High Alanine Aminotransferase Is Associated With Decreased Hepatic Insulin Sensitivity and Predicts the Development of Type 2 Diabetes
- Barbora Vozarova,
- Norbert Stefan,
- Robert S. Lindsay,
- Aramesh Saremi,
- Richard E. Pratley,
- Clifton Bogardus and
- P. Antonio Tataranni
- From the Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
It has been proposed that liver dysfunction may contribute to the development of type 2 diabetes. The aim of the present study was to examine whether elevated hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or γ -glutamyltranspeptidase [GGT]) are associated with prospective changes in liver or whole-body insulin sensitivity and/or insulin secretion and whether these elevated enzymes predict the development of type 2 diabetes in Pima Indians. We measured ALT, AST, and GGT in 451 nondiabetic (75-g oral glucose tolerance test) Pima Indians (aged 30 ± 6 years, body fat 33 ± 8%, ALT 45 ± 29 units/l, AST 34 ± 18 units/l, and GGT 56 ± 40 units/l [mean ± SD]) who were characterized for body composition (hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M), and hepatic insulin sensitivity (hepatic glucose output [HGO] during the low-dose insulin infusion of a hyperinsulinemic clamp) and acute insulin response (AIR) (25-g intravenous glucose challenge). Sixty-three subjects developed diabetes over an average follow-up of 6.9 ± 4.9 years. In 224 subjects, who remained nondiabetic, follow-up measurements of M and AIR were available. At baseline, ALT, AST, and GGT were related to percent body fat (r = 0.16, 0.17, and 0.11, respectively), M (r = −0.32, − 0.28, and −0.24), and HGO (r = 0.27, 0.12, and 0.14; all P < 0.01). In a proportional hazard analysis with adjustment for age, sex, body fat, M, and AIR, higher ALT [relative hazard 90th vs. 10th centiles (95% CI): 1.9 (1.1–3.3), P = 0.02], but not AST or GGT, predicted diabetes. Elevated ALT at baseline was associated prospectively with an increase in HGO (r = 0.21, P = 0.001) but not with changes in M or AIR (both P = 0.1). Higher ALT concentrations were cross-sectionally associated with obesity and whole-body and hepatic insulin resistance and prospectively associated with a decline in hepatic insulin sensitivity and the development of type 2 diabetes. Our findings indicate that high ALT is a marker of risk for type 2 diabetes and suggest a potential role of the liver in the pathogenesis of type 2 diabetes.
Address correspondence and reprint requests to Barbora Vozarova, Clinical Diabetes and Nutrition Section, National Institutes of Health, 4212 N. 16th St., Rm. 5-41, Phoenix, AZ 85016. E-mail:.
Received for publication 17 December 2001 and accepted in revised form 6 March 2002.
AIR, acute insulin response; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyltranspeptidase; HGO, hepatic glucose output; IGT, impaired glucose tolerance; M, whole-body insulin sensitivity; M-high, high-dose insulin infusion; M-low, low-dose insulin infusion; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; WBC, white blood cell count; WTR, waist-to-thigh ratio.