Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) was recently identified as a new intracellular binding partner for glucokinase (GK). Therefore, we studied the importance of this interaction for the activity status of GK and glucose metabolism in insulin-producing cells by overexpression of the rat liver and pancreatic islet isoforms of PFK-2/FBPase-2. PFK-2/FBPase-2 overexpression in RINm5F-GK cells significantly increased the GK activity by 78% in cells expressing the islet isoform, by 130% in cells expressing the liver isoform, and by 116% in cells expressing a cAMP-insensitive liver S32A/H258A double mutant isoform. Only in cells overexpressing the wild-type liver PFK-2/FBPase-2 isoform was the increase of GK activity abolished by forskolin, apparently due to the regulatory site for phosphorylation by a cAMP-dependent protein kinase. In cells overexpressing any isoform of the PFK-2/FBPase-2, the increase of the GK enzyme activity was antagonized by treatment with anti-FBPase-2 antibody. Increasing the glucose concentration from 2 to 10 mmol/l had a significant stimulatory effect on the GK activity in RINm5F-GK cells overexpressing any isoform of PFK-2/FBPase-2. The interaction of GK with PFK-2/FBPase-2 takes place at glucose concentrations that are physiologically relevant for the activation of GK and the regulation of glucose-induced insulin secretion. This new mechanism of posttranslational GK regulation may also represent a new site for pharmacotherapeutic intervention in type 2 diabetes treatment.
 ...
PMID:Interaction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) with glucokinase activates glucose phosphorylation and glucose metabolism in insulin-producing cells. 1504 17

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.
 ...
PMID:Improved metabolic stimulus for glucose-induced insulin secretion through GK and PFK-2/FBPase-2 coexpression in insulin-producing RINm5F cells. 1698 Apr 36

The glucose phosphorylating enzyme glucokinase plays a crucial role in stimulus-secretion coupling in pancreatic beta cells and in glucose metabolism in liver. Glucose mediates a shift of the enzyme's conformational equilibrium towards the closed conformation with high glucokinase activity. Further activation of glucokinase is endogenously mediated by interaction with the bisphosphatase domain (FBPase-2) of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) and can be achieved also by a new class of glucokinase activators (GKA), chemical compounds that might be suited for type 2 diabetes therapy. While FBPase-2 increased only the phosphorylating capacity of glucokinase, the GKA LY2121260 augmented in addition the affinity of glucokinase for glucose. PFK-2/FBPase-2 but not LY2121260 antagonized glucokinase inhibition by the competitive glucokinase inhibitor mannoheptulose at increasing glucose concentrations. Interestingly, an additive activation of glucokinase was observed by use of recombinant FBPase-2 together with LY2121260. This new crucial observation could be confirmed with cellular extracts containing the glucokinase and PFK-2/FBPase-2 proteins. Addition of LY2121260 resulted in a further significant increase in glucokinase activity. Because the glucokinase-PFK-2/FBPase-2 complex was conserved under LY2121260 treatment as shown by size exclusion chromatography a concerted action of both activators towards the closed active glucokinase conformation can be anticipated. Thus, as a result of the additive effect of both activators on glucokinase activity, the largest increase of glucose-induced insulin secretion was observed in the combined presence of PFK-2/FBPase-2 and LY2121260.
 ...
PMID:Additive activation of glucokinase by the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and the chemical activator LY2121260. 2230 45