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Endocrinology. 2012 Feb;153(2):574-82. doi: 10.1210/en.2011-0259. Epub 2011 Dec 6.

Glucagon-like peptide-1 enhances glucokinase activity in pancreatic β-cells through the association of Epac2 with Rim2 and Rab3A.

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1
Department of Physiology, Keimyung University School of Medicine, Daegu 704-701, Korea.

Erratum in

  • Endocrinology. 2012 Apr;153(4):2047.

Abstract

Glucokinase (GK), which phosphorylates D-glucose, is a major glucose sensor in β-cells for glucose-stimulated insulin secretion (GSIS) and is a promising new drug target for type 2 diabetes (T2D). In T2D, pancreatic β-cells exhibit defective glucose sensitivity, which leads to impaired GSIS. Although glucagon-like peptide-1-(7-36)-amide (GLP-1) is known to enhance β-cell glucose sensitivity, the effect of GLP-1 on GK activity is still unknown. The present study demonstrated that GLP-1 pretreatment for 30 min significantly enhanced GK activity in a glucose-dependent manner, with a lower Michaelis-Menten constant (K(m)) but unchanged maximal velocity (V(max)). Thus, GLP-1 acutely enhanced cellular glucose uptake, mitochondrial membrane potential, and cellular ATP levels in response to glucose in rat INS-1 and native β-cells. This effect of GLP-1 occurred via its G protein-coupled receptor pathway in a cAMP-dependent but protein kinase A-independent manner with evidence of exchange protein activated by cAMP (Epac) involvement. Silencing Epac2, interacting molecule of the small G protein Rab3 (Rim2), or Ras-associated protein Rab3A (Rab3A) significantly blocked the effect of GLP-1. These results suggested that GLP-1 can further potentiate GSIS by enhancing GK activity through the signaling of Epac2 to Rim2 and Rab3A, which is the similar pathway for GLP-1 to potentiate Ca(2+)-dependent insulin granule exocytosis. The present finding may also be an important mechanism of GLP-1 for recovery of GSIS in T2D.

PMID:
22147008
DOI:
10.1210/en.2011-0259
[Indexed for MEDLINE]
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