The capacity of ?-cells to expand in response to insulin resistance is critical to develop type-2 diabetes and ?- cell proliferation is a major component for these adaptive responses. The long-term goal of our previous and proposed studies under this award is to understand the molecular mechanisms that regulate ?-cell mass and function. During the current funding period, we identified mTOR/raptor complex (mTORC1) as a major player in regulating ?-cell mass and insulin secretion. We uncovered the individual contribution of the mTORC1 downstream targets 4E-BP, S6 kinases (S6K) and ULK on the regulation of ?-cell growth, proliferation, survival, insulin processing and secretion. We also discovered a novel mTORC1/4E-BP2/eIF4E/SH2B1 positive feedback loop that increases IRS2 signaling. However, uncertainty remains as to how mTORC1 acting on 4E-BP2, S6K and ULK controls ?-cell mass and insulin secretion. The objective of this application is to build on these observations and determine how mTORC1 regulates ?-cell mass and insulin secretion. We hypothesize that mTORC1 regulates (i) ?-cell mass in a 4E-BP2/SH2B1 and JNK3-dependent manner and (ii) insulin secretion by regulating stages proximal to calcium influx and autophagy mediated process.
The specific aims are (1) Establish how 4E-BP2/eIF4E acting on SH2B1 and JNK3 regulates ?-cell mass expansion. (2) Determine how mTORC1 modulates insulin secretion and adaptation to diabetogenic conditions. This proposal will provide important insights into the molecular mechanisms that govern ?-cell mass and insulin secretion by mTORC1. This information can be used to expand drug development opportunities for diabetes.

Public Health Relevance

Failure of ?-cells to expand or adapt to insulin resistance results in type 2 diabetes. The current evidence support the concept that mTORC1 is active in states of increased insulin demand and plays a major role in ?- cell adaptation to insulin resistance. The goal of this application is to unravel how mTORC1 regulates ?-cell mass and insulin secretion in an effort to develop strategies to identify pharmacological targets to improve ?- cell mass and function for the treatment of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073716-14
Application #
10093016
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Silva, Corinne M
Project Start
2019-04-11
Project End
2023-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
14
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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