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Diabetes. 2018 Oct;67(10):1999-2011. doi: 10.2337/db17-1174. Epub 2018 Jul 9.

Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets.

Author information

1
Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA rveluthakal@coh.org.
2
Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY.
3
Department of Surgery, State University of New York, Upstate Medical University, Syracuse, NY.
4
BIOLOG Life Science Institute, Bremen, Germany.
5
Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY.
6
Department of Molecular and Cellular Endocrinology, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA.

Abstract

Glucose metabolism stimulates cell division control protein 42 homolog (Cdc42)-p21-activated kinase (Pak1) activity and initiates filamentous actin (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 cross talk of cAMP signaling with Cdc42-Pak1 activation might be of fundamental importance to glucose-stimulated insulin secretion (GSIS). Previously, the type-2 isoform of cAMP-regulated guanine nucleotide exchange factor 2 (Epac2) was established to mediate a potentiation of GSIS by cAMP-elevating agents. Here we report that nondiabetic 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 mmol/L glucose and that the magnitude of this effect was equivalent to that which was measured during stimulation with 20 mmol/L 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 donors with type 2 diabetes 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.

PMID:
29986926
PMCID:
PMC6152341
[Available on 2019-10-01]
DOI:
10.2337/db17-1174
[Indexed for MEDLINE]
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