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 the understanding of the molecular mechanisms that regulate ?-cell mass with emphasis in proliferation. During the current funding period, we focused on the mechanisms by which Akt and the tuberous sclerosis complex 2 (TSC2) regulate ?-cell mass and cell cycle progression. These studies identified the TSC2 and the mTOR/raptor complex (mTORC1) as important molecules regulating ?-cell mass and proliferation. mTORC1 controls growth and proliferation by activation of 4E-BP and S6 kinases (S6K). Moreover, mTORC1 also mediates a negative feedback loop to attenuate Akt signaling. However, uncertainty remains as to the underlying mechanism and key downstream effectors responsible for controlled ?-cell expansion by mTORC1. The objective of this application is to understand how mTORC1 targets regulate ?-cell mass and proliferation. We hypothesize that ?-cell mass expansion by mTORC1 signaling is mediated by a balance between two processes: activation of downstream targets and negative feedback inhibition of IRS/Akt signaling.
The specific aims are (1) to establish how mTORC1 targets regulate ?-cell mass expansion. These studies will evaluate the individual contributions of S6K1 and 4E-BP on regulation of cell growth and proliferation. (2) Determine how decreased Akt signaling by mTORC1-mediated negative feedback modulates ?-cell mass expansion. These experiments will evaluate the role of GSK3? and FoxO on mTORC1-S6K mediated feedback inhibition on IRS/Akt signaling. This proposal will provide important insights into the molecular mechanisms that govern ?-cell mass expansion 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 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 #
5R01DK073716-08
Application #
8479346
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Silva, Corinne M
Project Start
2005-12-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$329,709
Indirect Cost
$117,678
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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