Stimulating Effects of Low-Dose Fructose on Insulin-Stimulated Hepatic Glycogen Synthesis in Humans

• Published in: Diabetes (New York, N.Y.) Vol. 50; no. 6; pp. 1263 - 1268
• Main Authors: Petersen, Kitt Falk, Laurent, Didier, Yu, Chunli, Cline, Gary W., Shulman, Gerald I.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2001
• Subjects: Adult; Biological and medical sciences; Carbohydrates; Diabetes; Diabetes research; Dose-Response Relationship, Drug; Female; Fructose; Fructose - administration & dosage; Fructose - pharmacology; Fundamental and applied biological sciences. Psychology; Gas chromatography; Glucose; Glucose - pharmacology; Glycogen; Glycogen - biosynthesis; Glycogen - metabolism; Glycogen Synthase - metabolism; Hormones - blood; Humans; Insulin; Insulin - pharmacology; Liver; Liver - drug effects; Liver - metabolism; Male; Mass spectrometry; Metabolism; Metabolisms and neurohumoral controls; NMR; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Osmolar Concentration; Phosphorylases - metabolism; Physiological aspects; Proteins; Vertebrates: anatomy and physiology, studies on body, several organs or systems; United States; Human; Digestive system; Glycogen; Liver; Biosynthesis; Glycogenolysis; Metabolism; Fructose
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.50.6.1263

Stimulating Effects of Low-Dose Fructose on Insulin-Stimulated Hepatic Glycogen Synthesis in Humans Kitt Falk Petersen 1 , Didier Laurent 1 , Chunli Yu 2 , Gary W. Cline 1 and Gerald I. Shulman 1 2 3 1 Internal Medicine and 2 Cellular and Molecular Physiology and the 3 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut Abstract 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 13 C nuclear magnetic resonance (NMR) spectroscopy to noninvasively assess rates of hepatic glycogen synthesis and glycogenolysis under euglycemic (∼5 mmol/l) hyperinsulinemic conditions (∼400 pmol/l) with and without a low-dose infusion of fructose (∼3.5 μmol · kg –1 · min –1 ). Six healthy overnight-fasted subjects were infused for 4 h with somatostatin (0.1 μg · 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 ∼120-min infusion of unlabeled glucose to assess rates of glycogen phosphorylase flux. Acetaminophen was given to assess the percent contribution of the direct and indirect (gluconeogenic) pathways of glycogen synthesis by the 13 C enrichment of plasma UDP-glucuronide and C-1 of glucose. In the control studies, the flux through glycogen synthase and glycogen phosphorylase 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 min. In the fructose studies, the glycogen synthase flux increased 2.5-fold to 0.79 ± 0.16 mmol/l per min ( P = 0.018 vs. control), whereas glycogen phosphorylase 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 hepatic glycogen synthesis (0.54 ± 0.12 mmol/l per min; P = 0.008 vs. control) without affecting the pathways of hepatic glycogen synthesis (direct pathway ∼60% in both groups). We conclude that during euglycemic hyperinsulinemia, a low-dose fructose infusion causes a threefold increase in net hepatic glycogen synthesis exclusively through stimulation of glycogen synthase flux. Because net hepatic glycogen synthesis has been shown to be diminished in patients with poorly controlled type 1 and type 2 diabetes, stimulation of hepatic glycogen synthesis by this mechanism may be of potential therapeutic value. Footnotes Address correspondence and reprint requests to Kitt Falk Petersen, Dept. of Internal Medicine, Yale University School of Medicine, 333 Cedar St., FMP 104, P.O. Box 208020, New Haven, CT 06520-8020. E-mail: kitt.petersen{at}yale.edu . Received for publication 1 August 2000 and accepted in revised form 5 March 2001. APE, atom percent enrichment; GC-MS, gas chromatography–mass spectrometry; GCRC, General Clinical Research Center; NMR, nuclear magnetic resonance.