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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

Institute of Clinical Biochemistry (S.B., S.La., L.M., M.T., S.Le.), Hannover Medical School, 30623 Hannover, Germany; and Institute of Medical Biochemistry and Molecular Biology (M.T.), University of Rostock, 18057 Rostock, Germany

Address all correspondence and requests for reprints to: Dr. Simone Baltrusch, Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany. E-mail: baltrusch.simone{at}mh-hannover.de.

The glucose sensor enzyme glucokinase plays a pivotal role in the regulation of glucose-induced insulin secretion in pancreatic ß-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 ß-cells.

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