Worldwide, the combined syndromes of Type 1 and Type 2 diabetes mellitus affect nearly 387 million individuals, with a prevalence that is expected to increase by more than 50% over the next 10 years. Inadequate insulin secretion from the pancreatic beta cell plays a central role in the pathophysiology of both forms of diabetes, however the pathways that lead to beta cell failure remain poorly understood. This knowledge gap has led to a paucity of clinical therapies specifically focused on restoration of beta cell health in either disease. The long-term goal of our research is to define common and overlapping pathways of beta cell dysfunction in Type 1 and Type 2 diabetes and to delineate the role of altered beta cell calcium homeostasis in disease pathophysiology. Calcium plays a vital role in many processes that govern beta cell function, including the production, maturation, and regulated secretion of insulin. The fidelity of these processes depends on the maintenance of calcium subcompartments and their respective transmembrane gradients, which are organized at both the cellular and organelle level. The endoplasmic reticulum, Golgi apparatus, and secretory granules comprise a functional module referred to as the beta cell secretory pathway, through which insulin mRNA is translated and preproinsulin protein is processed to mature insulin and packaged for exocytosis. In aggregate, these organelles also represent the largest depots of intracellular calcium. Here, we will test the hypothesis that calcium dyshomeostasis arising within this integrated secretory unit is a key determinant of impaired beta cell health in both Type 1 and Type 2 diabetes. The specific goals of this work are to: (1) elucidate a role for the sarco-endoplasmic reticulum calcium ATPase 2b (SERCA2b) pump in the molecular regulation of calcium in the proximal secretory pathway; (2) define a complementary yet distinct role for the secretory pathway calcium ATPase 1 (SPCA1) pump within the distal secretory pathway; (3) identify how altered calcium levels within this functional module impact insulin translation, processing, and secretion; (4) dissect calcium-regulated communication between secretory pathway organelles; (5) establish a novel role for beta cell Golgi stress in diabetes pathophysiology; and (6) test genetic and pharmacologic strategies to restore secretory pathway calcium homeostasis and beta cell function.

Public Health Relevance

Diabetes mellitus affects nearly 1 in every 11 Americans, is a leading cause of blindness, kidney failure, amputation, and cardiovascular disease, and results in over 234,000 U.S. deaths each year. Pancreatic ? cell dysfunction contributes to both major forms of diabetes, yet the pathways that trigger altered ? cell function and survival remain incompletely understood. This proposal seeks to define the role of disrupted ? cell calcium regulation in diabetes pathophysiology in order to inform the development of new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093954-08
Application #
9540858
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sato, Sheryl M
Project Start
2011-09-15
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Kono, Tatsuyoshi; Tong, Xin; Taleb, Solaema et al. (2018) Impaired Store-Operated Calcium Entry and STIM1 Loss Lead to Reduced Insulin Secretion and Increased Endoplasmic Reticulum Stress in the Diabetic ?-Cell. Diabetes 67:2293-2304
DiMeglio, Linda A; Evans-Molina, Carmella; Oram, Richard A (2018) Type 1 diabetes. Lancet 391:2449-2462
Beli, Eleni; Yan, Yuanqing; Moldovan, Leni et al. (2018) Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice. Diabetes 67:1867-1879
Sims, Emily K; Evans-Molina, Carmella; Tersey, Sarah A et al. (2018) Biomarkers of islet beta cell stress and death in type 1 diabetes. Diabetologia 61:2259-2265
Sims, Emily K; Lakhter, Alexander J; Anderson-Baucum, Emily et al. (2017) MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells. Diabetologia 60:1057-1065
Gordon, Hannah M; Majithia, Neil; MacDonald, Patrick E et al. (2017) STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation. Endocrine 56:528-537
Ocaña, Gail J; Pérez, Liliana; Guindon, Lynette et al. (2017) Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90?. Immunology 151:198-210
Hatanaka, Masayuki; Anderson-Baucum, Emily; Lakhter, Alexander et al. (2017) Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation. Sci Rep 7:3758
Maddatu, Judith; Anderson-Baucum, Emily; Evans-Molina, Carmella (2017) Smoking and the risk of type 2 diabetes. Transl Res 184:101-107
Bone, Robert N; Evans-Molina, Carmella (2017) Combination Immunotherapy for Type 1 Diabetes. Curr Diab Rep 17:50

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