Numerous recent studies link development of diabetes to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein-folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in ?-cells, to ?-cell apoptosis, and to general peripheral insulin resistance, all hallmarks of type 2 diabetes; additionally ER stress is evident in type 1 diabetes. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that key components of the UPR, act as toggling switches between homeostatic and apoptotic outputs, ultimately controlling ?-cell fate. Our project goal is to study these switches at the molecular level, using interventional approaches.

Public Health Relevance

Type 2 diabetes mellitus (T2D) affects 18 million Americans, with national healthcare and lost productivity costs exceeding $100 billion per year. T2D begins as a state of compensated insulin resistance; frank disease develops when approximately 50% of insulin-producing pancreatic islet ?-cells of affected individuals undergo cell death. A detaile understanding of how ?-cells die is necessary to rationally mount an assault on all forms of diabetes, including also type 1 diabetes (T1D). We hypothesize that the stress from having to overwork may be generally responsible for ?-cell death in diabetes. In this proposal we are testing this concept using molecular, cellular, and interventional approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080955-09
Application #
9280930
Study Section
Special Emphasis Panel (ZRG1-CADO-Q (08)F)
Program Officer
Haft, Carol R
Project Start
2008-04-01
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
9
Fiscal Year
2017
Total Cost
$332,850
Indirect Cost
$122,850
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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