Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans

Fructose has been shown to have a catalytic effect on glucokinase activity in vitro; however, its effects on hepatic glycogen metabolism in humans is unknown. To address this question, we used C-13 nuclear magnetic resonance (NMR) spectroscopy to noninvasively assess rates of hepatic glycogen synthe sis and glycogenolysis under euglycemic (similar to5 mmol/l) hyperinsulinem ic conditions (similar to 400 pmol/l) with and without a low-dose infusion of fructose (similar to3,5 mu mol.kg(-1).min(-1)). Six healthy overnight-fa sted subjects were infused for 4 h with somatostatin (0.1 mug.kg(-1).min(-1 )) and insulin (240 pmol.m(-2).min(-1)). During the initial 120 min, [1(-13 )C]glucose was infused to assess glycogen synthase flux followed by an simi lar to 120-min infusion of unlabeled glucose to assess rates of glycogen ph osphorylase flux. Acetaminophen was given to assess the percent contributio n of the direct and indirect (gluconeogenic) pathways of glycogen synthesis by the C-13 enrichment of plasma UDP-glucuronide and C-1 of glucose. In th e control studies, the flux through glycogen synthase and glycogen phosphor ylase was 0.31 +/- 0.06 and 0.17 +/- 0.04 mmol/l per min, respectively, and the rate of net hepatic glycogen synthesis was 0.14 +/- 0.05 mmol/l per mi n, In the fructose studies, the glycogen synthase flux increased 2.5-fold t o 0.79 +/- 0.16 mmol/l per min (P = 0.018 vs. control), whereas glycogen ph osphorylase flux remained unchanged (0.24 +/- 0.06; P = 0.16 vs. control). The infusion of fructose resulted in a threefold increase in rates of net h epatic glycogen synthesis (0.54 +/- 0.12 mmol/l per min; P = 0.008 vs. cont rol) without affecting the pathways of hepatic glycogen synthesis (direct p athway similar to 60% in both groups). We conclude that during euglycemic h yperinsulinemia, a low-dose fructose infusion causes a threefold increase i n net hepatic glycogen synthesis exclusively through stimulation of glycoge n synthase flux. Because net hepatic glycogen synthesis has been shown to b e diminished in patients with poorly controlled type 1 and type 2 diabetes, stimulation of hepatic glycogen synthesis by this mechanism may be of pote ntial therapeutic value.