***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The effects of metformin therapy on whole body and splanchnic amino acid turnover are not known . Therefore , we have studied fasting and postpr and ial phenylalanine kinetics in type 2 diabetic subjects ( non-insulin-dependent diabetes mellitus ) , previously treated with diet only , both before and after 4 weeks of either metformin ( 850 mg twice a day ) ( n = 11 ) or placebo administration ( n = 6 ) .  Phenylalanine kinetic was evaluated by means of a multiple isotope technique : tritiated phenylalanine was infused i.v . , whereas carbon-labeled phenylalanine was incorporated into a chemically-defined meal . Compared with placebo , metformin administration decreased both fasting ( from 162 + /- 17 to 141 + /- 20 mg/dl ) and postpr and ial ( from 217 + /- 20 to 164 + /- 20 mg/dl ) glucose concentrations ( P < 0.05-P < 0.01 ) . Fasting insulin concentrations were unaffected , but postmeal insulin tended to be lower ( P < 0.06 ) after metformin . Compared with the pretreatment period , metformin administration did not change total phenylalanine rate of appearance ( fasted state , 0.74 + /- 0.10 vs. 0.71 + /- 0.08 mumol/kg.min ; fed state , 0.77 + /- 0.10 vs. 0.75 + /- 0.08 mumol/kg.min , respectively ) , dietary and endogenous phenylalanine rate of appearance , dietary phenylalanine oxidation , and splanchnic uptake , similar to what was observed in the placebo group . Our data indicate that , at least after a 4-week treatment , metformin does not affect fasting and postpr and ial protein turnover , as indicated by phenylalanine data , in subjects with mild non-insulin-dependent diabetes mellitus 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVES This study was design ed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus . BACKGROUND Abnormalities in vascular endothelial function are well recognized among patients with type 2 ( insulin-resistant ) diabetes mellitus . Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction . The effects of metformin , an antidiabetic agent that improves insulin sensitivity , on endothelial function have not been reported . METHODS Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily ( n = 29 ) or placebo ( n = 15 ) for 12 weeks . Before and after treatment , blood flow responses to intraarterial administration of endothelium-dependent ( acetylcholine ) , endothelium-independent ( sodium nitroprusside ) and nitrate-independent ( verapamil ) vasodilators were measured using forearm plethysmography . Whole-body insulin resistance was assessed on both occasions using the homeostasis model ( HOMA-IR ) . RESULTS Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo ( p = 0.0027 by 2-way analysis of variance ) , whereas no significant effect was seen on nitroprusside-stimulated ( p = 0.27 ) or verapamil-stimulated ( p = 0.40 ) flows . There was a significant improvement in insulin resistance with metformin ( 32.5 % reduction in HOMA-IR , p = 0.01 ) , and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment ( r = -0.659 , p = 0.0012 ) . CONCLUSIONS Metformin treatment improved both insulin resistance and endothelial function , with a strong statistical link between these variables . This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus . This has important implication s for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus BACKGROUND Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus ( NIDDM ) in the United States . Recently , however , metformin has been approved for the treatment of NIDDM . METHODS We performed two large , r and omized , parallel-group , double-blind , controlled studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes was inadequately controlled by diet ( protocol 1 : metformin vs. placebo ; 289 patients ) , or diet plus glyburide ( protocol 2 :  metformin and glyburide vs. metformin vs. glyburide  ; 632 patients ) . To determine efficacy we measured plasma glucose ( while the patients were fasting and after the oral administration of glucose ) , lactate , lipids , insulin , and glycosylated hemoglobin before , during , and at the end of the study . RESULTS In protocol 1 , at the end of the study the 143 patients in the metformin group , as compared with the 146 patients in the placebo group , had lower mean ( + /- SE ) fasting plasma glucose concentrations ( 189 + /- 5 vs. 244 + /- 6 mg per deciliter [ 10.6 + /- 0.3 vs. 13.7 + /- 0.3 mmol per liter ] , P < 0.001 ) and glycosylated hemoglobin values ( 7.1 + /- 0.1 percent vs. 8.6 + /- 0.2 percent , P < 0.001 ) . In protocol 2 , the 213 patients given metformin and glyburide , as compared with the 210 patients treated with glyburide alone , had lower mean fasting plasma glucose concentrations ( 187 + /- 4 vs. 261 + /- 4 mg per deciliter [ 10.5 + /- 0.2 vs. 14.6 + /- 0.2 mmol per liter ] , P < 0.001 ) and glycosylated hemoglobin values ( 7.1 + /- 0.1 percent vs. 8.7 + /- 0.1 percent , P < 0.001 ) . The effect of metformin alone was similar to that of glyburide alone . Eighteen percent of the patients given metformin and glyburide had symptoms compatible with hypoglycemia , as compared with 3 percent in the glyburide group and 2 percent in the metformin group . In both protocol s the patients given metformin had statistically significant decreases in plasma total and low-density lipoprotein cholesterol and triglyceride concentrations , whereas the values in the respective control groups did not change . There were no significant changes in fasting plasma lactate concentrations in any of the groups . CONCLUSIONS Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone OBJECTIVE To determine the effect of metformin on the acute metabolic response to submaximal exercise , the effect of exercise on plasma metformin concentrations , and the interaction between metformin and exercise on the subsequent response to a st and ardized meal . RESEARCH DESIGN AND METHODS Ten participants with type 2 diabetes were recruited for this r and omized crossover study . Metformin or placebo was given for 28 days , followed by the alternate condition for 28 days . On the last 2 days of each condition , participants were assessed during a nonexercise and a subsequent exercise day . Exercise took place in the morning and involved a total of 35 min performed at three different submaximal intensities . RESULTS Metformin  increased heart rate and plasma lactate during exercise ( both P ≤ 0.01 ) but lowered respiratory exchange ratio ( P = 0.03 ) without affecting total energy expenditure , which suggests increased fat oxidation  . Metformin plasma concentrations were greater at several , but not all , time points on the exercise day compared with the nonexercise day . The glycemic response to a st and ardized meal was reduced by metformin , but the reduction was attenuated when exercise was added ( metformin × exercise interaction , P = 0.05 ) . Glucagon levels were highest in the combined exercise and metformin condition . CONCLUSIONS This study reveals several ways by which metformin and exercise therapies can affect each other . By increasing heart rate , metformin could lead to the prescription of lower exercise workloads . Furthermore , under the tested conditions , exercise interfered with the glucose-lowering effect of metformin BACKGROUND In patients with type 2 diabetes , intensive blood-glucose control with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks . This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage . METHODS Of 4075 patients recruited to UKPDS in 15 centres , 1704 overweight ( > 120 % ideal bodyweight ) patients with newly diagnosed type 2 diabetes , mean age 53 years , had raised fasting plasma glucose ( FPG ; 6.1 - 15.0 mmol/L ) without hyperglycaemic symptoms after 3 months ' initial diet . 753 were included in a r and omised controlled trial , median duration 10.7 years , of conventional policy , primarily with diet alone ( n=411 ) versus intensive blood-glucose control policy with metformin , aim ing for FPG below 6 mmol/L ( n=342 ) . A secondary analysis compared the 342 patients allocated metformin with 951 overweight patients allocated  intensive blood-glucose control with chlorpropamide ( n=265 ) , glibenclamide ( n=277 ) , or insulin ( n=409 ) . The primary outcome measures were aggregates of any diabetes-related clinical endpoint , diabetes-related death , and all-cause mortality . In a supplementary r and omised controlled trial , 537 non-overweight and overweight patients , mean age 59 years , who were already on maximum sulphonylurea therapy but had raised FPG ( 6.1 - 15.0 mmol/L ) were allocated continuing sulphonylurea therapy alone ( n=269 ) or addition of metformin ( n=268 ) . FINDINGS Median glycated haemoglobin ( HbA1c ) was 7.4 % in the metformin group compared with 8.0 % in the conventional group . Patients allocated metformin , compared with the conventional group , had risk reductions of 32 % ( 95 % CI 13 - 47 , p=0.002 ) for any diabetes-related endpoint , 42 % for diabetes-related death ( 9 - 63 , p=0.017 ) , and 3 
    Output:
    
This study provides the precise effects of metformin monotherapy regarding the decreases in fasting plasma glucose and glycosated hemoglobin that physician can expected in drug-naive patients with type 2 diabetes mellitus .
No evidence was found for the effects on weight