Type 2 diabetes is increasingly common, is developing at an earlier age and causing devastating complications to many Americans (25 million already have the disease and another 25 million are at high risk). The underlying cause of the disease is a failure of the pancreas to make sufficient insulin, a hormone that regulates the blood glucose levels and prevents diabetes. This competitive renewal seeks continued funding of a research group at the Hillblom Islet Research Center at UCLA to support our efforts to establish the underlying cause of failure of the cells that make and secrete insulin in type 2 diabetes, and in doing so to develop new approaches to treatment of this disease. Our focus is on the role of small tangles of proteins called oligomers that form in the pancreatic beta cells that make and secrete insulin in people who develop type 2 diabetes. Our work has shown that in people with type 2 diabetes these tangles cause leakage of the cell membranes that allows calcium ions into compartments of the cell that are not appropriate and drives the activation of enzymes that inappropriately remodel the cells protein skeleton (cytoskeleton) causing a series of subsequent damaging alterations into how the cell functions as well as limiting the ability of the cell to repair itself. The mitochondria are particularly vulnerable to this damage. We propose studies to investigate these processes and to test a new approach to treating type 2 diabetes, in particular, to blunt the undesirable cytoskeleton remodeling.

Public Health Relevance

Type 2 diabetes is developed as a consequence of inadequate insulin secretion in response to relative insulin resistance. The basis for the inadequate insulin secretion remains unclear, but the molecular and pathololgical changes in the islet in human with type 2 diabetes is highly reminiscent of that in the brain in neurodegenerative diseases, with protein misfolding and toxic oligomers disrupting cellular function and viability. The burden of type 2 diabetes and neurodegenerative diseases to public health is huge and novel more effective strategies to combat these diseases would have great impact on public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059579-15
Application #
9015771
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2001-06-01
Project End
2020-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
15
Fiscal Year
2016
Total Cost
Indirect Cost
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
Montemurro, Chiara; Vadrevu, Suryakiran; Gurlo, Tatyana et al. (2017) Cell cycle-related metabolism and mitochondrial dynamics in a replication-competent pancreatic beta-cell line. Cell Cycle 16:2086-2099
Butler, Peter C (2016) Glucagon-like Peptide 1 Drugs as Second-line Therapy for Type 2 Diabetes. JAMA Intern Med 176:1-3
Gurlo, Tatyana; Costes, Safia; Hoang, Jonathan D et al. (2016) ? Cell-specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity. JCI Insight 1:e89590
Gurlo, T; Rivera, J F; Butler, A E et al. (2016) CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced ?-Cell Apoptosis. Mol Endocrinol 30:446-54
Mukherjee, Abhisek; Morales-Scheihing, Diego; Butler, Peter C et al. (2015) Type 2 diabetes as a protein misfolding disease. Trends Mol Med 21:439-49
Kegulian, Natalie C; Sankhagowit, Shalene; Apostolidou, Melania et al. (2015) Membrane Curvature-sensing and Curvature-inducing Activity of Islet Amyloid Polypeptide and Its Implications for Membrane Disruption. J Biol Chem 290:25782-93
Satin, Leslie S; Butler, Peter C; Ha, Joon et al. (2015) Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes. Mol Aspects Med 42:61-77
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; Gurlo, Tatyana; Rivera, Jacqueline F et al. (2014) UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in ?-cells: evidence of interplay between the ubiquitin/proteasome system and autophagy. Autophagy 10:1004-14

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