4.6 Article

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

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 5, 页码 3208-3218

出版社

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.437145

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资金

  1. Swedish Medical Research Council [2008-4216]
  2. Novo Nordisk Foundation
  3. European Foundation for the Study of Diabetes
  4. Merck Sharpe and Dohme
  5. Medical Faculty at Lund University
  6. The Crafoord Foundation
  7. The Gyllenstiernska Krapperup Foundation
  8. The Tore Nilsson Foundation
  9. The Ake Wibergs Foundation
  10. The Fredrik and Ingrid Thuring Foundation
  11. The Magnus Bergwall Foundation
  12. The Albert Pahlsson Foundation
  13. Novo Nordisk Fonden [NNF13OC0005033] Funding Source: researchfish

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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. Glucotoxicity in INS-1 (832/13) cells also caused a 50% reduction of endogenous CART protein. We show that CART increased proliferation in INS-1 (832/13) cells, an effect that was blocked by PKA, PKB, and MEK1 inhibitors. In addition, CART induced phosphorylation of CREB, IRS, PKB, FoxO1, p44/42 MAPK, and p90RSK in INS-1 (832/13) cells and isolated rat islets, 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 point 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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