The islet in humans with type 2 diabetes (T2DM) is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP), a protein that is co-expressed and secreted with insulin. Human IAPP (hIAPP) has the propensity to form oligomers in solution. These oligomers appear to form in membranes inducing non selective membrane leakage, for example of Ca2+ into cytosol. In studies supported by this grant we established that ?-cell mass is decreased in humans with T2DM, with increased ?-cell apoptosis. We reproduced the islet and metabolic phenotype of T2DM in rodents over expressing human IAPP, and documented that the toxic form of IAPP oligomers form intracellularly within the secretory pathway leading to endoplasmic reticulum (ER) stress induced apoptosis as well as organelle (mitochondrial) damage. We have established that ?-cells in humans with T2DM are also characterized by intracellular formation of toxic hIAPP oligomers, leakage of Ca2+ into cytosol leading to hyperactivation of the Ca2+ sensitive protease calpain. Collectively these characteristics reproduce those in neurodegenerative diseases mediated by proteotoxicity of amyloidogenic proteins (e.g. Alzheimers). In the neurodegenerative diseases there is an increasing appreciation that proteotoxicity by amyloidogenic proteins is mediated in part through disruption of the cellular mechanisms that remove misfolded and aggregated proteins, the ubiquitin/proteosome system and autophagy. In the proposed studies we propose studies to address the following aims. 1) To establish the specific mechanisms by which IAPP oligomers induce ?-cell apoptosis and dysfunction. 2) To establish if the ubiquitin proteosome system to protect against proteotoxicty is impaired by hIAPP toxic oligomers, and if so through which mechanism(s). 3) To establish if autophagy, the cellular system for removal of toxic oligomers and damaged organelles, is disrupted by hIAPP toxic oligomers, and if so, through which mechanisms. This program of studies would allow us to shed light into the underlying cause of loss of ?-cells in humans, and to establish a rationale approach to preventing this.

Public Health Relevance

More than 25 million Americans now have Type 2 diabetes. The complications arising from type 2 diabetes (blindness, early death through heart disease, loss of limb, kidney failure) are the single largest cost to the US health system. The present studies are targeted to establish a better understanding of the underlying cause of type 2 diabetes so that more rationale efforts can be used to prevent and treat it.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059579-13
Application #
8434259
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
2001-06-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2013
Total Cost
$375,042
Indirect Cost
$131,508
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Costes, Safia; Butler, Peter C (2014) Insulin-degrading enzyme inhibition, a novel therapy for type 2 diabetes? Cell Metab 20:201-3
Rivera, Jacqueline F; Costes, Safia; Gurlo, Tatyana et al. (2014) Autophagy defends pancreatic ? cells from human islet amyloid polypeptide-induced toxicity. J Clin Invest 124:3489-500
Costes, Safia; Langen, Ralf; Gurlo, Tatyana et al. (2013) ?-Cell failure in type 2 diabetes: a case of asking too much of too few? Diabetes 62:327-35
Butler, Peter C; Elashoff, Michael; Elashoff, Robert et al. (2013) A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 36:2118-25
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Saisho, Yoshifumi; Butler, Alexandra E; Manesso, Erica et al. (2013) Response to Comment on: Saisho et al. *-cell mass and turnover in humans: effects of obesity and aging. Diabetes Care 2013;36:111-117. Diabetes Care 36:e112
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Daval, Marie; Gurlo, Tatyana; Costes, Safia et al. (2011) Cyclin-dependent kinase 5 promotes pancreatic ýý-cell survival via Fak-Akt signaling pathways. Diabetes 60:1186-97
Costes, Safia; Huang, Chang-jiang; Gurlo, Tatyana et al. (2011) ?-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency. Diabetes 60:227-38

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