Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes.
Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to increase hepatic fructose 2,6-bisphosphate to determine if the hyperglycemia in KK mice, polygenic models of type 2 diabetes, could be ameliorated by reduction of hepatic glucose production. Seven days after treatment with virus encoding a mutant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase designed to increase fructose 2,6-bisphosphate levels, plasma glucose, lipids, and insulin were significantly reduced in KK/H1J and KK.Cg-A(y)/J mice. Moreover, high fructose 2,6-bisphosphate levels downregulated glucose-6-phosphatase and upregulated glucokinase gene expression, thereby reversing the insulin-resistant pattern of hepatic gene expression of these two key glucose-metabolic enzymes. The increased hepatic fructose 2,6-bisphosphate also reduced adiposity in both KK mice. These results clearly indicate that increasing hepatic fructose 2,6-bisphosphate overcomes the impairment of insulin in suppressing hepatic glucose production, and it provides a potential therapy for type 2 diabetes.
Wu
Chaodong
C
Department of Biochemistry, Molecular Biology and Biophysics, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Okar
David A
DA
Newgard
Christopher B
CB
Lange
Alex J
AJ
D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001769:Blood / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D004822:Epididymis; D005260:Female; D005635:Fructosediphosphates / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D025481:Phosphofructokinase-2 / Q000494:pharmacology*
D005635:Fructosediphosphates; D007328:Insulin; C027652:fructose 2,6-diphosphate; D006003:Glycogen; D025481:Phosphofructokinase-2; D005941:Glucokinase; D005952:Glucose-6-Phosphatase