Emerging physiologic and genetic data suggest that dysfunction of the pancreatic beta cell is the key determinant of whether an insulin resistant individual will progress to frank hyperglycemia and diabetes. The long-range goal of this applicant is to define the pathways that govern beta cell function and survival in states of health in order to understand how these regulatory circuits are impaired in the pathologic state of Type 2 diabetes mellitus. The sarco-endoplasmic reticulum calcium ATPase or SERCA pump resides in the endoplasmic reticulum membrane and is responsible for maintaining a steep calcium concentration gradient between the cytosol and endoplasmic reticulum. In the beta cell, this gradient plays a key role in regulated insulin secretion and the maintenance of endoplasmic reticulum health and function. Preliminary and published work has revealed that expression of the predominant beta cell isoform, SERCA2, is markedly downregulated in rodent and human models of Type 2 diabetes mellitus. Furthermore, loss of SERCA2 expression leads to profound changes in beta cell secretory function and intracellular calcium flux in response to glucose. Given this background, the overall hypothesis of this proposal is that dysregulation of SERCA2 activity and expression is a key contributor to the beta cell dysfunction and death observed in Type 2 diabetes mellitus. To test this hypothesis, three aims are proposed.
Aim 1 : elucidate the in vivo role of SERCA2 in beta cell function using two novel mouse models of SERCA2 deficiency.
Aim 2 : delineate the transcriptional pathways that regulate SERCA2 expression in the pancreatic beta cell under normal conditions and in diabetes.
Aim 3 : elucidate the contribution of microRNAs in disruption of the SERCA2 gene regulatory network. The successful completion of these aims will precisely define the role of islet beta cell SERCA2 in metabolic and glucose homeostasis and identify the pathways that lead to its transcriptional dysregulation in Type 2 diabetes mellitus.

Public Health Relevance

Type 2 diabetes mellitus affects nearly 1 in 12 Americans and is a leading cause of blindness, kidney failure, amputations, and heart disease. Dysfunction of the insulin producing beta cells in the pancreas plays a prominent role in the development of diabetes. The goal of this project is to define the molecular pathways that lead to beta cell failure in Type 2 diabetes in order to inform the development of novel and improved therapeutic strategies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University-Purdue University at Indianapolis
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Morris, David L; Oatmen, Kelsie E; Mergian, Taleen A et al. (2016) CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity. J Leukoc Biol 99:1107-19
Saeed, Zeb; Taleb, Solaema; Evans-Molina, Carmella (2016) A case of extragastrointestinal stromal tumor complicated by severe hypoglycemia: a unique presentation of a rare tumor. BMC Cancer 16:930
Watkins, Renecia A; Evans-Molina, Carmella; Terrell, Jennifer K et al. (2016) Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes. Transl Res 168:96-106.e1
Sims, Emily K; Chaudhry, Zunaira; Watkins, Renecia et al. (2016) Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes. Diabetes Care 39:1519-26
Mirmira, Raghavendra G; Sims, Emily K; Syed, Farooq et al. (2016) Biomarkers of β-Cell Stress and Death in Type 1 Diabetes. Curr Diab Rep 16:95
Syed, Farooq; Evans-Molina, Carmella (2016) Nucleic acid biomarkers of β cell stress and death in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 23:312-7
Meah, Farah A; DiMeglio, Linda A; Greenbaum, Carla J et al. (2016) The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants. Diabetologia 59:1186-95
Tong, Xin; Kono, Tatsuyoshi; Anderson-Baucum, Emily K et al. (2016) SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity. Diabetes 65:3039-52
Fujimaki, Kyoko; Ogihara, Takeshi; Morris, David L et al. (2015) SET7/9 Enzyme Regulates Cytokine-induced Expression of Inducible Nitric-oxide Synthase through Methylation of Lysine 4 at Histone 3 in the Islet β Cell. J Biol Chem 290:16607-18
Johnson, Justin S; Evans-Molina, Carmella (2015) Translational implications of the β-cell epigenome in diabetes mellitus. Transl Res 165:91-101

Showing the most recent 10 out of 35 publications