Reversal of Nonalcoholic Hepatic Steatosis, Hepatic Insulin Resistance, and Hyperglycemia by Moderate Weight Reduction in Patients With Type 2 Diabetes

Diabetes - Tập 54 Số 3 - Trang 603-608 - 2005
Kitt Falk Petersen1, Sylvie Dufour1,2, Douglas E. Befroy1, Michael Lehrke3, Rosa E. Hendler1, Gerald I. Shulman4,1,2
1Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut
3Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
4Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut

Tóm tắt

To examine the mechanism by which moderate weight reduction improves basal and insulin-stimulated rates of glucose metabolism in patients with type 2 diabetes, we used 1H magnetic resonance spectroscopy to assess intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) content in conjunction with hyperinsulinemic-euglycemic clamps using [6,6-2H2]glucose to assess rates of glucose production and insulin-stimulated peripheral glucose uptake. Eight obese patients with type 2 diabetes were studied before and after weight stabilization on a moderately hypocaloric very-low-fat diet (3%). The diabetic patients were markedly insulin resistant in both liver and muscle compared with the lean control subjects. These changes were associated with marked increases in IHL (12.2 ± 3.4 vs. 0.6 ± 0.1%; P = 0.02) and IMCL (2.0 ± 0.3 vs. 1.2 ± 0.1%; P = 0.02) compared with the control subjects. A weight loss of only ∼8 kg resulted in normalization of fasting plasma glucose concentrations (8.8 ± 0.5 vs. 6.4 ± 0.3 mmol/l; P < 0.0005), rates of basal glucose production (193 ± 7 vs. 153 ± 10 mg/min; P < 0.0005), and the percentage suppression of hepatic glucose production during the clamp (29 ± 22 vs. 99 ± 3%; P = 0.003). These improvements in basal and insulin-stimulated hepatic glucose metabolism were associated with an 81 ± 4% reduction in IHL (P = 0.0009) but no significant change in insulin-stimulated peripheral glucose uptake or IMCL (2.0 ± 0.3 vs. 1.9 ± 0.3%; P = 0.21). In conclusion, these data support the hypothesis that moderate weight loss normalizes fasting hyperglycemia in patients with poorly controlled type 2 diabetes by mobilizing a relatively small pool of IHL, which reverses hepatic insulin resistance and normalizes rates of basal glucose production, independent of any changes in insulin-stimulated peripheral glucose metabolism.

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Tài liệu tham khảo

Henry RR, Scheaffer L, Olefsky JM: Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 61:917–925,1985

Petersen KF, Price T, Cline GW, Rothman DL, Shulman GI: Contribution of net hepatic glycogenolysis to glucose production during the early postprandial period. Am J Physiol 270:E186–E191,1996

Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI: Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 109:1345–1350,2002

Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF: The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51:797–802,2002

Lusk G: Animal calorimetry: analysis of the oxidation of mixtures of carbohydrates and fat: a correction. J Biol Chem 59:41–42,1924

Petersen KF, Krssak M, Inzucchi S, Cline GW, Dufour S, Shulman GI: Mechanism of troglitazone action in type 2 diabetes. Diabetes 49:827–831,2000

Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI: Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 128:176–185,1998

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 24:96–99,1983

Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI: Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 98:7522–7527,2001

Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI: Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 297:32345–53,2004

Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, Yki-Jarvinen H: Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023–3028,2002

Oakes ND, Cooney GJ, Camilleri S, Chisholm DJ, Kraegen EW: Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes 46:1768–1774,1997

Lewis GF, Vranic M, Harley P, Giacca A: Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans. Diabetes 46:1111–1119,1997

Shulman GI: Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176,2000

Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76,1999

Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI: Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 275:8456–8460,2000

Magnusson I, Rothman DL, Katz LD, Shulman RG, Shulman GI: Increased rate of gluconeogenesis in type II diabetes mellitus: a 13C nuclear magnetic resonance study. J Clin Invest 90:1323–1327,1992

Hundal HS, Ramlal T, Reyes R, Leiter LA, Klip A: Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinology 131:1165–1173,1992

Gastaldelli A, Baldi S, Pettiti M, Toschi E, Camastra S, Natali A, Landau BR, Ferrannini E: Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 49:1367–1373,2000

Boden G, Chen X, Capulong E, Mozzoli M: Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes. Diabetes 50:810–816,2001

Roden M, Stingl H, Chandramouli V, Schumann WC, Hofer A, Landau BR, Nowotny P, Waldhausl W, Shulman GI: Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes 49:701–707,2000

Stingl H, Krssak M, Krebs M, Bischof MG, Nowotny P, Furnsinn C, Shulman GI, Waldhausl W, Roden M: Lipid-dependent control of hepatic glycogen stores in healthy humans. Diabetologia 44:48–54,2001

Ohsumi J, Sakakibara S, Yamaguchi J, Miyadai K, Yoshioka S, Fujiwara T, Horikoshi H, Serizawa N: Troglitazone prevents the inhibitory effects of inflammatory cytokines on insulin-induced adipocyte differentiation in 3T3–L1 cells. Endocrinology 135:2279–2282,1994

Fernandez-Real JM, Broch M, Vendrell J, Gutierrez C, Casamitjana R, Pugeat M, Richart C, Ricart W: Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes 49:517–520,2000

Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature 409:307–312,2001

Steppan CM, Lazar MA: Resistin and obesity-associated insulin resistance. Trends Endocrinol Metab 13:18–23,2002

Tsao TS, Lodish HF, Fruebis J: ACRP30, a new hormone controlling fat and glucose metabolism. Eur J Pharmacol 440:213–221,2002

Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T: Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295,2002

Pajvani UB, Scherer PE: Adiponectin: systemic contributor to insulin sensitivity. Curr Diab Rep 3:207–213,2003

Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM: Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Invest 49:837–848,1970

Shulman GI, Lacy WW, Liljenquist JE, Keller U, Williams PE, Cherrington AD: Effect of glucose, independent of changes in insulin and glucagon secretion, on alanine metabolism in the conscious dog. J Clin Invest 65:496–505,1980

Cherrington AD, Chiasson JL, Liljenquist JE, Jennings AS, Keller U, Lacy WW: The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog. J Clin Invest 58:1407–1418,1976

Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF: Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 277:1531–1537,2002

Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF: Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334:292–295,1996

Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT: Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol 276:E977–E989,1999

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Diabetes

Tập 54 Số 3

603-608

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