# mTOR signaling and regulation of alpha-cell mass and function

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2022 · —

## Abstract

Diabetes mellitus is one of the most prevalent conditions affecting human health including veterans in the 21st
century. Most of the focus of our efforts to understand the pathogenesis and therapy of the disease has
focused on two major components: insulin sensitivity and insulin secretion. However, dysregulation in glucagon
secretion is a major component in diabetes. Hyperglucagonemia plays key roles in the pathogenesis of
hyperglycemia in type 2 diabetes and has a major impact in the glycemic volatility and susceptibility to
hypoglycemia in type 1 diabetes. Our observations published during the current funding period suggest that
downstream of insulin/Akt, the nutrient sensitive pathway (mTOR/Raptor or mTORC1) plays a major role in
regulation of alpha cell mass and glucagon secretion. However, how mTORC1 acting on key downstream
targets (4E-BPs and S6K) regulates the function and mass of alpha-cells in vivo and the potential contribution
of these targets to the regulation of glucose metabolism remain unclear. The long-term goal of these studies is
to uncover how the nutrient sensitive insulin/Akt/mTORC1 axis regulates α-cell mass and glucagon secretion
in rodent models and humans. Our studies showed that loss of mTORC1 function in alpha-cells results in
major abnormalities in alpha-cell mass and glucagon secretion. We also demonstrate that gain of mTORC1
results in chronic hyperglucagonemia and alpha cell mass expansion suggesting that this signaling pathway is
critical for alpha cell mass and glucagon secretion. Based on these observations, we hypothesize that
mTORC1 regulates alpha-cell mass mainly by a balance between S6K and 4E-BP signaling. The specific aims
will assess the individual contribution of downstream targets of mTORC1 by establishing the role of
mTORC1/4E-BP/eIF4E axis in regulation of alpha-cell mass, glucagon secretion and adaptation to
diabetogenic conditions using novel alpha cell specific models. In addition, we will also identify the importance
of mTORC1/S6K on the control of alpha-cell mass and glucagon secretion by generation of novel models with
inducible gain of S6K function in alpha cells. Finally, how mTORC1 activation alters human alpha-cell
responses will be determined using a model of human islet transplantation in the anterior chamber of the
mouse eye. This proposal will provide important insights into the molecular mechanisms that govern alpha-cell
mass expansion by mTORC1. This information can be used to uncover novel targets that can be used for
treatment of diabetes and design interventions to rescue the defects in glucagon secretion in response to
hypoglycemia in patients with diabetes.

## Key facts

- **NIH application ID:** 10455409
- **Project number:** 5I01BX002728-07
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** Ernesto Bernal-Mizrachi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-01-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455409

## Citation

> US National Institutes of Health, RePORTER application 10455409, mTOR signaling and regulation of alpha-cell mass and function (5I01BX002728-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455409. Licensed CC0.

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