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 .
Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus.
The effects of metformin on glycaemia , insulin and c-peptide levels , hepatic glucose production and insulin sensitivity ( using the euglycaemic , hyperinsulinaemic clamp ) were evaluated at fortnightly intervals in 9 Type 2 diabetic patients using a stepwise dosing protocol : Stage 1 - -no metformin for four weeks ; stage 2 - -metformin 500 mg mane ; stage 3 - -metformin 500 mg thrice daily ; stage 4 - -metformin 1000 mg thrice daily . Results are expressed as Mean + /- SEM . Fasting blood glucose decreased from basal values ( 9.7 + /- 1.0 mmol/L ) by 13 % at stage 2 , 34 % at stage 3 and 41 % at stage 4 ( p less than 0.02 vs basal for all stages ; p less than 0.02 stage 2 vs stage 3 ) . Post-pr and ial glycaemia was significantly improved only with metformin 3000mg/day ( p less than 0.05 ) . Fasting , meal-stimulated and total insulin and c-peptide levels showed no change . Hepatic glucose output did not change significantly with metformin . Insulin sensitivity , measured as total glucose utilisation during hyperinsulinaemia , increased from stage 1 ( 10.3 + /- 2.1 mumoL/kg/min ) by 23 % at stage 3 ( p less than 0.05 ) and by 29 % at stage 4 ( p less than 0.02 ) . Basal metabolic clearance of glucose increased compared to stage 1 ( 1.69 + /- 0.16 mL/kg/min ) by 30 % at stage 2 , 53 % at stage 3 and 44 % at stage 4 ( all p less than 0.02 ) . This study demonstrates that improved efficiency of glucose utilisation , both basally and under conditions of euglycaemic hyperinsulinaemia , is the basis of metformin 's antihyperglycaemic action
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 .