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 .
Troglitazone treatment increases protein kinase B phosphorylation in skeletal muscle of normoglycemic subjects at risk for the development of type 2 diabetes.
We investigated whether the effect of troglitazone on glucose disposal is associated with altered insulin signaling . Nondiabetic first-degree relatives of type 2 diabetic patients ( age 30 + /- 2 years , BMI 30 + /- 1 kg/m(2 ) ; n = 20 ) were r and omized in a double-blind manner to 3 months of troglitazone ( 200 mg/day ) or placebo treatment . Before and after treatment , 3-h euglycemic-hyperinsulinemic glucose clamps ( 40 mU. m(-2 ) . min(-1 ) ) were performed , and muscle biopsies were obtained immediately before and after the clamps . In the biopsies , insulin receptor kinase ( IRK ) activity , insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase ( PI3 K ) activity , Ser(473 ) and Thr(308 ) phosphorylation of protein kinase B ( PKB ) , and protein expression of IRS-1 , IRS-2 , phosphoinositol-dependent kinase-1 ( PDK-1 ) , PKB , and GLUT-4 were determined . After troglitazone treatment , insulin-stimulated glucose disposal was increased compared with pretreatment and placebo ( 279 + /- 37 vs. 211 + /- 26 and 200 + /- 25 mg . m(-2 ) . min(-1 ) ; both P < 0.05 ) . IRK and PI3 K activities were not altered by troglitazone , but PKB Ser(473 ) phosphorylation was enhanced compared with pretreatment and placebo at the clamp insulin level ( 138 + /- 36 vs. 77 + /- 16 and 55 + /- 13 internal st and ard units ; both P < 0.05 ) and with pretreatment at the basal level ( 31 + /- 9 vs. 14 + /- 4 internal st and ard units ; P < 0.05 ) . PKB Thr(308 ) phosphorylation also tended to be higher , but this was not statistically significant . Troglitazone did not alter insulin receptor number or IRS-1 , IRS-2 , PKB , PDK-1 , or GLUT-4 protein expression . We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle
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 .