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 .
Acute Antihyperglycemic Mechanisms of Metformin in NIDDM: Evidence for Suppression of Lipid Oxidation and Hepatic Glucose Production
To establish the antihyperglycemic mechanisms of metformin in non-insulin-dependent diabetes mellitus ( NIDDM ) independently of the long-term , aspecific effects of removal of glucotoxicity , 21 NIDDM subjects ( 14 obese , 7 nonobese ) were studied on two separate occasions , with an isoglycemic ( plasma glucose ∼9 mM ) hyperinsulinemic ( two-step insulin infusion , 2 h each , at the rate of 4 and 40 mU · m−2 · min−1 ) clamp combined with [3−3H]glucose infusion and indirect calorimetry , after administration of either metformin ( 500 mg per os , at –5 and –1 h before the clamp ) or placebo . Compared with  placebo , hepatic glucose production ( HGP ) decreased ∼30 % more after metformin ( from 469 ± 50 to 330 ± 54 μmol/min ) , but glucose uptake did not increase . Metformin  suppressed free fatty acids ( FFAs ) by ∼17 % ( from 0.42 ± 0.04 to 0.35 ± 0.04 mM ) and lipid oxidation by ∼25 % ( from 4.5 ± 0.4 to 3.4 ± 0.4 μmol · kg−1 · min−1 ) and increased glucose oxidation by ∼ 16 % ( from 16.2 ± 1.4 to 19.3 ± 1.3 μmol.kg−1 · min−1 ) compared with placebo ( P < 0.05 ) , but did not affect nonoxidative glucose metabolism , protein oxidation , or total energy expenditure . Suppression of FFA and lipid oxidation  after metformin correlated with suppression of HGP ( r = 0.70 and r = 0.51 , P < 0.001 ) . The effects of metformin in obese and nonobese subjects were no different . We conclude that the specific , antihyperglycemic effects of metformin in the clinical condition of hyperglycemia in NIDDM are primarily due to suppression of HGP , not stimulation of glucose uptake , and are mediated , at least in part , by suppression of FFA and lipid oxidation
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 .