This grant will continue to focus on insulin secretion and the role of the pancreatic beta-cell in diabetes as it has since 1983 when it was originally funded. In the next funding period, we will attempt to understand the gene-phenotype relationships of recently identified diabetes genes, to define the mechanisms responsible for the loss of pancreatic beta-cell mass and to develop novel approaches to its preservation in diabetes. Recent genome wide association (GWA) studies have identified novel genetic variants that increase risk for Type 2 diabetes (T2DM). Although many of these variants reduce insulin levels, in most cases the mechanisms operative in the beta-cell to cause a reduction in insulin secretion remain to be worked out. We now propose to characterize, compare and contrast the physiological changes in insulin secretion in non-diabetic subjects with different genetic variants associated with T2DM. Understanding the mechanisms responsible for reduced pancreatic beta-cell mass in T2DM and developing novel scientific approaches to promoting increased pancreatic beta-cell survival is the second scientific focus of this application. We have demonstrated that deficiency of the beta-cell transcription factor Pdx1 leads to accelerated pancreatic beta-cell death due to autophagy and apoptosis. In the next funding cycle, we will continue to define the mechanisms responsible for beta-cell death in Pdx1-deficient states. There are 2 specific aims:
Specific Aim 1 : To study the clinical physiology of genetic variants associated with T2DM. We will test the hypothesis that subjects with genetic variants associated with reduced insulin secretion and increased risk for T2DM will have phenotypic abnormalities detectable even when glucose tolerance is normal and different genetic variants will lead to different clinical phenotypes. We propose to study the T2DM-associated genes KCNJ11, TCF7L2, KCNQ1, CDKAL1, IGF2BP2 and SLC30A8 since it appears that diabetes-associated variants in these genes increase T2DM risk by decreasing insulin secretion.
Specific Aim 2 : To study the mechanisms of beta-cell death due to Pdx1 deficiency and to develop novel approaches to the preservation of beta-cell mass. Our studies will identify the mechanisms responsible for the increase in beta-cell death in Pdx1 mice and will determine whether inhibiting the pathways involved will prevent the reduction of beta-cell mass, preserve beta-cell function and delay or prevent the onset of hyperglycemia. Preliminary data show that Pdx1 deficiency leads to increased expression of pro-apoptotic proteins in the pancreatic beta-cell including NIX, PUMA and BIM as well as CHOP, a mediator of apoptosis in response to ER stress. We will now explore the hypothesis that if the expression of any of these factors or Cyclophilin D, a component of the mitochondrial permeability transition pore is reduced in Pdx1 deficient MIN6 cells or Pdx1 mice, survival of beta-cells is increased, beta-cell mass preserved and hyperglycemia delayed or prevented.

Public Health Relevance

The American Diabetes Association [Diabetes Care, 31:1-2, (2008)] points out that in the United States alone, greater than 17.5 million persons have been diagnosed with type 2 diabetes mellitus (T2DM) with an associated yearly economic burden exceeding $174 billion. The incidence of the disease is increasing rapidly on a worldwide basis with staggering impact on cost of healthcare and quality of life. Thus, there is an urgent need to increase our understanding of the pathogenesis of this disorder in order to develop more targeted approaches to prevention and treatment. The proposed studies will define the effects on insulin secretion of specific genes that are associated with increased T2DM risk in the population. We will also study the molecular mechanisms responsible for the death of pancreatic beta-cells in diabetes and explore novel mechanisms to preventing beta-cell loss. If successful these studies could contribute to advances that would have a positive impact on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031842-33
Application #
8489285
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Appel, Michael C
Project Start
1983-01-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
33
Fiscal Year
2013
Total Cost
$474,792
Indirect Cost
$159,888
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Ren, Decheng; Sun, Juan; Wang, Changzheng et al. (2014) Role of BH3-only molecules Bim and Puma in ?-cell death in Pdx1 deficiency. Diabetes 63:2744-50
Pedersen, Morten Gram; Mosekilde, Erik; Polonsky, Kenneth S et al. (2013) Complex patterns of metabolic and Ca²? entrainment in pancreatic islets by oscillatory glucose. Biophys J 105:29-39
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Wice, Burton M; Wang, Songyan; Crimmins, Dan L et al. (2010) Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism. J Biol Chem 285:19842-53
Fujimoto, Kei; Chen, Yun; Polonsky, Kenneth S et al. (2010) Targeting cyclophilin D and the mitochondrial permeability transition enhances beta-cell survival and prevents diabetes in Pdx1 deficiency. Proc Natl Acad Sci U S A 107:10214-9
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Uchizono, Yuji; Baldwin, Aaron C; Sakuma, Hiroya et al. (2009) Role of HNF-1alpha in regulating the expression of genes involved in cellular growth and proliferation in pancreatic beta-cells. Diabetes Res Clin Pract 84:19-26

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