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 .
The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients.
The effect of metformin therapy on glucose metabolism was examined in eight overweight newly presenting untreated type II diabetic patients ( five males , three females ) . Patients were treated for 12 weeks with either metformin ( 850 mg x 3 ) or matching placebo using a double-blind crossover study design ; patients were studied at presentation and at the end of each treatment period . Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase ( GS ) before and during a 4-hour hyperinsulinemic euglycemic clamp ( 100 mU.kg-1 x h-1 ) . Metformin therapy was associated with a significant decrease in fasting blood glucose ( 6.8 + /- 0.6 v 8.3 + /- 0.9 mmol . L-1 , P < .01 ) and glycosylated hemoglobin ( [ HbA1 ] 7.7 % + /- 0.4 % v 8.5 % + /- 0.5 % , P < .01 ) levels . Fasting hepatic glucose production ( HGP ) was also significantly decreased following metformin therapy ( 1.98 + /- 0.13 v 2.41 + /- 0.20 mg.kg-1 x min-1 , P < .02 ) , whereas fasting insulin and C-peptide concentrations remained unaltered . The decrease in basal HGP correlated closely with the decrease in fasting blood glucose concentration ( r = .92 , P < .001 ) . Insulin-stimulated glucose uptake was assessed using the hyperinsulinemic euglycemic clamp technique and was increased post-metformin ( 3.8 + /- 0.6 v 3.1 + /- 0.7 mg.kg-1 x min-1 , P < .05 ) . This was primarily the result of increased nonoxidative glucose metabolism ( 1.1 + /- 0.6 v 0.4 + /- 0.6 mg.kg-1 x min-1 , P < .05 ) ; oxidative glucose metabolism did not change . Metformin had no measurable effect on insulin activation of skeletal muscle GS , the rate-limiting enzyme controlling muscle glucose storage . ( ABSTRACT TRUNCATED AT 250 WORDS
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 .