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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Moin, Abu Saleh Md; Cory, Megan; Choi, Jennifer et al. (2018) Increased Chromogranin A-Positive Hormone-Negative Cells in Chronic Pancreatitis. J Clin Endocrinol Metab 103:2126-2135
Butler, Alexandra E; Kirakossian, David; Gurlo, Tatyana et al. (2018) In the Setting of Beta Cell Stress, the Pancreatic Duct Gland Transcriptome Shows Characteristics of an Activated Regenerative Response. Am J Physiol Gastrointest Liver Physiol :
Ruiz, Lucie; Gurlo, Tatyana; Ravier, Magalie A et al. (2018) Proteasomal degradation of the histone acetyl transferase p300 contributes to beta-cell injury in a diabetes environment. Cell Death Dis 9:600
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
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
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
Butler, Peter C (2016) Glucagon-like Peptide 1 Drugs as Second-line Therapy for Type 2 Diabetes. JAMA Intern Med 176:1-3
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

Showing the most recent 10 out of 58 publications