Elevated Serum GGT Concentrations Predict Reduced Insulin Sensitivity and Increased Intrahepatic Lipids

Abstract

Elevated serum gamma-glutamyltransferase (GGT) concentrations have been related to features of the metabolic syndrome as well as increased risk of cardiovascular and liver disease. More recently, elevated GGT levels were shown to predict development of type 2 diabetes in a longitudinal study from Korea. The aim of the present study was to test the hypothesis that serum GGT is associated with glucose tolerance, insulin sensitivity and beta-cell function in a healthy, non-diabetic Caucasian population from the Tübingen family study. Insulin sensitivity was estimated by oGTT (n = 850) or measured by hyperinsulinemic euglycemic clamp (n = 245), respectively. A subgroup (n = 70) underwent additional determination of intrahepatic lipid content using ¹H magnetic resonance spectroscopy. Serum GGT was positively correlated with two-hour glucose during oGTT (r = 0.15, p < 0.0001) and negatively correlated with insulin sensitivity from oGTT (r = - 0.31, p < 0.0001) and clamp (r = - 0.27, p < 0.0001). The relationship between GGT and insulin sensitivity remained significant after adjusting for sex, age, BMI, and AST using multivariate regression analysis. Inclusion of serum triglyceride levels as a parameter of lipid metabolism kept the relationship significant in the oGTT group (p < 0.0001), but not in the smaller clamp group (p = 0.11). Additionally, serum GGT was positively correlated with hepatic lipid content (r = 0.49, p < 0.001) independent of sex, age, BMI, AST or serum triglycerides. There was no significant correlation between GGT and the index for beta-cell function after adjusting for age, sex, BMI and insulin sensitivity (p = 0.74). In conclusion, elevated serum GGT levels predict glucose intolerance probably via insulin resistance rather than beta-cell dysfunction. This may be primarily related to hepatic insulin resistance and increased intrahepatic lipids. The association observed between elevated hepatic lipids and reduced insulin sensitivity might explain the increased diabetes risk observed in subjects with elevated serum GGT concentrations. In the absence of overt liver disease, elevated serum GGT concentrations may point the clinician to incipient disturbances in the glucose metabolism.

Key words

Intrahepatic lipids - Type 2 diabetes - Insulin resistance - Obesity - Gamma-glutamyltransferase

References

• 1 Rantala A O, Lilja M, Kauma H, Savolainen M J, Reunanen A, Kesaniemi Y A. Gamma-glutamyl transpeptidase and the metabolic syndrome.  J Intern Med. 2000;  248 230-238
• 2 Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men.  Diabetes Care. 2004;  27 1427-1432
• 3 Sakugawa H, Nakayoshi T, Kobashigawa K, Nakasone H, Kawakami Y, Yamashiro T, Maeshiro T, Tomimori K, Miyagi S, Kinjo F, Saito A. Metabolic syndrome is directly associated with gamma glutamyl transpeptidase elevation in Japanese women.  World J Gastroenterol. 2004;  10 1052-1055
• 4 Perry I J, Wannamethee S G, Shaper A G. Prospective study of serum gamma-glutamyltransferase and risk of NIDDM.  Diabetes Care. 1998;  21 732-737
• 5 Lee D H, Jacobs D R Jr, Gross M, Kiefe C I, Roseman J, Lewis C E, Steffes M. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.  Clin Chem. 2003;  49 1358-1366
• 6 Lee D H, Ha M H, Kim J H, Christiani D C, Gross M D, Steffes M, Blomhoff R, Jacobs D R Jr. Gamma-glutamyltransferase and diabetes - a 4 year follow-up study.  Diabetologia. 2003;  46 359-364
• 7 Seppala-Lindroos A, Vehkavaara S, Hakkinen A M, 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. 2002;  87 3023-3028
• 8 Matsuda M, DeFronzo R A. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.  Diabetes Care. 1999;  22 1462-1470
• 9 Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, Van Haeften T, Renn W, Gerich J. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.  Diabetes Care. 2000;  23 295-301
• 10 Whitfield J B, Zhu G, Nestler J E, Heath A C, Martin N G. Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascular risk factors.  Clin Chem. 2002;  48 1426-1431
• 11 Nomura F, Ohnishi K, Satomura Y, Ohtsuki T, Fukunaga K, Honda M, Ema M, Tohyama T, Sugita S, Saito M. Liver function in moderate obesity-study in 534 moderately obese subjects among 4613 male company employees.  Int J Obes. 1986;  10 349-354
• 12 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough A J, Natale S, Forlani G, Melchionda N. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome.  Diabetes. 2001;  50 1844-1850
• 13 Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, Liddle C, Samarasinghe D, George J. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity?.  Hepatology. 2002;  36 403-409
• 14 Tiikkainen M, Bergholm R, Vehkavaara S, Rissanen A, Hakkinen A M, Tamminen M, Teramo K, Yki-Jarvinen H. Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content.  Diabetes. 2003;  52 701-707
• 15 Carlisle M L, King M R, Karp D R. gamma-Glutamyl transpeptidase activity alters the T cell response to oxidative stress and Fas-induced apoptosis.  Int Immunol. 2003;  15 17-27
• 16 West I C. Radicals and oxidative stress in diabetes.  Diabet Med. 2000;  17 171-180
• 17 Fernandez-Real J M, Ricart W. Insulin resistance and inflammation in an evolutionary perspective: the contribution of cytokine genotype/phenotype to thriftiness.  Diabetologia. 1999;  42 1367-1374
• 18 Yin M, Wheeler M D, Kono H, Bradford B U, Gallucci R M, Luster M I, Thurman R G. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice.  Gastroenterology. 1999;  117 942-952
• 19 Holbrook T L, Barrett-Connor E, Wingard D L. A prospective population-based study of alcohol use and non-insulin-dependent diabetes mellitus.  Am J Epidemiol. 1990;  132 902-909
• 20 Ajani U A, Hennekens C H, Spelsberg A, Manson J E. Alcohol consumption and risk of type 2 diabetes mellitus among US male physicians.  Arch Intern Med. 2000;  160 1025-1030
• 21 Monterrosa A E, Haffner S M, Stern M P, Hazuda H P. Sex difference in lifestyle factors predictive of diabetes in Mexican-Americans.  Diabetes Care. 1995;  18 448-456
• 22 Yokoyama H, Hirose H, Moriya S, Saito I. Significant correlation between insulin resistance and serum gamma-glutamyl transpeptidase (gamma-GTP) activity in non-drinkers.  Alcohol Clin Exp Res. 2002;  26 91S-94S