The chronic exposure of islets to fatty acids is believed to promote the development of diabetes in obesity by damaging ? cells. Paradoxically, fatty acids also augment insulin secretion acutely. Therefore a better understanding of the regulation of lipid metabolism in islets, especially from spatial and chronological aspects, is critical for the effective strategy to prevent adverse effects of lipid overload. Adipose differentiation-related protein (ADFP), found on the surface of lipid droplets in wide range of cells, is proposed to play a critical role in spatial organization of intracellular lipid metabolism through the interaction with other intracellular organelles such as cell membrane, ER, and mitochondria. The preliminary data from Dr. Imai's laboratory showed that ADFP is increased in human and mouse islets exposed to fatty acids in vivo and ex vivo. Furthermore the reduction of ADFP in insulin secreting cells (MIN6) impairs fatty acid usage and acute augmentation of insulin secretion by fatty acids. Therefore Dr. Imai hypothesizes that ADFP coated lipid droplets in ? cells are critical for the efficient use of fatty acids. They facilitate the generation of fatty acid derived signaling for insulin secretion, while preventing islet dysfunction from lipid overload. The hypothesis will be tested as below.
Specific aim 1 : Analyze the role of ADFP in the acute augmentation of insulin secretion by fatty acids. The importance of ADFP in this process will be confirmed by reducing ADFP in human islets using adenovirus expressing shRNA, and in vivo using ADFP deficient mice. The mechanisms by which ADFP regulates the generation of signals for insulin secretion will be studied in mouse islets using shRNA for ADFP.
Specific aim 2 : Analyze the role of ADFP in the development of islet dysfunction in obesity. Since ADFP may promote fatty acid utilization in ? cells, it potentially protects islet from stress of fatty acid overload. Here the efficacy of ADFP upregulation in the prevention of lipid-induced islet dysfunction will be tested using adenovirus in vitro, and using the transgenic approach in vivo.
Specific aim 3 : Address the roles of islet lipid droplets beyond the regulation of fatty acids-triglycerides metabolism. Recent studies in various cells indicate that the regulatory role played by lipid droplets is not limited to fatty acid metabolism. From several areas where ADFP is implicated, two pathways relevant to islet function will be studied. The change in cholesterol metabolism and eicosanoids production will be analyzed after modulating ADFP levels in MIN6 cells and mouse islets as above. The study will provide innovative, unique information about the spatial and dynamic regulation of lipid metabolism in islets, which will aid the designing of new approaches towards the prevention and treatment of islet dysfunction commonly seen in obesity.

Public Health Relevance

This study addresses a role of adipose differentiation-related protein in the development of islet dysfunction from lipid overload that contributes to the development of diabetes in obesity. Anticipated results will provide better understanding of the regulation of lipid metabolism in islets and will facilitate new approaches towards the prevention and treatment 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 #
5R01DK090490-02
Application #
8228038
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Appel, Michael C
Project Start
2011-02-15
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$312,113
Indirect Cost
$94,613
Name
Eastern Virginia Medical School
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
058625146
City
Norfolk
State
VA
Country
United States
Zip Code
23501
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Butcher, Matthew J; Hallinger, Daniel; Garcia, Eden et al. (2014) Association of proinflammatory cytokines and islet resident leucocytes with islet dysfunction in type 2 diabetes. Diabetologia 57:491-501
Imai, Y; Dobrian, A D; Weaver, J R et al. (2013) Interaction between cytokines and inflammatory cells in islet dysfunction, insulin resistance and vascular disease. Diabetes Obes Metab 15 Suppl 3:117-29
Taylor-Fishwick, D A; Weaver, J R; Grzesik, W et al. (2013) Production and function of IL-12 in islets and beta cells. Diabetologia 56:126-35
Imai, Yumi; Dobrian, Anca D; Morris, Margaret A et al. (2013) Islet inflammation: a unifying target for diabetes treatment? Trends Endocrinol Metab 24:351-60