# AKT/mTOR signaling and regulation of cell cycle in B-cells

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $446,573

## Abstract

Project Summary/Abstract
The capacity of β-cells to expand in response to insulin resistance is critical to develop type-2 diabetes and β-
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 β-cell mass and
function. During the current funding period, we identified mTOR/raptor complex (mTORC1) as a major player in
regulating β-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) β-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 β-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 β-cell mass and insulin secretion by
mTORC1. This information can be used to expand drug development opportunities for diabetes.

## Key facts

- **NIH application ID:** 10093016
- **Project number:** 5R01DK073716-14
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Ernesto Bernal-Mizrachi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $446,573
- **Award type:** 5
- **Project period:** 2019-04-11 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093016

## Citation

> US National Institutes of Health, RePORTER application 10093016, AKT/mTOR signaling and regulation of cell cycle in B-cells (5R01DK073716-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10093016. Licensed CC0.

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