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Improved metabolic stimulus for glucose-induced insulin secretion through GK and PFK-2/FBPase-2 coexpression in insulin-producing RINm5F cells.

Authors: Baltrusch, S  Langer, S  Massa, L  Tiedge, M  Lenzen, S 
Citation: Baltrusch S, etal., Endocrinology. 2006 Dec;147(12):5768-76. Epub 2006 Sep 15.
Pubmed: (View Article at PubMed) PMID:16980436
DOI: Full-text: DOI:10.1210/en.2006-0694

The glucose sensor enzyme glucokinase plays a pivotal role in the regulation of glucose-induced insulin secretion in pancreatic beta-cells. Activation of glucokinase represents a promising concept for the treatment of type 2 diabetes. Therefore, we analyzed the glucokinase activation through its physiological interaction partner, the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) and the resulting effect on glucose metabolism in insulin-producing cells. In RINm5F-GK-PFK-2/FBPase-2 cells stably overexpressing glucokinase plus islet PFK-2/FBPase-2, colocalization between both enzymes as well as elevation of glucokinase activity were significantly increased at a stimulatory glucose concentration of 10 mmol/liter. RINm5F-GK-PFK-2/FBPase-2 cells showed under this culture condition a significant increase in glucose utilization and in the ATP/ADP ratio compared with RINm5F-GK cells, which only overexpress glucokinase. Also glucose-induced insulin secretion was elevated in RINm5F-GK-PFK-2/FBPase-2 cells in comparison to RINm5F-GK cells. Furthermore, pyruvate accumulation and lactate production in RINm5F-GK-PFK-2/FBPase-2 cells were significantly lower at both 10 and 30 mmol/liter glucose than in RINm5F-GK and RINm5F cells. The significant improvement of glucose metabolism after PFK-2/FBPase-2 overexpression is apparently not exclusively the result of high glucokinase enzyme activity. Stabilization of the closed glucokinase conformation by PFK-2/FBPase-2 may not only activate the enzyme but also improve metabolic channeling in beta-cells.

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CRRD Object Information
CRRD ID: 2304071
Created: 2009-03-05
Species: All species
Last Modified: 2009-03-05
Status: ACTIVE



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