Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus. (original) (raw)

• Journal List
• J Clin Invest
• v.91(2); 1993 Feb
• PMC287962

J Clin Invest. 1993 Feb; 91(2): 484–494.

Division of Diabetes, University of Texas Health Science Center, San Antonio.

Abstract

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.

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• Kimmerling G, Javorski C, Olefsky JM, Reaven GM. Locating the site(s) of insulin resistance in patients with nonketotic diabetes mellitus. Diabetes. 1976 Aug;25(8):673–678. [PubMed] [Google Scholar]
• Rizza RA, Mandarino LJ, Gerich JE. Mechanism and significance of insulin resistance in non-insulin-dependent diabetes mellitus. Diabetes. 1981 Dec;30(12):990–995. [PubMed] [Google Scholar]
• Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest. 1984 Oct;74(4):1238–1246. [PMC free article] [PubMed] [Google Scholar]
• DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. [PubMed] [Google Scholar]
• Arner P, Pollare T, Lithell H, Livingston JN. Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1987 Jun;30(6):437–440. [PubMed] [Google Scholar]
• Caro JF, Sinha MK, Raju SM, Ittoop O, Pories WJ, Flickinger EG, Meelheim D, Dohm GL. Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes. J Clin Invest. 1987 May;79(5):1330–1337. [PMC free article] [PubMed] [Google Scholar]
• Kolterman OG, Gray RS, Griffin J, Burstein P, Insel J, Scarlett JA, Olefsky JM. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981 Oct;68(4):957–969. [PMC free article] [PubMed] [Google Scholar]
• Olefsky JM, Kolterman OG. Mechanisms of insulin resistance in obesity and noninsulin-dependent (type II) diabetes. Am J Med. 1981 Jan;70(1):151–168. [PubMed] [Google Scholar]
• DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000–1007. [PubMed] [Google Scholar]
• Golay A, DeFronzo RA, Ferrannini E, Simonson DC, Thorin D, Acheson K, Thiébaud D, Curchod B, Jéquier E, Felber JP. Oxidative and non-oxidative glucose metabolism in non-obese type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1988 Aug;31(8):585–591. [PubMed] [Google Scholar]
• Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest. 1989 Jul;84(1):205–213. [PMC free article] [PubMed] [Google Scholar]
• Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WG, Bogardus C. Glucose storage is a major determinant of in vivo "insulin resistance" in subjects with normal glucose tolerance. J Clin Endocrinol Metab. 1986 May;62(5):922–927. [PubMed] [Google Scholar]
• Mandarino LJ, Wright KS, Verity LS, Nichols J, Bell JM, Kolterman OG, Beck-Nielsen H. Effects of insulin infusion on human skeletal muscle pyruvate dehydrogenase, phosphofructokinase, and glycogen synthase. Evidence for their role in oxidative and nonoxidative glucose metabolism. J Clin Invest. 1987 Sep;80(3):655–663. [PMC free article] [PubMed] [Google Scholar]
• Felber JP, Golay A, Felley C, Jéquier E. Regulation of glucose storage in obesity and diabetes: metabolic aspects. Diabetes Metab Rev. 1988 Nov;4(7):691–700. [PubMed] [Google Scholar]
• DeFronzo RA, Ferrannini E, Koivisto V. New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus. Am J Med. 1983 Jan 17;74(1A):52–81. [PubMed] [Google Scholar]
• Revers RR, Fink R, Griffin J, Olefsky JM, Kolterman OG. Influence of hyperglycemia on insulin's in vivo effects in type II diabetes. J Clin Invest. 1984 Mar;73(3):664–672. [PMC free article] [PubMed] [Google Scholar]
• Edelman SV, Laakso M, Wallace P, Brechtel G, Olefsky JM, Baron AD. Kinetics of insulin-mediated and non-insulin-mediated glucose uptake in humans. Diabetes. 1990 Aug;39(8):955–964. [PubMed] [Google Scholar]
• Baron AD, Laakso M, Brechtel G, Edelman SV. Reduced capacity and affinity of skeletal muscle for insulin-mediated glucose uptake in noninsulin-dependent diabetic subjects. Effects of insulin therapy. J Clin Invest. 1991 Apr;87(4):1186–1194. [PMC free article] [PubMed] [Google Scholar]
• Schoeller DA, van Santen E, Peterson DW, Dietz W, Jaspan J, Klein PD. Total body water measurement in humans with 18O and 2H labeled water. Am J Clin Nutr. 1980 Dec;33(12):2686–2693. [PubMed] [Google Scholar]
• DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. [PubMed] [Google Scholar]
• Simonson DC, DeFronzo RA. Indirect calorimetry: methodological and interpretative problems. Am J Physiol. 1990 Mar;258(3 Pt 1):E399–E412. [PubMed] [Google Scholar]
• Rossetti L, Giaccari A. Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. J Clin Invest. 1990 Jun;85(6):1785–1792. [PMC free article] [PubMed] [Google Scholar]
• HALES CN, RANDLE PJ. Immunoassay of insulin with insulin-antibody precipitate. Biochem J. 1963 Jul;88:137–146. [PMC free article] [PubMed] [Google Scholar]
• Miles J, Glasscock R, Aikens J, Gerich J, Haymond M. A microfluorometric method for the determination of free fatty acids in plasma. J Lipid Res. 1983 Jan;24(1):96–99. [PubMed] [Google Scholar]
• McMahon MM, Schwenk WF, Haymond MW, Rizza RA. Underestimation of glucose turnover measured with [6-3H]- and [6,6-2H]- but not [6-14C]glucose during hyperinsulinemia in humans. Diabetes. 1989 Jan;38(1):97–107. [PubMed] [Google Scholar]
• Scheinberg P, Stead EA. THE CEREBRAL BLOOD FLOW IN MALE SUBJECTS AS MEASURED BY THE NITROUS OXIDE TECHNIQUE. NORMAL VALUES FOR BLOOD FLOW, OXYGEN UTILIZATION, GLUCOSE UTILIZATION, AND PERIPHERAL RESISTANCE, WITH OBSERVATIONS ON THE EFFECT OF TILTING AND ANXIETY. J Clin Invest. 1949 Sep;28(5 Pt 2):1163–1171. [PMC free article] [PubMed] [Google Scholar]
• ROWE GG, MAXWELL GM, CASTILLO CA, FREEMAN DJ, CRUMPTON CW. A study in man of cerebral blood flow and cerebral glucose, lactate and pyruvate metabolism before and after eating. J Clin Invest. 1959 Dec;38:2154–2158. [PMC free article] [PubMed] [Google Scholar]
• Young AA, Bogardus C, Wolfe-Lopez D, Mott DM. Muscle glycogen synthesis and disposition of infused glucose in humans with reduced rates of insulin-mediated carbohydrate storage. Diabetes. 1988 Mar;37(3):303–308. [PubMed] [Google Scholar]
• Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N Engl J Med. 1990 Jan 25;322(4):223–228. [PubMed] [Google Scholar]
• Mandarino LJ, Madar Z, Kolterman OG, Bell JM, Olefsky JM. Adipocyte glycogen synthase and pyruvate dehydrogenase in obese and type II diabetic subjects. Am J Physiol. 1986 Oct;251(4 Pt 1):E489–E496. [PubMed] [Google Scholar]
• Kelley DE, Mandarino LJ. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. J Clin Invest. 1990 Dec;86(6):1999–2007. [PMC free article] [PubMed] [Google Scholar]
• Garvey WT, Huecksteadt TP, Matthaei S, Olefsky JM. Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. J Clin Invest. 1988 May;81(5):1528–1536. [PMC free article] [PubMed] [Google Scholar]
• Dohm GL, Tapscott EB, Pories WJ, Dabbs DJ, Flickinger EG, Meelheim D, Fushiki T, Atkinson SM, Elton CW, Caro JF. An in vitro human muscle preparation suitable for metabolic studies. Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects. J Clin Invest. 1988 Aug;82(2):486–494. [PMC free article] [PubMed] [Google Scholar]
• DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985 Jul;76(1):149–155. [PMC free article] [PubMed] [Google Scholar]
• Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest. 1990 Jun;85(6):1844–1852. [PMC free article] [PubMed] [Google Scholar]
• DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J. Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes. 1983 Jan;32(1):35–45. [PubMed] [Google Scholar]
• Grill V. A comparison of brain glucose metabolism in diabetes as measured by positron emission tomography or by arteriovenous techniques. Ann Med. 1990 Jun;22(3):171–176. [PubMed] [Google Scholar]
• Kelley DE, Reilly JP, Veneman T, Mandarino LJ. Effects of insulin on skeletal muscle glucose storage, oxidation, and glycolysis in humans. Am J Physiol. 1990 Jun;258(6 Pt 1):E923–E929. [PubMed] [Google Scholar]
• Groop LC, Bonadonna RC, Shank M, Petrides AS, DeFronzo RA. Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. J Clin Invest. 1991 Jan;87(1):83–89. [PMC free article] [PubMed] [Google Scholar]
• RANDLE PJ, GARLAND PB, HALES CN, NEWSHOLME EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. [PubMed] [Google Scholar]
• Thorburn AW, Gumbiner B, Bulacan F, Wallace P, Henry RR. Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. J Clin Invest. 1990 Feb;85(2):522–529. [PMC free article] [PubMed] [Google Scholar]
• Butler PC, Kryshak EJ, Marsh M, Rizza RA. Effect of insulin on oxidation of intracellularly and extracellularly derived glucose in patients with NIDDM. Evidence for primary defect in glucose transport and/or phosphorylation but not oxidation. Diabetes. 1990 Nov;39(11):1373–1380. [PubMed] [Google Scholar]
• DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1982 Oct;23(4):313–319. [PubMed] [Google Scholar]
• Ferrannini E, Simonson DC, Katz LD, Reichard G, Jr, Bevilacqua S, Barrett EJ, Olsson M, DeFronzo RA. The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. Metabolism. 1988 Jan;37(1):79–85. [PubMed] [Google Scholar]
• Firth RG, Bell PM, Marsh HM, Hansen I, Rizza RA. Postprandial hyperglycemia in patients with noninsulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues. J Clin Invest. 1986 May;77(5):1525–1532. [PMC free article] [PubMed] [Google Scholar]
• Golay A, Felber JP, Jequier E, DeFronzo RA, Ferrannini E. Metabolic basis of obesity and noninsulin-dependent diabetes mellitus. Diabetes Metab Rev. 1988 Dec;4(8):727–747. [PubMed] [Google Scholar]
• Bogardus C, Lillioja S, Stone K, Mott D. Correlation between muscle glycogen synthase activity and in vivo insulin action in man. J Clin Invest. 1984 Apr;73(4):1185–1190. [PMC free article] [PubMed] [Google Scholar]

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