Title | Noncanonical CDK4 signaling rescues diabetes in a mouse model by promoting β cell differentiation. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Stamateris RE, Landa-Galvan HV, Sharma RB, Darko C, Redmond D, Rane SG, Alonso LC |
Journal | J Clin Invest |
Volume | 133 |
Issue | 18 |
Date Published | 2023 Sep 15 |
ISSN | 1558-8238 |
Keywords | Animals, Cell Dedifferentiation, Cell Differentiation, Diabetes Mellitus, Type 2, Disease Models, Animal, Insulin Resistance, Islets of Langerhans, Mice |
Abstract | <p>Expanding β cell mass is a critical goal in the fight against diabetes. CDK4, an extensively characterized cell cycle activator, is required to establish and maintain β cell number. β cell failure in the IRS2-deletion mouse type 2 diabetes model is, in part, due to loss of CDK4 regulator cyclin D2. We set out to determine whether replacement of endogenous CDK4 with the inhibitor-resistant mutant CDK4-R24C rescued the loss of β cell mass in IRS2-deficient mice. Surprisingly, not only β cell mass but also β cell dedifferentiation was effectively rescued, despite no improvement in whole body insulin sensitivity. Ex vivo studies in primary islet cells revealed a mechanism in which CDK4 intervened downstream in the insulin signaling pathway to prevent FOXO1-mediated transcriptional repression of critical β cell transcription factor Pdx1. FOXO1 inhibition was not related to E2F1 activity, to FOXO1 phosphorylation, or even to FOXO1 subcellular localization, but rather was related to deacetylation and reduced FOXO1 abundance. Taken together, these results demonstrate a differentiation-promoting activity of the classical cell cycle activator CDK4 and support the concept that β cell mass can be expanded without compromising function.</p> |
DOI | 10.1172/JCI166490 |
Alternate Journal | J Clin Invest |
PubMed ID | 37712417 |
PubMed Central ID | PMC10503800 |
Grant List | T32 GM107000 / GM / NIGMS NIH HHS / United States K08 DK076562 / DK / NIDDK NIH HHS / United States U2C DK093000 / DK / NIDDK NIH HHS / United States R01 DK095140 / DK / NIDDK NIH HHS / United States F30 DK112591 / DK / NIDDK NIH HHS / United States R01 DK124906 / DK / NIDDK NIH HHS / United States R01 DK114686 / DK / NIDDK NIH HHS / United States |