Summary
We examined the interrelationship of lipid and glucose metabolism in the basal state and during insulin stimulus in 19 healthy men (27 ±2 years, body mass index 23.6 ±0.6 kg/m2). In each subject, we performed a 4-h euglycaemic (5.3 ±0.1 mmol/1) hyperinsulinaemic (647 ±21 pmol/1) insulin clamp with indirect calorimetry in the basal state and during insulin infusion, and muscle biopsies before and at the end of the clamp. In the basal state, serum non-esterified fatty acid levels correlated directly with lipid oxidation (r = 0.56, p < 0.05) and indirectly with glucose oxidation (r = −0.80, p < 0.001). Lipid and glucose oxidation rates were inversely related in the basal state (r = −0.47, p < 0.05) and during insulin infusion (r = −0.65, p < 0.01). Basal lipid oxidation and glycogen synthase total activity correlated inversely (r = −0.54, p < 0.05). Lipid oxidation both in the basal state (r = −0.61, p < 0.01) and during insulin infusion (r = −0.62, p < 0.05) was inversely related to muscle glycogen content after the insulin clamp. Fasting plasma triglyceride concentration correlated directly to fasting insulin (r = 0.55, p < 0.05) and C-peptide (r = 0.50, p < 0.03) concentrations and inversely to non-oxidative glucose disposal rate at the end of clamp (r = −0.54, p < 0.05). In conclusion: 1) Serum non-esterified fatty acid concentration enhances lipid and reduces glucose oxidation. 2) Lipid oxidation is inversely related to total glycogen synthase activity. 3) Lipid oxidation both in the basal state and during insulin stimulus correlates inversely with muscle glycogen content after insulin infusion. 4) Even in normotriglyceridaemic subjects, plasma triglycerides reduce insulin-stimulated non-oxidative glucose disposal. These data suggest that serum non-esterified fatty acids in physiologic concentrations have an important role in the regulation of lipid and glucose oxidation as well as glucose storage as glycogen.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet I: 785–789
Damsbo P, Vaag A, Hother-Nielsen O, Beck-Nielsen H (1991) Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 34: 239–245
DeFronzo RA, Bonadonna RC, Ferrannini E (1992) Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15: 316–368
Eriksson J, Franssila-Kallunki A, Ekstrand A et al. (1989) Early metabolic defects in persons at increased risk for noninsulin dependent diabetes mellitus. N Engl J Med 321: 337–343
Ferrannini E, Buzzigoli G, Bonadonna R et al. (1987) Insulin resistance in essential hypertension. N Engl J Med 317: 350–357
Yki-Järvinen H, Puhakainen I, Koivisto VA (1991) Effect of free fatty acids on glucose uptake and nonoxidative glycolysis across human forearm tissues in the basal state and during insulin stimulation. J Clin Endocrinol Metab 72: 1268–1277
Nuutila, P, Koivisto VA, Knuuti J et al. (1992) Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest 89: 1767–1744
Groop LC, Bonadonna RC, Del Prato S et al. (1989) Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus: evidence for multiple sites of insulin resistance. J Clin Invest 84: 205–213
Vaag A, Henriksen JE, Beck-Nielsen H (1992) Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus. J Clin Invest 89: 782–788
Thorburn AW, Gumbiner B, Bulacan F, Brectel G, Henry RR (1991) Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin dependent diabetes mellitus. J Clin Invest 87: 489–495
Schalin-Jäntti C, Härkönen M, Groop LC (1992) Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes 41: 598–604
Taylor AW, Thayer R, Rao S (1972) Human skeletal muscle glycogen synthase activities with exercise and training. Can J Physiol Pharmacol 50: 411–415
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237: E214-E224
Yki-Järvinen H, Koivisto VA (1986) Natural course of insulin resistance in type I diabetes. N Engl J Med 315: 224–230
Koivisto VA, Yki-Järvinen H, Puhakainen I, Virkamäki A, Kolaczynski J, DeFronzo RA (1990) No evidence for isotope discrimination of tritiated glucose tracers in measurements of glucose turnover rates in man. Diabetologia 33: 168–173
Yki-Järvinen H, Sahlin K, Ren JM, Koivisto VA (1990) Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients. Diabetes 39: 157–167
Vuorinen-Markkola H, Koivisto VA, Yki-Järvinen H (1992) Mechanisms of hyperglycemia-induced insulin resistance in whole body and skeletal muscle of type 1 diabetic patients. Diabetes 41: 571–580
Ferrannini E (1987) The theoretical basis for indirect calorimetry: a review. Metabolism 37: 287–301
Hornbrook KR, Birch HB, Lowry OH (1966) The effects of adrenalectomy and hydrocortisone on rat liver metabolites and glycogen synthase activity. Mol Pharmacol 2: 106–116
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193: 265–275
Borg, G (1962) Physical performance and perceived exertion. Gleerup, Lund, pp 1–62
Desbuquois B, Aurbach GD (1971) Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassays. J Clin Endocrinol Metab 33: 732–738
Heding LG (1975) Radioimmunological determination of human C-peptide in serum. Diabetologia 11: 541–548
Miles J, Glasscock R, Aikens J, Gerich J, Haymond M (1983) A microfluorometric method for the determination of free fatty acids in plasma. J Lipid Res 24: 96–99
Siedel J, Hagele EO, Ziegenhorn J, Wahlefeld AW (1983) Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency. Clin Chem 29: 1075–1080
Finley PR, Schifman RB, Williams RJ, Lichti DA (1978) Cholesterol in high density lipoprotein: use of Mg2+/dextran sulphate in its enzymic measurement. Clin Chem 26: 931–933
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18: 499–502
Bergmeyer HU (1974) Metoden der enzymatischen Analyse, 3. Auflage, Bd. II. Verlag Chemie, Weinheim, p 1878
Ferrannini E, Barrett EJ, Bevilaqua S, DeFronzo RA (1989) Effect of fatty acids on glucose production and utilization in man. J Clin Invest 72: 1737–1747
Saloranta C, Koivisto VA, Widen E et al. (1993) Contribution of muscle and liver to the glucose/fatty acid cycle in man. Am J Physiol 264: E599-E605
Tobey TA, Greenfield M, Kreamer F, Reaven GM (1981) Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics and plasma triglyceride levels in normotriglyceridemic man. Metabolism 30: 165–171
Yki-Järvinen H, Taskinen M-R, Koivisto VA, Nikkilä EA (1984) Response of adipose tissue lipoprotein lipase activity and serum lipoproteins to acute hyperinsulinaemia in man. Diabetologia 27: 364–369
Lillioja S, Bogardus C, Mott DM, Kennedy AL, Knowler WC, Howard BV (1985) Relationship between insulin-mediated glucose disposal and lipid metabolism in man. J Clin Invest 75: 1106–1115
Lee KU, Lee HK, Koh CS, Min KH (1988) Artificial induction of intravascular lipolysis by lipid-heparin infusion leads to insulin resistance in man. Diabetologia 31: 285–290
Felber J-P, Ferrannini E, Golay A (1987) Role of lipid oxidation in the pathogenesis of insulin resistance in obesity and type II diabetes. Diabetes 36: 1341–1350
Godsland IF, Crook D, Walton C, Wynn V, Oliver MF (1992) Influence of insulin resistance, secretion and clearance on serum cholesterol, triglycerides, lipoprotein cholesterol and blood pressure in healthy men. Arteriosclerosis Thrombosis 12: 1030–1035
Larner J (1988) Insulin-signaling mechanisms. Lessons from the old testament of glycogen metabolism and the new testament of molecular biology. Diabetes 37: 262–275
Chait A, Bierman EL, Albers J (1979) Low-density lipoprotein receptor activity in cultured human skin fibroblasts. J Clin Invest 64: 14A
Kissebah AH, Alfarsi S, Evans DJ, Adams PW (1983) Plasma low density lipoprotein transport kinetics in non-insulin dependent diabetes mellitus. J Clin Invest 71: 655–667
Sadur CN, Eckel RH (1983) Insulin-mediated increases in the HDL cholesterol/cholesterol ratio in humans. Arteriosclerosis 3: 339–343
Vuorinen-Markkola H, Yki-Järvinen H, Taskinen M-R (1993) Lowering of triglycerides by gemfibrozil affects neither the glucoregulatory nor antilipolytic effect of insulin in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36: 161–169
Taskinen M-R, Kahri J, Koivisto VA, Packard CJ (1992) Metabolism of HDL apolipoprotein A-I and A-II in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 35: 347–356
Rosenstock J, Vega GL, Raskin P (1988) Effect of intensive diabetes treatment on low-density lipoprotein apolipoprotein B kinetics in type 1 diabetes. Diabetes 37: 393–397
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ebeling, P., Koivisto, V.A. Non-esterified fatty acids regulate lipid and glucose oxidation and glycogen synthesis in healthy man. Diabetologia 37, 202–209 (1994). https://doi.org/10.1007/s001250050094
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/s001250050094