Lipids within cells are stored in an organelle termed lipid droplets (LDs) that consist of neutral lipids core of diacylglycerides, triglycerides, and cholesterol ester covered by a single layer of phospholipids. Recent evidence indicates a pivotal role of LD in the spatial and temporal regulation of intracellular lipid metabolism. Our project aims to understand the regulation of intracellular lipid metabolism through the study of LD in beta cells considering the critical role of lipids in beta cell. Metabolites produced by lipolysis augment insulin secretion, while unregulated accumulation of lipids impair beta cell health and leads to diabetes. The perilipin (PLIN1-5) family of proteins resides on the surface of LD and plays a key role in the formation and mobilization of LD. Our goal is to understand the mechanisms by which PLIN affects insulin secretion and to clarify the role of PLIN in the pathogenesis of abnormal lipid metabolism in beta cells under type 2 diabetes (T2D). We have demonstrated that both PLIN2 and PLIN5 are expressed in human and mouse islets, but their expression is differentially regulated. We have shown that PLIN5 plays a significant role in increasing insulin secretion likely through the regulation of lipid metabolism acutely, especially lipolysis in beta cells. PLIN2 may aid adaptation of beta cells to nutritional stress. Thus, we hypothesize that PLIN2 and 5, each with unique molecular characteristics coordinately achieve the efficient regulation of insulin secretion and protect beta cells under nutritional stress. The hypothesis will be tested by 2 aims.
Specific Aim 1 : Determine the mechanism by which PLIN5 augments GSIS and lipolysis. PLIN5 augments GSIS both in vitro and in vivo, which we hypothesize is mediated by lipolysis. Here, we will delineate the pathway connecting PLIN5 and GSIS. The impact of PLIN5 deficiency in beta cells on glucose homeostasis will be tested in beta cell specific PLIN5 knockout mice. The contribution of PLIN5 phosphorylation in lipid metabolism and GSIS will be tested using phosphorylation resistant mutant PLIN5 expressed in cultured cell and in beta cells of mice. Lastly, the molecular target that mediates the augmentation of PLIN5 will be determined by increase lipolysis through mutant PLIN5 and pharmacological modulation of lipolysis.
Specific Aim 2 : Determine how perilipins protect beta cells under nutritional stress. Studies in yeast, drosophila, and mouse liver implicate that LDs protect cells under nutritional stress. In beta cells, PLIN2 is highly expressed and increased by fatty acids. We have obtained preliminary data that the loss of PLIN2 in beta cells impair GSIS and islet adaptation to high fat feeding. We will determine the mechanism by which PLIN2 protect beta cells under nutritional stress. Also, we will analyze how islet PLINs and lipidome are altered in human islets affected by T2D. Our study holds promise to identify a new target that supports GSIS and protects beta cells under nutritional stress associated with T2D.

Public Health Relevance

Lipids play an important role for proper functions of insulin producing beta cells by serving as energy source and as signaling molecules to increase insulin secretion. However, unregulated accumulation of lipids damages beta cells resulting in type 2 diabetes. By examining how intracellular trafficking of lipids are regulated by protein termed perilipins to achieve effective use of lipids within cells and to prevent accumulation of toxic lipids, the study will provide an important knowledge for the prevention of type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK090490-07A1
Application #
9240032
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sato, Sheryl M
Project Start
2011-02-15
Project End
2020-01-31
Budget Start
2017-02-20
Budget End
2018-01-31
Support Year
7
Fiscal Year
2017
Total Cost
$356,335
Indirect Cost
$121,335
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246
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