Cocaine- and Amphetamine-regulated Transcript (CART) Protects Beta Cells against Glucotoxicity and Increases Cell Proliferation

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Abstract

Cocaine and amphetamine-regulated transcript (CART) is an islet peptide that promotes glucose stimulated insulin secretion in beta cells via cAMP/PKA-dependent pathways. In addition, CART is a regulator of neuronal survival. In this study, we examined the effect of exogenous CART 55-102 on beta cell viability and dissected its signaling mechanisms. Evaluation of DNA fragmentation and chromatin condensation revealed that CART 55-102 reduced glucotoxicity-induced apoptosis in both INS-1 (832/13) cells and isolated rat islets. Furthermore, glucotoxicity in INS-1 (832/13) cells caused a 50% reduction of endogenous CART protein. In addition, CART increased proliferation in INS-1 (832/13) cells; an effect that was blocked by PKA, PKB, and MEK1 inhibitors. Further, in INS-1 (832/13) cells and isolated rat islets, CART induced phosphorylation of CREB, IRS-2, PKB, FoxO1, p44/42 MAPK, and p90RSK; all key mediators of cell survival and proliferation. Thus, we demonstrate that CART 55-102 protects beta cells against glucotoxicity and promotes proliferation. Taken together our data points to the potential use of CART in therapeutic interventions targeted at enhancing functional beta cell mass and long-term insulin secretion in T2D.

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Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)3208-3218
JournalJournal of Biological Chemistry
Volume288
Issue number5
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes

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