Results Both TZDs and metformin  enhance insulin suppression of endogenous glucose production and fasting plasma glucose clearance .
TZDs , but not metformin , also improve insulin-mediated glucose uptake at all insulin levels .
Conclusions /interpretationIn patients with type 2 diabetes , metformin improves fasting hepatic insulin sensitivity and glucose clearance ; TZDs improve fasting hepatic insulin sensitivity and glucose clearance , and potentiate glucose disposal under insulinised conditions
Aims /hypothesisInsulin resistance , which manifests itself as endogenous glucose overproduction and reduced insulin-mediated glucose uptake , is a core defect in type 2 diabetes .
Metformin and the peroxisome proliferator-activated receptor-γ agonists , the thiazolidinediones ( TZDs ) , both lower glucose , although their mechanism of action is still subject to debate .
This review analyses the evidence relevant to these mechanisms in vivo .
Effects of troglitazone in young first-degree relatives of patients with type 2 diabetes.
OBJECTIVE Insulin resistance is a key characteristic of first-degree relatives of patients with type 2 diabetes . We therefore treated young , glucose-tolerant relatives with the insulin action enhancer troglitazone in order to determine the effects on insulin sensitivity , glucose metabolism , and glycogen synthase activity . RESEARCH DESIGN AND METHODS Relatives were r and omized in a double-blind manner and treated for 12 weeks with either 200 mg troglitazone or placebo . Before and after treatment , an oral glucose tolerance test ( OGTT ) and a euglycemic-hyperinsulinemic clamp ( 40 mU. m(-2 ) . min(-1 ) ) were performed , including 3-(3)H glucose infusion , glycolytic flux calculations , indirect calorimetry , and muscle biopsies . RESULTS Twelve relatives received troglitazone and 12 placebo ( aged 30.8 + /- 2.0 vs. 30.3 + /- 1.6 years , BMI 29.6 + /- 0.8 vs. 30.5 + /- 1.3 kg/m(2 ) ; means + /- SE ) . Area under the curve ( AUC ) for plasma glucose at the second OGTT was unchanged after troglitazone . In contrast , troglitazone reduced fasting ( from 70.3 + /- 6.9 to 52.2 + /- 5.8 vs. 73.6 + /- 11.0 to 73.3 + /- 6.5 pmol/l , P < 0.02 ) and AUC plasma insulin ( mean [ CI ] from 335.7 [ 230.9 - 488.1 ] to 277.4 [ 179.4 - 428.8 ] vs. 313.8 [ 218.2 - 451.2 ] to 353.9 [ 208.3 - 601.3 ] pmol/l , P < 0.05 ) . Additionally , fasting plasma triglycerides were reduced by troglitazone ( from 1.86 + /- 0.33 to 1.38 + /- 0.27 vs. 2.22 + /- 0.44 to 2.35 + /- 0.46 mmol/l , P < 0.01 ) . Insulin-stimulated glucose disposal increased in the troglitazone group ( from 208.3 + /- 23.7 to 263.5 + /- 30.4 vs. 197.1 + /- 20.0 to 200.8 + /- 20.8 mg . m(-2 ) . min(-1 ) , P < 0.02 ) mainly due to increased glucose storage ( from 99.9 + /- 17.9 to 146.0 + /- 25.3 vs. 87.1 + /- 16.7 to 87.9 + /- 15.7 mg . m(-2 ) . min(-1 ) , P < 0.02 ) , which took place without altering insulin-stimulated glycogen synthase activity . CONCLUSIONS In glucose-tolerant first-degree relatives , treatment with troglitazone improved insulin sensitivity almost 50 % , primarily due to increased glucose storage . It is suggested that the use of insulin action enhancers can be especially valuable in this group of subjects with a known high risk for developing type 2 diabetes
Results Both TZDs and metformin  enhance insulin suppression of endogenous glucose production and fasting plasma glucose clearance .
TZDs , but not metformin , also improve insulin-mediated glucose uptake at all insulin levels .
Conclusions /interpretationIn patients with type 2 diabetes , metformin improves fasting hepatic insulin sensitivity and glucose clearance ; TZDs improve fasting hepatic insulin sensitivity and glucose clearance , and potentiate glucose disposal under insulinised conditions
Aims /hypothesisInsulin resistance , which manifests itself as endogenous glucose overproduction and reduced insulin-mediated glucose uptake , is a core defect in type 2 diabetes .
Metformin and the peroxisome proliferator-activated receptor-γ agonists , the thiazolidinediones ( TZDs ) , both lower glucose , although their mechanism of action is still subject to debate .
This review analyses the evidence relevant to these mechanisms in vivo .