Diabetes afflicts 366 million worldwide and results in one death every 7 seconds, with 80% of deaths occurring in low- and middle-income countries. Additionally, diabetes creates $465 billion in healthcare costs every year. Central to the pathology of type 1 and 2 diabetes is dysfunction and death of insulin-producing beta cells. Our search for mechanisms to prevent beta-cell dysfunction and death, and to regenerate the lost beta-cell mass, led us to organisms with extreme metabolic physiology. Through millions of years of evolution, extreme organisms have arisen that thrive under conditions otherwise pathological to humans. One such group of organisms are binge-eating snakes, whose beta cells survive under conditions that are pathological to human beta cells. We have identified a group of such snakes whose beta cells can withstand hypoxia, hyperoxia, lipotoxic stress, and undergo non-pathologic hypertrophy when these snakes eat their large meals. Further, our data suggests that these snakes possess molecules that can induce desirable phenotypes in mammalian beta cells. The goal of this proposal is to identify the molecules that enhance human beta-cell mass and function. We also propose to delineate the signaling pathways that underlie the other extreme phenotypes exhibited by the beta cells of these snakes, with the ultimate aim of manipulate these pathways in human beta cells using small molecules.

Public Health Relevance

Diabetes is characterized by dysfunction and death of insulin-producing beta. We have identified a particular adult amniote which possesses the unmatched capacity to increase its beta cell mass and function under conditions that are pathological to the human beta cells. The goal of this proposal is to identify the molecules and understand the molecular mechanism by which this amniote's beta cells survive conditions pathological to human beta cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK113597-03
Application #
9525334
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pawlyk, Aaron C
Project Start
2016-09-25
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
Andrew, Audra L; Perry, Blair W; Card, Daren C et al. (2017) Growth and stress response mechanisms underlying post-feeding regenerative organ growth in the Burmese python. BMC Genomics 18:338