human
***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: Objectives To study the effects of metformin on the incidence of vitamin B-12 deficiency ( < 150 pmol/l ) , low concentrations of vitamin B-12 ( 150 - 220 pmol/l ) , and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin . Design Multicentre r and omised placebo controlled trial . Setting Outpatient clinics of three non-academic hospitals in the Netherl and s. Participants 390 patients with type 2 diabetes receiving treatment with insulin . Intervention 850 mg metformin or placebo three times a day for 4.3 years . Main outcome measures Percentage change in vitamin B-12 , folate , and homocysteine concentrations from baseline at4 , 17 , 30 , 43 , and 52 months . Results Compared with placebo , metformin treatment was associated with a mean decrease in vitamin B-12 concentration of −19 % ( 95 % confidence interval −24 % to −14 % ; P<0.001 ) and in folate concentration of −5 % ( 95 % CI −10 % to −0.4 % ; P=0.033 ) , and an increase in homocysteine concentration of 5 % ( 95 % CI −1 % to 11 % ; P=0.091 ) . After adjustment for body mass index and smoking , no significant effect of metformin  on folate concentrations was found . The absolute risk of vitamin B-12 deficiency ( < 150 pmol/l ) at study end was 7.2 percentage points higher in the metformin group than in the placebo group ( 95 % CI 2.3 to 12.1 ; P=0.004 ) , with a number needed to harm of 13.8 per 4.3 years ( 95 % CI 43.5 to 8.3 ) . The absolute risk of low vitamin B-12 concentration ( 150 - 220 pmol/l ) at study end was 11.2 percentage points higher in the metformin group ( 95 % CI 4.6 to 17.9 ; P=0.001 ) , with a number needed to harm of 8.9 per 4.3 years ( 95 % CI 21.7 to 5.6 ) . Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 µmol/l ( 95 % CI 18.8 to 30.0 µmol/l ) , compared with a mean homocysteine level of 18.1 µmol/l ( 95 % CI 16.7 to 19.6 µmol/l ; P=0.003 ) for patients with a low vitamin B-12 concentration and 14.9 µmol/l ( 95 % CI 14.3 to 15.5 µmol/l ; P<0.001 compared with vitamin B-12 deficiency ; P=0.005 compared with low vitamin B-12 ) for patients with a normal vitamin B-12 concentration ( > 220 pmol/l ) . Conclusions Long term treatment with metformin increases the risk of vitamin B-12 deficiency , which results in raised homocysteine concentrations . Vitamin B-12 deficiency is preventable ; therefore , our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered . Trial registration Clinical trials.gov NCT00375388 Background . Women with polycystic ovary syndrome have elevated homocysteine levels . Elevated homocysteine levels associate with pregnancy complications . Women with polycystic ovary syndrome are often treated with metformin , a drug that may increase homocysteine levels . Hence , we investigated the effect of metformin treatment on homocysteine levels in nonpregnant and pregnant women with polycystic ovary syndrome . Methods . Two prospect i ve r and omized placebo‐controlled studies included women with polycystic ovary syndrome in a university hospital setting . Sixty‐three infertile women were treated with metformin 1,000 mg bid or placebo for 16 weeks and 38 pregnant women with metformin 850 mg bid or placebo from the first trimester and throughout pregnancy . All the women had polycystic ovary syndrome and all participants received diet and lifestyle advice , and oral folate and vitamin B12 substitution , and a daily oral multivitamin tablet . The main outcome measures were serum levels of homocysteine , folate , and vitamin B12 . Results . Serum homocysteine levels were unaffected by metformin treatment both in nonpregnant and pregnant women with polycystic ovary syndrome . However , in nonpregnant women both serum folate and vitamin B12 levels decreased with treatment . At inclusion in nonpregnant women , serum homocysteine levels associated negatively with serum levels of folate and methyl malonic acid and positively with free testosterone index . No such associations were seen in pregnant women . Conclusions . Metformin treatment in women with polycystic ovary does not increase serum homocysteine levels in the nonpregnant or the pregnant state Background Women with polycystic ovary syndrome ( PCOS ) are at increased risk for cardiovascular ( CV ) and metabolic disorders . There is a close relationship between elevated and rogen plasma levels and the ultrasound findings of stromal hypertrophy . In r and omized trials , the administration of metformin has been shown to be followed by an improvement in insulin sensitivity and decrease in and rogen levels in most women . In the present study , we investigate the association between reduced ovarian volume in PCOS patients after administration of metformin with improvement in CV risk factors . Material s and Methods This was a r and omized clinical trial study . A total of 28 women diagnosed with PCOS who referred to the infertility clinic were selected .  Anthropometric characteristics of the patients , mean ovarian volume and plasma levels of fasting blood sugar ( FBS ) , lipid profile , luteinizing hormone ( LH ) , follicle stimulating hormone ( FSH ) , estradiol , testosterone , 17-α-OH progesterone ( 17OHP ) , dehydroepi and rosterone sulfate ( DHEAS ) , C-reactive protein ( CRP ) and homocysteine ( Hcy ) were evaluated before and after treatment with 500 mg metformin , three times daily for three months . Statistics were calculated with the aid of SPSS 16.0 with student ’s paired t- and Pearson ’s correlation coefficient tests . Significance was set at p<0.05 . Results There were significant reductions in mean ovarian volume and body mass index ( BMI ) , in addition to CRP , Hcy , testosterone , FBS , HDL and LDL levels . There was a positive correlation between mean ovarian volume and waist-to-hip ratio (WHR).After treatment , there correlation noted with reduction in mean ovarian volume and decreased BMI , in addition to reductions in CRP , LDL , Hcy and testosterone levels . Conclusion A positive correlation may exist between reduced mean ovarian volume and improvement in CV risk factors  after administration of metformin ( Registeration Number : I RCT 138903244176N1 ) OBJECTIVE The severity of peripheral neuropathy in diabetic patients varies for unclear reasons . Long-term use of metformin is associated with malabsorption of vitamin B12 ( cobalamin [ Cbl ] ) and elevated homocysteine ( Hcy ) and methylmalonic acid ( MMA ) levels , which may have deleterious effects on peripheral nerves . The intent of this study was to clarify the relationship among metformin exposure , levels of Cbl , Hcy , and MMA , and severity of peripheral neuropathy in diabetic patients . We hypothesized that metformin exposure would be associated with lower Cbl levels , elevated Hcy and MMA levels , and more severe peripheral neuropathy . RESEARCH DESIGN AND METHODS This was a prospect i ve case-control study of patients with type 2 diabetes and concurrent symptomatic peripheral neuropathy , comparing those who had received > 6 months of metformin therapy ( n = 59 ) with those without metformin exposure ( n = 63 ) . Comparisons were made using clinical ( Toronto Clinical Scoring System and Neuropathy Impairment Score ) , laboratory ( serum Cbl , fasting Hcy , and fasting MMA ) , and electrophysiological measures ( nerve conduction studies ) . RESULTS Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels . Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients ; the cumulative metformin dose correlated strongly with these clinical and para clinical group differences . CONCLUSIONS Metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes . Interval screening for Cbl deficiency and systemic Cbl therapy should be considered upon initiation of , as well as during , metformin therapy to detect potential secondary causes of worsening peripheral neuropathy OBJECTIVE The objective of this study was to evaluate and compare the effects of gliclazide-modified release ( gliclazide-MR ) , metformine ( MET ) and pioglitazone ( PIO ) monotherapies on glycemic control and conventional/non-conventional cardiovascular risk factors in patients with newly diagnosed type 2 diabetes mellitus ( T2DM ) . MATERIAL AND METHODS A single center , r and omized , 52-wk comparator-controlled clinical study was carried out in patients with newly diagnosed uncontrolled T2DM . A total of 57 patients were r and omized into gliclazide-MR , metformin and pioglitazone groups . Drugs were administered for 12 months . Anthropometric measurements , fasting plasma glucose ( FPG ) , postpr and ial plasma glucose ( PPG ) , HbA1c , insulin , HOMA-IR , lipid parameters , the markers of coagulation/fibrinolysis , inflammation and endothelial dysfunction were measured at baseline and at months 3 , 6 , and 12 . RESULTS In the gliclazide-MR group , HC , FPG , HbA1c , insulin , HOMA-IR , TC , trigylcerides , Lp ( a ) , E-selectin and Hcy were significantly decreased after treatment compared to baseline . In the MET group , BMI , WC , FPG , PPG , HbA1c , ICAM-1 and Hcy significantly decreased after treatment compared to baseline . In PIO group , WC , HC , FPG , PPG , HbA1c , C-peptid , HOMA-IR , trigylcerides , vWF , IL-6 , ICAM-1 , E-selectin and Hcy significantly decreased after treatment compared to baseline , whereas , HDL-C increased . At the end of the month 12 , the decreases in insulin and HOMA-IR score were more pronounced with PIO compared to gliclazide . CONCLUSIONS Gliclazide-MR , MET and PIO monotherapies , were equally effective in proving glycemic control in patients with newly diagnosed , oral antidiabetic (OAD)-naive T2DM . But , improvements in conventional/non-conventional cardiovascular risk factors were more pronounced in patients on PIO therapy compared to gliclazide and MET therapies . Also , all of the 3 drugs represent effective and safe first-line pharmacological treatment options in these patients OBJECTIVE Metformin is a key treatment option in type 2 diabetes . However , metformin may decrease vitamin B12 levels and increase levels of homocysteine , a cardiovascular risk factor . We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine , folate and vitamin B12 in subjects with type 2 diabetes treated with insulin . DESIGN Placebo-controlled , r and omized trial . MEASUREMENTS at baseline and 16 weeks later . SETTING This trial was conducted in the outpatient clinics of three general hospitals in The Netherl and s. SUBJECTS A total of 745 patients with type 2 diabetes , treated with insulin and not known with a contraindication for the use of metformin , were approached ; 390 gave informed consent and entered the study . Thirty-seven subjects dropped out ( 12 placebo and 25 metformin users ) . INTERVENTION Addition of metformin or placebo to insulin therapy . PRIMARY OUTCOME PARAMETERS : Serum homocysteine , folate , vitamin B12 , indices of glycaemic control and body weight . RESULTS Amongst those who completed 16 weeks of treatment , metformin use , as compared with placebo , was associated with an increase in homocysteine of 4 % ( 0.2 to 8 ; P=0.039 ) and with decreases in folate [ -7 % ( -1.4 to -13 ) ; P=0.024 ] and vitamin B12 [ -14 % ( -4.2 to -24 ) ; P<0.0001 ] . In addition , the increase in homocysteine could be explained by the decreases in folate and vitamin B12 . CONCLUSION In patients with type 2 diabetes , 16 weeks of treatment with metformin reduces levels of folate and vitamin B12 , which results in a modest increase in homocysteine . The clinical significance 
    Output:
    
agent
Therefore , although the overall effect of metformin on the concentration of serum Hcy was neutral , our results suggested that metformin could increase the concentration of Hcy when exogenous B-group vitamins or folic acid supplementation was not given
***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: Objectives To study the effects of metformin on the incidence of vitamin B-12 deficiency ( < 150 pmol/l ) , low concentrations of vitamin B-12 ( 150 - 220 pmol/l ) , and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin . Design Multicentre r and omised placebo controlled trial . Setting Outpatient clinics of three non-academic hospitals in the Netherl and s. Participants 390 patients with type 2 diabetes receiving treatment with insulin . Intervention 850 mg metformin or placebo three times a day for 4.3 years . Main outcome measures Percentage change in vitamin B-12 , folate , and homocysteine concentrations from baseline at4 , 17 , 30 , 43 , and 52 months . Results Compared with placebo , metformin treatment was associated with a mean decrease in vitamin B-12 concentration of −19 % ( 95 % confidence interval −24 % to −14 % ; P<0.001 ) and in folate concentration of −5 % ( 95 % CI −10 % to −0.4 % ; P=0.033 ) , and an increase in homocysteine concentration of 5 % ( 95 % CI −1 % to 11 % ; P=0.091 ) . After adjustment for body mass index and smoking , no significant effect of metformin  on folate concentrations was found . The absolute risk of vitamin B-12 deficiency ( < 150 pmol/l ) at study end was 7.2 percentage points higher in the metformin group than in the placebo group ( 95 % CI 2.3 to 12.1 ; P=0.004 ) , with a number needed to harm of 13.8 per 4.3 years ( 95 % CI 43.5 to 8.3 ) . The absolute risk of low vitamin B-12 concentration ( 150 - 220 pmol/l ) at study end was 11.2 percentage points higher in the metformin group ( 95 % CI 4.6 to 17.9 ; P=0.001 ) , with a number needed to harm of 8.9 per 4.3 years ( 95 % CI 21.7 to 5.6 ) . Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 µmol/l ( 95 % CI 18.8 to 30.0 µmol/l ) , compared with a mean homocysteine level of 18.1 µmol/l ( 95 % CI 16.7 to 19.6 µmol/l ; P=0.003 ) for patients with a low vitamin B-12 concentration and 14.9 µmol/l ( 95 % CI 14.3 to 15.5 µmol/l ; P<0.001 compared with vitamin B-12 deficiency ; P=0.005 compared with low vitamin B-12 ) for patients with a normal vitamin B-12 concentration ( > 220 pmol/l ) . Conclusions Long term treatment with metformin increases the risk of vitamin B-12 deficiency , which results in raised homocysteine concentrations . Vitamin B-12 deficiency is preventable ; therefore , our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered . Trial registration Clinical trials.gov NCT00375388 Background . Women with polycystic ovary syndrome have elevated homocysteine levels . Elevated homocysteine levels associate with pregnancy complications . Women with polycystic ovary syndrome are often treated with metformin , a drug that may increase homocysteine levels . Hence , we investigated the effect of metformin treatment on homocysteine levels in nonpregnant and pregnant women with polycystic ovary syndrome . Methods . Two prospect i ve r and omized placebo‐controlled studies included women with polycystic ovary syndrome in a university hospital setting . Sixty‐three infertile women were treated with metformin 1,000 mg bid or placebo for 16 weeks and 38 pregnant women with metformin 850 mg bid or placebo from the first trimester and throughout pregnancy . All the women had polycystic ovary syndrome and all participants received diet and lifestyle advice , and oral folate and vitamin B12 substitution , and a daily oral multivitamin tablet . The main outcome measures were serum levels of homocysteine , folate , and vitamin B12 . Results . Serum homocysteine levels were unaffected by metformin treatment both in nonpregnant and pregnant women with polycystic ovary syndrome . However , in nonpregnant women both serum folate and vitamin B12 levels decreased with treatment . At inclusion in nonpregnant women , serum homocysteine levels associated negatively with serum levels of folate and methyl malonic acid and positively with free testosterone index . No such associations were seen in pregnant women . Conclusions . Metformin treatment in women with polycystic ovary does not increase serum homocysteine levels in the nonpregnant or the pregnant state Background Women with polycystic ovary syndrome ( PCOS ) are at increased risk for cardiovascular ( CV ) and metabolic disorders . There is a close relationship between elevated and rogen plasma levels and the ultrasound findings of stromal hypertrophy . In r and omized trials , the administration of metformin has been shown to be followed by an improvement in insulin sensitivity and decrease in and rogen levels in most women . In the present study , we investigate the association between reduced ovarian volume in PCOS patients after administration of metformin with improvement in CV risk factors . Material s and Methods This was a r and omized clinical trial study . A total of 28 women diagnosed with PCOS who referred to the infertility clinic were selected .  Anthropometric characteristics of the patients , mean ovarian volume and plasma levels of fasting blood sugar ( FBS ) , lipid profile , luteinizing hormone ( LH ) , follicle stimulating hormone ( FSH ) , estradiol , testosterone , 17-α-OH progesterone ( 17OHP ) , dehydroepi and rosterone sulfate ( DHEAS ) , C-reactive protein ( CRP ) and homocysteine ( Hcy ) were evaluated before and after treatment with 500 mg metformin , three times daily for three months . Statistics were calculated with the aid of SPSS 16.0 with student ’s paired t- and Pearson ’s correlation coefficient tests . Significance was set at p<0.05 . Results There were significant reductions in mean ovarian volume and body mass index ( BMI ) , in addition to CRP , Hcy , testosterone , FBS , HDL and LDL levels . There was a positive correlation between mean ovarian volume and waist-to-hip ratio (WHR).After treatment , there correlation noted with reduction in mean ovarian volume and decreased BMI , in addition to reductions in CRP , LDL , Hcy and testosterone levels . Conclusion A positive correlation may exist between reduced mean ovarian volume and improvement in CV risk factors  after administration of metformin ( Registeration Number : I RCT 138903244176N1 ) OBJECTIVE The severity of peripheral neuropathy in diabetic patients varies for unclear reasons . Long-term use of metformin is associated with malabsorption of vitamin B12 ( cobalamin [ Cbl ] ) and elevated homocysteine ( Hcy ) and methylmalonic acid ( MMA ) levels , which may have deleterious effects on peripheral nerves . The intent of this study was to clarify the relationship among metformin exposure , levels of Cbl , Hcy , and MMA , and severity of peripheral neuropathy in diabetic patients . We hypothesized that metformin exposure would be associated with lower Cbl levels , elevated Hcy and MMA levels , and more severe peripheral neuropathy . RESEARCH DESIGN AND METHODS This was a prospect i ve case-control study of patients with type 2 diabetes and concurrent symptomatic peripheral neuropathy , comparing those who had received > 6 months of metformin therapy ( n = 59 ) with those without metformin exposure ( n = 63 ) . Comparisons were made using clinical ( Toronto Clinical Scoring System and Neuropathy Impairment Score ) , laboratory ( serum Cbl , fasting Hcy , and fasting MMA ) , and electrophysiological measures ( nerve conduction studies ) . RESULTS Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels . Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients ; the cumulative metformin dose correlated strongly with these clinical and para clinical group differences . CONCLUSIONS Metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes . Interval screening for Cbl deficiency and systemic Cbl therapy should be considered upon initiation of , as well as during , metformin therapy to detect potential secondary causes of worsening peripheral neuropathy OBJECTIVE The objective of this study was to evaluate and compare the effects of gliclazide-modified release ( gliclazide-MR ) , metformine ( MET ) and pioglitazone ( PIO ) monotherapies on glycemic control and conventional/non-conventional cardiovascular risk factors in patients with newly diagnosed type 2 diabetes mellitus ( T2DM ) . MATERIAL AND METHODS A single center , r and omized , 52-wk comparator-controlled clinical study was carried out in patients with newly diagnosed uncontrolled T2DM . A total of 57 patients were r and omized into gliclazide-MR , metformin and pioglitazone groups . Drugs were administered for 12 months . Anthropometric measurements , fasting plasma glucose ( FPG ) , postpr and ial plasma glucose ( PPG ) , HbA1c , insulin , HOMA-IR , lipid parameters , the markers of coagulation/fibrinolysis , inflammation and endothelial dysfunction were measured at baseline and at months 3 , 6 , and 12 . RESULTS In the gliclazide-MR group , HC , FPG , HbA1c , insulin , HOMA-IR , TC , trigylcerides , Lp ( a ) , E-selectin and Hcy were significantly decreased after treatment compared to baseline . In the MET group , BMI , WC , FPG , PPG , HbA1c , ICAM-1 and Hcy significantly decreased after treatment compared to baseline . In PIO group , WC , HC , FPG , PPG , HbA1c , C-peptid , HOMA-IR , trigylcerides , vWF , IL-6 , ICAM-1 , E-selectin and Hcy significantly decreased after treatment compared to baseline , whereas , HDL-C increased . At the end of the month 12 , the decreases in insulin and HOMA-IR score were more pronounced with PIO compared to gliclazide . CONCLUSIONS Gliclazide-MR , MET and PIO monotherapies , were equally effective in proving glycemic control in patients with newly diagnosed , oral antidiabetic (OAD)-naive T2DM . But , improvements in conventional/non-conventional cardiovascular risk factors were more pronounced in patients on PIO therapy compared to gliclazide and MET therapies . Also , all of the 3 drugs represent effective and safe first-line pharmacological treatment options in these patients OBJECTIVE Metformin is a key treatment option in type 2 diabetes . However , metformin may decrease vitamin B12 levels and increase levels of homocysteine , a cardiovascular risk factor . We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine , folate and vitamin B12 in subjects with type 2 diabetes treated with insulin . DESIGN Placebo-controlled , r and omized trial . MEASUREMENTS at baseline and 16 weeks later . SETTING This trial was conducted in the outpatient clinics of three general hospitals in The Netherl and s. SUBJECTS A total of 745 patients with type 2 diabetes , treated with insulin and not known with a contraindication for the use of metformin , were approached ; 390 gave informed consent and entered the study . Thirty-seven subjects dropped out ( 12 placebo and 25 metformin users ) . INTERVENTION Addition of metformin or placebo to insulin therapy . PRIMARY OUTCOME PARAMETERS : Serum homocysteine , folate , vitamin B12 , indices of glycaemic control and body weight . RESULTS Amongst those who completed 16 weeks of treatment , metformin use , as compared with placebo , was associated with an increase in homocysteine of 4 % ( 0.2 to 8 ; P=0.039 ) and with decreases in folate [ -7 % ( -1.4 to -13 ) ; P=0.024 ] and vitamin B12 [ -14 % ( -4.2 to -24 ) ; P<0.0001 ] . In addition , the increase in homocysteine could be explained by the decreases in folate and vitamin B12 . CONCLUSION In patients with type 2 diabetes , 16 weeks of treatment with metformin reduces levels of folate and vitamin B12 , which results in a modest increase in homocysteine . The clinical significance 
    Output:
    