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Original Research
Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets
Rajakrishnan Veluthakal, Oleg G. Chepurny, Colin A. Leech, Frank Schwede, George G. Holz and Debbie C. Thurmond
Diabetes 2018 Jul; db171174. https://doi.org/10.2337/db17-1174
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Abstract

Glucose metabolism stimulates Cdc42-Pak1 activity and initiates F-actin cytoskeleton remodeling in pancreatic β-cells so that cytoplasmic secretory granules can translocate to the plasma membrane where insulin exocytosis occurs. Since glucose metabolism also generates cAMP in β-cells, the crosstalk of cAMP signaling with Cdc42-Pak1 activation might be of fundamental importance to glucose-stimulated insulin secretion (GSIS). Previously, the cAMP-regulated guanine nucleotide exchange factor Epac2 was established to mediate a potentiation of GSIS by cAMP-elevating agents. Here we report that non-diabetic (ND) human islets and INS-1 832/13 β-cells treated with the selective Epac activator 8-pCPT-2'-O-Me-cAMP-AM exhibited Cdc42-Pak1 activation at 1 mM glucose, and that the magnitude of this effect was equivalent to that which was measured during stimulation with 20 mM glucose in the absence of 8-pCPT-2'-O-Me-cAMP-AM. Conversely, the cAMP antagonist Rp-8-Br-cAMPS-pAB prevented glucose-stimulated Cdc42-Pak1 activation, thereby blocking GSIS while also increasing cellular F-actin content. Although islets from type 2 diabetic (T2D) donors had profound defects in glucose-stimulated Cdc42-Pak1 activation and insulin secretion, these defects were rescued by the Epac activator so that GSIS was restored. Collectively, these findings indicate an unexpected role for cAMP as a permissive or direct metabolic coupling factor in support of GSIS that is Epac2 and Cdc42-Pak1 regulated.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db17-1174.

  • Received September 29, 2017.
  • Accepted June 27, 2018.
  • © 2018 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets
Rajakrishnan Veluthakal, Oleg G. Chepurny, Colin A. Leech, Frank Schwede, George G. Holz, Debbie C. Thurmond
Diabetes Jul 2018, db171174; DOI: 10.2337/db17-1174

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Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets
Rajakrishnan Veluthakal, Oleg G. Chepurny, Colin A. Leech, Frank Schwede, George G. Holz, Debbie C. Thurmond
Diabetes Jul 2018, db171174; DOI: 10.2337/db17-1174
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© 2019 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.