title: Discordant effects on central obesity, hepatic insulin resistance, and alanine aminotransferase of low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance.
abstract: Alanine aminotransferase (ALT) predicts incident type 2 diabetes (T2DM), possibly reflecting early fatty liver and hepatic insulin resistance. Thiazolidinediones and metformin can improve fatty liver and hepatic insulin resistance, respectively. In the Canadian Normoglycemia Outcome Evaluation trial, rosiglitazone/metformin (Rosi/Met, 4/1000 mg) reduced incident T2DM by 66% in subjects with impaired glucose tolerance. For insight on the hepatic effects of this therapy in relation to T2DM, we evaluated the temporal changes in waist, hepatic insulin sensitivity (1/Homeostasis Model Assessment of Insulin Resistance) and ALT in the Rosi/Met (n = 103) and placebo (n = 104) arms over median of 3.9 years. Waist did not differ between the arms. Hepatic insulin sensitivity improved in the Rosi/Met arm in year 1, but deteriorated thereafter as in the placebo arm. In contrast, Rosi/Met lowered ALT in year 1 and maintained this effect throughout the trial. Thus, low-dose Rosi/Met had no effect on central obesity, a transient effect on hepatic insulin sensitivity, and a sustained effect on ALT.
authors.affiliation: Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada. rretnakaran@mtsinai.on.ca
authors.forename: R
authors.initials: R
authors.lastname: Retnakaran
authors.forename: C
authors.initials: C
authors.lastname: Ye
authors.forename: A J
authors.initials: AJ
authors.lastname: Hanley
authors.forename: S B
authors.initials: SB
authors.lastname: Harris
authors.forename: B
authors.initials: B
authors.lastname: Zinman
mesh_terms: D000410:Alanine Transaminase / Q000187:drug effects*; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D004338:Drug Combinations; D005234:Fatty Liver / Q000188:drug therapy / Q000517:prevention & control; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D056128:Obesity, Abdominal / Q000097:blood / Q000188:drug therapy*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D049629:Waist-Hip Ratio
chemical_list: D001786:Blood Glucose; D004338:Drug Combinations; D007004:Hypoglycemic Agents; D013844:Thiazoles; C471074:rosiglitazone-metformin combination; D008687:Metformin; D000410:Alanine Transaminase