifiable factors, such as diet and environmental exposures, on reproductive endocrinology, lactation physiology, and the ability to successfully produce milk. To identify factors that may affect lactation in women, we highlight some information gleaned from studies in experimental animal models and production animals. Finally, we highlight the gaps in current knowledge and provide commentary on future research opportunities aimed at improving lactation outcomes in breastfeeding women to improve the health of mothers and their infants.

    View details for DOI 10.1152/ajpendo.00495.2015

    View details for PubMedID 27354238

    View details for PubMedCentralID PMC5005964

  • Molecular regulation of lactation: The complex and requisite roles for zinc. Archives of biochemistry and biophysics Lee, S., Kelleher, S. L. 2016


    Lactation provides many health benefits to the nursing infant and breastfeeding mother. In order to successfully breastfeed, the mammary gland must expand and differentiate to activate numerous processes that regulate milk production and secretion. This involves a complex series of molecular, biochemical and cellular events driven largely by lactogenic hormones. Recent advances implicate zinc as a critical modulator of mammary gland function. Here, we provide an overview of our current understanding of the role and regulation of zinc in promoting proliferation, differentiation and secretion in the mammary gland during lactation, and highlight critical gaps in knowledge.

    View details for DOI 10.1016/

    View details for PubMedID 27059852

  • ZnT4 (SLC30A4)-null ("lethal milk") mice have defects in mammary gland secretion and hallmarks of precocious involution during lactation AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY McCormick, N. H., Lee, S., Hennigar, S. R., Kelleher, S. L. 2016; 310 (1): R33-R40


    During lactation, highly specialized secretory mammary epithelial cells (MECs) produce and secrete huge quantities of nutrients and nonnutritive factors into breast milk. The zinc (Zn) transporter ZnT4 (SLC30A4) transports Zn into the trans-Golgi apparatus for lactose synthesis, and across the apical cell membrane for efflux from MECs into milk. This is consistent with observations in "lethal milk" (lm/lm) mice, which have a truncation mutation in SLC30A4, and present with not only low milk Zn concentration, but also smaller mammary glands, decreased milk volume, and lactation failure by lactation day 2. However, the molecular underpinnings of these defects are not understood. Here, we used lactating C57BL/6J(lm/lm) (ZnT4-null) mice to explore the consequences of a ZnT4-null phenotype on mammary gland function during early lactation. Lactating C57BL/6J(lm/lm) mice had significantly fewer, smaller, and collapsed alveoli comprising swollen, lipid-filled MECs during early lactation. These defects were associated with decreased Akt expression and STAT5 activation, indicative of defects in MEC secretion. In addition, increased expression of ZnT2, TNF-α, and cleaved e-cadherin concomitant with increased activation of STAT3 implicated the loss of ZnT4 in precocious activation of involution. Collectively, our study indicates that the loss of ZnT4 has profound consequences on MEC secretion and may promote tissue remodeling in the mammary gland during early lactation.

    View details for DOI 10.1152/ajpregu.00315.2014

    View details for Web of Science ID 000367478900004

    View details for PubMedID 26538236

  • Paradoxical zinc toxicity and oxidative stress in the mammary gland during marginal dietary zinc deficiency REPRODUCTIVE TOXICOLOGY Bostanci, Z., Mack, R. P., Lee, S., Soybel, D. I., Kelleher, S. L. 2015; 54: 84-92


    Zinc (Zn) regulates numerous cellular functions. Zn deficiency is common in females; ∼80% of women and 40% of adolescent girls consume inadequate Zn. Zn deficiency enhances oxidative stress, inflammation and DNA damage. Oxidative stress and inflammation is associated with breast disease. We hypothesized that Zn deficiency increases oxidative stress in the mammary gland, altering the microenvironment and architecture. Zn accumulated in the mammary glands of Zn deficient mice and this was associated with macrophage infiltration, enhanced oxidative stress and over-expression of estrogen receptor α. Ductal and stromal hypercellularity was associated with aberrant collagen deposition and disorganized e-cadherin. Importantly, these microenvironmental alterations were associated with substantial impairments in ductal expansion and mammary gland development. This is the first study to show that marginal Zn deficiency creates a toxic microenvironment in the mammary gland impairing breast development. These changes are consistent with hallmarks of potential increased risk for breast disease and cancer.

    View details for DOI 10.1016/j.reprotox.2014.07.076

    View details for Web of Science ID 000356401300011

    View details for PubMedID 25088245

  • Essential Role for Zinc Transporter 2 (ZnT2)-mediated Zinc Transport in Mammary Gland Development and Function during Lactation JOURNAL OF BIOLOGICAL CHEMISTRY Lee, S., Hennigar, S. R., Alam, S., Nishida, K., Kelleher, S. L. 2015; 290 (21): 13064-13078


    The zinc transporter ZnT2 (SLC30A2) imports zinc into vesicles in secreting mammary epithelial cells (MECs) and is critical for zinc efflux into milk during lactation. Recent studies show that ZnT2 also imports zinc into mitochondria and is expressed in the non-lactating mammary gland and non-secreting MECs, highlighting the importance of ZnT2 in general mammary gland biology. In this study we used nulliparous and lactating ZnT2-null mice and characterized the consequences on mammary gland development, function during lactation, and milk composition. We found that ZnT2 was primarily expressed in MECs and to a limited extent in macrophages in the nulliparous mammary gland and loss of ZnT2 impaired mammary expansion during development. Secondly, we found that lactating ZnT2-null mice had substantial defects in mammary gland architecture and MEC function during secretion, including fewer, condensed and disorganized alveoli, impaired Stat5 activation, and unpolarized MECs. Loss of ZnT2 led to reduced milk volume and milk containing less protein, fat, and lactose compared with wild-type littermates, implicating ZnT2 in the regulation of mammary differentiation and optimal milk production during lactation. Together, these results demonstrate that ZnT2-mediated zinc transport is critical for mammary gland function, suggesting that defects in ZnT2 not only reduce milk zinc concentration but may compromise breast health and increase the risk for lactation insufficiency in lactating women.

    View details for DOI 10.1074/jbc.M115.637439

    View details for Web of Science ID 000354975700011

    View details for PubMedID 25851903

  • Prolactin (PRL)-stimulated Ubiquitination of ZnT2 Mediates a Transient Increase in Zinc Secretion Followed by ZnT2 Degradation in Mammary Epithelial Cells JOURNAL OF BIOLOGICAL CHEMISTRY Seo, Y. A., Lee, S., Hennigar, S. R., Kelleher, S. L. 2014; 289 (34): 23653-23661


    The zinc transporter ZnT2 imports zinc into secretory vesicles and regulates zinc export from the mammary epithelial cell. Mutations in ZnT2 substantially impair zinc secretion into milk. The lactogenic hormone prolactin (PRL) transcriptionally increases ZnT2 expression through the Jak2/STAT5 signaling pathway, increasing zinc accumulation in secretory vesicles and zinc secretion. Herein, we report that PRL post-translationally stimulated ZnT2 ubiquitination, which altered ZnT2 trafficking and augmented vesicular zinc accumulation and secretion from mammary epithelial cells in a transient manner. Ubiquitination then down-regulated zinc secretion by stimulating degradation of ZnT2. Mutagenesis of two N-terminal lysine residues (K4R and K6R) inhibited ZnT2 ubiquitination, vesicular zinc accumulation and secretion, and protein degradation. These findings establish that PRL post-translationally regulates ZnT2-mediated zinc secretion in a multifactorial manner, first by enhancing zinc accumulation in vesicles to transiently enhance zinc secretion and then by activating ubiquitin-dependent ZnT2 degradation. This provides insight into novel mechanisms through which ZnT2 and zinc transport is tightly regulated in mammary epithelial cells.

    View details for DOI 10.1074/jbc.M113.531145

    View details for Web of Science ID 000341505000033

    View details for PubMedID 25016022