title: Effects of troglitazone in young first-degree relatives of patients with type 2 diabetes. Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Effects of metformin and rosiglitazone treatment on insulin signaling and glucose uptake in patients with newly diagnosed type 2 diabetes: a randomized controlled study. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. Troglitazone treatment increases protein kinase B phosphorylation in skeletal muscle of normoglycemic subjects at risk for the development of type 2 diabetes. Acute Antihyperglycemic Mechanisms of Metformin in NIDDM: Evidence for Suppression of Lipid Oxidation and Hepatic Glucose Production The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes.
abstract: 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 Rosiglitazone , a thiazolidinedione , enhances peripheral insulin sensitivity in patients with type 2 diabetes . Because the synergic action of insulin and exercise has been shown to be decreased in insulin resistance , the aim of this study was to compare the effects of rosiglitazone and metformin on muscle insulin responsiveness at rest and during exercise in patients with type 2 diabetes . Therefore , 45 patients with newly diagnosed or diet-treated type 2 diabetes were r and omized for treatment with rosiglitazone ( 4 mg b.i.d . ) , metformin ( 1 g b.i.d . ) , or placebo in a 26-week double-blind trial . Skeletal muscle glucose uptake was measured using fluorine-18-labeled fluoro-deoxy-glucose and positron emission tomography ( PET ) during euglycemic-hyperinsulinemic clamp and one-legged exercise before and after the treatment period . Rosiglitazone ( P < 0.05 ) and metformin ( P < 0.0001 ) treatment lowered the mean glycosylated hemoglobin . The skeletal muscle glucose uptake was increased by 38 % ( P < 0.01 ) and whole-body glucose uptake by 44 % in the rosiglitazone group . Furthermore , the exercise-induced increment during insulin stimulation was enhanced by 99 % ( P < 0.0001 ) . No changes were observed in skeletal muscle or whole-body insulin sensitivity in the metformin group . In conclusion , rosiglitazone but not metformin 1 ) improves insulin responsiveness in resting skeletal muscle and 2 ) doubles the insulin-stimulated glucose uptake rate during physical exercise in patients with type 2 diabetes . Our results suggest that rosiglitazone improves synergic action of insulin and exercise OBJECTIVE To examine the effect of rosiglitazone on insulin resistance and blood pressure in patients with essential hypertension , classified based on abnormalities of their renin-angiotensin system . RESEARCH DESIGN AND METHODS A total of 24 hypertensive nondiabetic patients ( age 58 + /- 6 years , BMI 30 + /- 5 kg/m2 ) were studied before and after rosiglitazone treatment . After 2 weeks off antihypertensive medication , subjects received a euglycemic-hyperinsulinemic clamp ( 40 mU. m(-2 ) . min(-1 ) ) with 6,6-[2H2]glucose infusion , ambulatory blood pressure monitoring , and blood tests for cardiovascular risk factors . Subjects were then placed on rosiglitazone ( 4 mg orally b.i.d . ) and their usual antihypertensive medications ( but not ACE inhibitors ) for 16 weeks , and baseline tests were repeated . RESULTS There was no change in fasting plasma glucose ( 83 + /- 2 vs. 82 + /- 2 mg/dl , P = 0.60 ) , but fasting insulin decreased ( 16.1 + /- 1.4 vs. 12.5 + /- 0.9 micro U/ml , P < 0.01 ) . Total glucose disposal during the clamp increased ( 5.0 + /- 0.4 vs. 5.9 + /- 0.5 mg . kg(-1 ) . min(-1 ) , P < 0.001 ) , with no change in suppression of hepatic glucose output . There were significant decreases in mean 24-h systolic ( 138 + /- 2 vs. 134 + /- 2 mmHg , P < 0.02 ) and diastolic ( 85 + /- 2 vs. 80 + /- 2 mmHg , P < 0.0001 ) blood pressure , and the decline in systolic blood pressure was correlated with the improvement in insulin sensitivity ( r = 0.59 , P < 0.005 ) . Triglycerides ( 135 + /- 16 vs. 89 + /- 8 mg/dl , P < 0.01 ) , LDL cholesterol ( 129 + /- 6 vs. 122 + /- 8 mg/dl , P = 0.18 ) , and HDL cholesterol ( 51 + /- 3 vs. 46 + /- 3 mg/dl , P < 0.02 ) all decreased , with no change in the LDL-to-HDL ratio . Plasminogen activator inhibitor-1 and C-reactive protein also declined significantly . CONCLUSIONS Rosiglitazone treatment of nondiabetic hypertensive patients improves insulin sensitivity , reduces systolic and diastolic blood pressure , and induces favorable changes in markers of cardiovascular risk . Insulin sensitizers may provide cardiovascular benefits when used in the treatment of patients with hypertension Troglitazone and metformin lower glucose levels in diabetic patients without increasing plasma insulin levels . We compared the insulin sparing actions of these two agents and their effects on insulin sensitivity and insulin secretion in 20 type 2 diabetic patients . To avoid the confounding effect of improved glycemic control on insulin action and secretion , patients were first rendered euglycemic with 4 weeks of continuous subcutaneous insulin infusion ( CSII ) before r and omization to CSII plus troglitazone ( n = 10 ) or CSII plus metformin ( n = 10 ) ; euglycemia was maintained for another 6 - 7 weeks . Insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp 1 ) at baseline , 2 ) after 4 weeks of CSII , and 3 ) after CSII plus either troglitazone or metformin . The 24-h glucose , insulin , and C-peptide profiles were performed on the day before the second and third glucose clamps . Good glycemic control was achieved with CSII alone and was maintained with CSII plus an oral agent ( mean 24-h glucose : troglitazone , 6.2+/-0.6 mmol/l ; metformin , 6.2 + /-0.3 mmol/l ) . Insulin requirements decreased 53 % with troglitazone compared with CSII alone ( 48+/-4 vs. 102+/-13 U/day , P < 0.001 ) , but only 31 % with metformin ( 76+/-13 vs. 110+/-18 U/day , P < 0.005 ) . The 24-h C-peptide profiles were similar . Normal fasting hepatic glucose output was maintained with both agents despite lower insulin levels than on CSII alone . Insulin sensitivity did not change significantly with CSII alone or with CSII plus metformin , but improved 29 % with CSII plus troglitazone ( P < 0.005 vs. CSII alone ) and was then 45 % higher than in the CSII plus metformin patients ( P < 0.005 ) . In conclusion , metformin has no effect on insulin-stimulated glucose disposal independent of glycemic control in type 2 diabetes . Troglitazone ( 600 mg/day ) has greater insulin-sparing effects than metformin ( 1,700 mg/day ) in CSII-treated euglycemic patients . This is probably explained by the peripheral tissue insulin-sensitizing effects of troglitazone UNLABELLED Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study . Metformin 0.5 g trice daily or placebo were given for 4 weeks . At the end of each period fasting and day-time postpr and ial values of plasma glucose , insulin , C-peptide and lactate were determined , and in vivo insulin action was assessed using the euglycemic clamp in combination with [3 - 3H]glucose tracer technique . Metformin treatment significantly reduced mean day-time plasma glucose levels ( 10.2 + /- 1.2 vs 11.4 + /- 1.2 mmol/l , P less than 0.01 ) without enhancing mean day-time plasma insulin ( 43 + /- 4 vs 50 + /- 7 mU/l , NS ) or C-peptide levels ( 1.26 + /- 0.12 vs 1.38 + /- 0.18 nmol/l , NS ) . Fasting plasma lactate was unchanged ( 1.57 + /- 0.16 vs 1.44 + /- 0.11 mmol/l , NS ) , whereas mean day-time plasma lactate concentrations were slightly increased ( 1.78 + /- 0.11 vs 1.38 + /- 0.11 mmol/l , P less than 0.01 ) . The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization ( 370 + /- 38 vs 313 + /- 33 mg.m-2.min-1 , P less than 0.01 ) , whereas insulin-mediated suppression of hepatic glucose production was unchanged . Also basal glucose clearance was improved ( 61.0 + /- 5.8 vs 50.6 + /- 2.8 ml.m-2.min-1 , P less than 0.05 ) , whereas basal hepatic glucose production was unchanged ( 81 + /- 6 vs 77 + /- 4 mg.m-2.min-1 , NS ) . CONCLUSIONS 1 ) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion . ( ABSTRACT TRUNCATED AT 250 WORDS The effect of metformin or rosiglitazone monotherapy versus placebo on insulin signaling and gene expression in skeletal muscle of patients with newly diagnosed type 2 diabetes was determined . A euglycemic-hyperinsulinemic clamp , combined with skeletal muscle biopsies and glucose uptake measurements over rested and exercised muscle , was performed before and after 26 weeks of metformin ( n = 9 ) , rosiglitazone ( n = 10 ) , or placebo ( n = 11 ) treatment . Insulin-mediated whole-body and leg muscle glucose uptake was enhanced 36 and 32 % , respectively , after rosiglitazone ( P < 0.01 ) but not after metformin or placebo treatment . Insulin increased insulin receptor substrate 1 ( IRS-1 ) tyrosine phosphorylation , IRS-1-associated phosphatidylinositol ( PI ) 3-kinase activity , and phosphorylation of Akt Ser473 and AS160 , a newly described Akt substrate that plays a role in GLUT4 exocytosis , approximately 2.3 fold before treatment . These insulin signaling parameters were unaltered after metformin , rosiglitazone , or placebo treatment . Expression of selected genes involved in glucose and fatty acid metabolism in skeletal muscle was unchanged between the treatment groups . Low-intensity acute exercise increased insulin-mediated glucose uptake but was without effect on insulin signaling . In conclusion , the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/AS160 in patients with newly diagnosed type 2 diabetes Pioglitazone increases the insulin sensitivity of peripheral tissues and may provide an alternative first-line treatment for type 2 diabetes . This study compared metabolic control in drug-naive type 2 diabetes patients given either pioglitazone or metformin .  Eleven hundred and ninety-nine patients with poorly controlled type 2 diabetes mellitus [ glycosylated hemoglobin ( HbA1c ) , 7.5 - 11 % ; normal , 4.3 - 6.1 % ] were r and omized to receive either pioglitazone ( < or = 45 mg/d ) or metformin ( < or = 850 mg , three times daily ) . HbA1c , fasting plasma glucose ( FPG ) , insulin levels , total cholesterol ( TC ) , high density lipoprotein cholesterol ( HDL-C ) , low density lipoprotein cholesterol , triglycerides , free fatty acids , and urinary albumin/creatinine ratio were measured . Mean HbA1c decreased in both treatment groups from baseline to wk 52 ( -1.4 % and -1.5 % ) . Significantly greater mean reductions in FPG were observed in the pioglitazone group ( -45.0 mg/dl ; -2.5 mmol/liter ) than in the metformin ( -39.6 mg/dl ; -2.2 mmol/liter ) group ( P = 0.016 ) . Favorable changes in triglycerides and HDL-C were more pronounced with pioglitazone . Although low density lipoprotein cholesterol and TC levels increased with pioglitazone , TC/HDL-C ratios decreased similarly with both treatments . The urinary albumin/creatinine ratio was reduced by 19 % with pioglitazone treatment , but remained unchanged with metformin therapy ( -1 % ; P = 0.002 ) . There was an increase in body weight of 1.9 kg in the pioglitazone group and a decrease of 2.5 kg in the metformin group . The overall frequency of adverse events was similar between treatment groups , but adverse event profiles were different between treatment groups . HbA1c reduction is similar after pioglitazone and metformin monotherapies , but differences in FPG , plasma lipids , and adverse effects between the two compounds may influence decision-making in individual prescribers 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 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 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 BACKGROUND Troglitazone decreases insulin resistance and hyperglycemia in patients with non-insulin-dependent diabetes mellitus ( NIDDM ) , but its effects on subjects without diabetes are not known . METHODS We performed oral and intravenous glucose-tolerance tests , studies with the euglycemic-hyperinsulinemic clamp , meal-tolerance tests , and 24-hour blood-pressure measurements at base line and after the administration of troglitazone , 200 mg orally twice daily , or placebo for 12 weeks in 18 nondiabetic obese subjects , 9 of whom had impaired glucose tolerance . RESULTS The mean ( + /- SD ) rates of glucose disposal increased from 4.7 + /- 1.7 to 6.0 + /- 1.7 mg per kilogram of body weight per minute ( P = 0.004 ) and from 9.0 + /- 1.8 to 9.9 + /- 1.3 mg per kilogram per minute ( P = 0.02 ) during insulin infusions of 40 and 300 mU per square meter of body-surface area per minute , respectively , in the troglitazone group . The insulin-sensitivity index , calculated from the results of intravenous glucose-tolerance tests , increased from 0.7 + /- 0.6 x 10(-4 ) to 1.6 + /- 0.9 x 10(-4 ) in subjects given troglitazone , and their glycemic response to oral glucose and to mixed meals decreased . The mean fasting plasma insulin concentration decreased by 48 percent ( P = 0.002 ) , and the plasma insulin response to oral glucose and mixed meals decreased by 40 and 41 percent , respectively . The changes were similar in the subjects with normal glucose tolerance and those with impaired glucose tolerance . Systolic and diastolic blood pressure decreased by 5 + /- 2 mm Hg ( P = 0.05 ) and 4 + /- 2 mm Hg ( P = 0.04 ) , respectively , after treatment with troglitazone . There were virtually no changes in the placebo group . CONCLUSIONS Troglitazone decreases insulin resistance and improves glucose tolerance in obese subjects with either impaired or normal glucose tolerance . The ability of troglitazone to reduce insulin resistance could be useful in preventing NIDDM Pioglitazone , a thiazolidinedione , improves glycemic control primarily by increasing peripheral insulin sensitivity in patients with type 2 diabetes , whereas metformin , a biguanide , exerts its effect primarily by decreasing hepatic glucose output . In the first head-to-head , double-blind clinical trial comparing these two oral antihyperglycemic medications ( OAMs ) , we studied the effect of 32-wk monotherapy on glycemic control and insulin sensitivity in 205 patients with recently diagnosed type 2 diabetes who were naive to OAM therapy . Subjects were r and omized to either 30 mg pioglitazone or 850 mg metformin daily with titrations upward to 45 mg ( 77 % of pioglitazone patients ) and 2550 mg ( 73 % of metformin patients ) , as indicated , to achieve fasting plasma glucose levels of less than 7.0 mmol/liter ( 126 mg/dl ) . Pioglitazone was comparable to metformin in improving glycemic control as measured by hemoglobin A1C and fasting plasma glucose . At endpoint , pioglitazone was significantly more effective than metformin in improving indicators of insulin sensitivity , as determined by reduction of fasting serum insulin ( P = 0.003 ) and by analysis of homeostasis model assessment for insulin sensitivity ( HOMA-S ; P = 0.002 ) . Both OAM therapies were well tolerated . Therefore , pioglitazone and metformin are equally efficacious in regard to glycemic control , but they exert significantly different effects on insulin sensitivity due to differing mechanisms of action . The more pronounced improvement in indicators of insulin sensitivity by pioglitazone , as compared with metformin monotherapy in patients recently diagnosed with type 2 diabetes who are OAM-naive , may be of interest for further clinical evaluation 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 Whereas thiazolidinediones ( TZDs ) are known to rapidly improve insulin action in animals , short duration s of TZD therapy have never been studied in humans . Among the many known actions of TZDs , increased circulating levels of the high molecular weight ( HMW ) multimer of adiponectin may be an important insulin-sensitizing mechanism . We examined the effects of only 21 days of 45 mg of pioglitazone ( P+ ) versus placebo ( P- ) in nine subjects with type 2 diabetes ( HbA(1c ) , 10.9 + /- 0.6 % ; BMI , 31.9 + /- 1.5 kg/m(2 ) ) .  Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression . However , plasma free fatty acid and glucose levels were unchanged , and there were only minimal changes in other " adipokines . " Glucose fluxes ( [3-(3)H]glucose infusion ) were measured during 6-h euglycemic ( 5 mmol/l ) " pancreatic clamp " studies ( somatostatin/glucagon/growth hormone ) with stepped insulin levels . Pioglitazone induced marked decreases in endogenous glucose production ( P+ = 0.9 + /- 0.1 vs. P- = 1.7 + /- 0.3 mg . kg(-1 ) . min(-1 ) ; P < 0.05 ) at physiologic hyperinsulinemia ( approximately 50 microU/ml ) , which was highly correlated with an increased ratio of HMW adiponectin/total levels ( r(2 ) = 0.90 ) . Maximal insulin stimulation ( approximately 400 microU/ml ) revealed pioglitazone-associated increases in glucose uptake ( P+ = 10.5 + /- 0.9 vs. P- = 8.9 + /- 0.8 mg . kg(-1 ) . min(-1 ) ; P < 0.05 ) , which did not correlate with HMW or total adiponectin levels . Thus , only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes . Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents
target: 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
background: 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 .