# Mechanism of cdk4 diabetes rescue in IRS2 knockout mice

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $32,470

## Abstract

PROJECT SUMMARY
Type 2 Diabetes (T2D) is a major public health issue in the United States with approximately 9.3% of the
population suffering from the disease. Additionally, 86 million people have prediabetes and the economic
impact is staggering, with 1 in 10 health care dollars being spent on T2D and its complications. T2D results
from insulin resistance and reduced beta cell mass; thus, strategies to increase functional beta cell mass are
critical goals for diabetes research. Although it is well established (from rodent models) that increased beta
cell mass results from enhanced beta cell proliferation, new research suggests that beta cell dedifferentiation
also contributes to reduced beta cell function. Some proteins involved in the G1/S transition of the cell cycle,
especially Cdk4, are critical for the maintenance of beta cell proliferation and mass. Insulin receptor substrate 2
knockout (Irs2 KO) mice develop diabetes due to peripheral insulin resistance and reduced beta cell mass, and
we previously found that in vitro re-expression of cyclin D2, which activates Cdk4, rescues the loss of
proliferation in beta cells lacking Irs2. Therefore, we hypothesized that expression of a constitutively active
form of Cdk4 (Cdk4 R24C) might be able to rescue the diabetic phenotype of Irs2 KO mice. Intriguingly,
preliminary results suggest that Cdk4 R24C is able to completely rescue not only beta cell mass, but also
insulin secretion and beta cell differentiation. Interestingly, recent studies show that the Cdk4 kinase plays
many roles independently of its known activity in the cell cycle. Therefore, the goal of this proposal is to
determine the mechanisms behind this rescue and determine what atypical roles cdk4 plays in the beta cell. In
Aim 1, we will determine how Cdk4 rescues beta cell proliferation, focusing on both the canonical Cdk4-Rb-
E2F pathway, and will also identify novel Cdk4 interactors in the beta cell using BioID. In Aim 2, we will
determine if Cdk4 R24C rescues 1st or 2nd phase insulin secretion in Irs2 KO islets using both islet perifusion
and hyperglycemic clamps studies. We will also perform molecular studies to determine whether the KATPase
Kir6.2, which was previously reported to be a target of the Cdk4-Rb-E2F1 pathway, is increased and is
sufficient to rescue insulin secretion in Irs2 KO islets. Finally, in Aim 3 we will explore how Cdk4 R24C is able
to restore beta cell differentiation markers. This is surprising and interesting, since it goes against the data
showing that when beta cells proliferate they lose differentiation markers, and I think the most likely
explanation is that Cdk4 is having effects unrelated to its cell cycle actions. I will investigate how Cdk4 rescues
Pdx1 expression, with a focus on FoxO1 and PPARγ, two transcription factors that regulate Pdx1 expression.
Using in silico analyses and reading the primary literature, I found that both contain Cdk4 consensus
phosphorylate sites. Therefore, I will determin...

## Key facts

- **NIH application ID:** 9975146
- **Project number:** 5F30DK112591-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Rachel Eileen Stamateris
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,470
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975146

## Citation

> US National Institutes of Health, RePORTER application 9975146, Mechanism of cdk4 diabetes rescue in IRS2 knockout mice (5F30DK112591-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975146. Licensed CC0.

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