二甲双胍对糖尿病患者血清同型半胱氨酸和维生素B12水平的影响

目的 探讨T2DM患者二甲双胍治疗后血清同型半胱氨酸(Hcy)、维生素B12(Vit B12)、叶酸(FA)水平的变化.方法 44例T2DM患者在原治疗的基础上口服二甲双胍,治疗前和治疗半年后测定血清Hcy、Vit B12、FA水平.结果 口服二甲双胍半年后,血清Vit B12、FA水平下降,Hcy水平升高,其升高与二甲双胍使用剂量、Vit B12、FA下降相关.结论 二甲双胍口服半年可降低T2DM患者Vit B12、FA水平,升高血清Hcy水平.     

Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial

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, randomized trial. Measurements: at baseline and 16 weeks later. SETTING: This trial was conducted in the outpatient clinics of three general hospitals in The Netherlands. 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 of these findings remains to be investigated.     

The effects of rosiglitazone and metformin on the plasma concentrations of resistin in patients with type 2 diabetes mellitus

Resistin is a protein secreted from adipose tissue that is thought to play a role in insulin sensitivity. We examined the effects of rosiglitazone and metformin on the plasma resistin levels in individuals with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus who showed poor glycemic control with glimepiride (4 mg/d) were randomized to rosiglitazone (4 mg/d) and metformin (500 mg bid) treatment groups. All subjects continued glimepiride treatment as well. The plasma concentrations of resistin were measured at baseline and at 6 months of treatment for both groups. The anthropometric parameters, fasting plasma glucose, HbA1c, total cholesterol, triglyceride, high-density lipoprotein cholesterol, free fatty acids, and adiponectin concentrations were also measured. After 6 months of treatment, the reduction in plasma glucose levels was similar between the 2 groups. There were no significant changes in the lipid profiles of either group during the study period. The plasma resistin levels decreased in the rosiglitazone group (2.49 +/- 1.93 vs 1.95 +/- 1.59 ng/ml; P < .05) but increased in the metformin group (2.61 +/- 1.69 vs 5.13 +/- 2.81 ng/ml; P < .05). The plasma adiponectin concentrations were increased in the rosiglitazone group (2.91 +/- 1.46 vs 4.23 +/- 1.77 microg/ml; P < .05) but were unchanged in the metformin group. In summary, rosiglitazone treatment decreased the plasma resistin levels whereas metformin treatment increased them in patients with type 2 diabetes mellitus showing poor glycemic control with sulfonylurea therapy. These results suggest that the observed changes in plasma resistin levels are not the consequences of improved insulin resistance, nor are they consequences of glycemic control. Considering the potential role of resistin in insulin resistance, decrease in resistin levels may contribute to improving insulin action with rosiglitazone treatment.     

Effects of rosiglitazone and metformin treatment on apelin, visfatin, and ghrelin levels in patients with type 2 diabetes mellitus

Visfatin, ghrelin, and apelin are the most recently identified adipocytokines; but their response to insulin-sensitizing agents is poorly clarified. We aimed to assess the differential effects of either rosiglitazone or metformin monotherapy on the aforementioned adipocytokines in patients with type 2 diabetes mellitus (T2DM). One hundred T2DM patients (30 men, 70 women), with poor glycemic control (glycosylated hemoglobin >6.5%) while taking 850 mg of metformin daily, were enrolled. All participants were randomized to receive either adjunctive therapy with rosiglitazone (8 mg/d, n = 50) or the maximum dose (2550 mg/d) of metformin (MET group, n = 50). Anthropometric parameters, glycemic and lipid profile, high-sensitivity CRP (hs-CRP), insulin resistance (homeostasis model assessment of insulin resistance index [HOMA-IR]), visfatin, ghrelin, and apelin were assessed at baseline and after 14 weeks of therapy. Both rosiglitazone and metformin led to similar, significant improvement in glycemic profile and apelin levels, whereas lipid parameters, fat mass, and visfatin remained almost unaffected (P > .05). Insulin resistance was significantly attenuated in both groups, but to a lesser degree in the MET group (P = .045). Rosiglitazone-treated patients experienced a significant decrease in hs-CRP and systolic blood pressure compared with baseline values and those of the MET group (P < .05). Besides, rosiglitazone treatment considerably increased plasma ghrelin (3.74 ± 1.52 ng/mL) in comparison with either baseline (P = .034) or metformin monotherapy values (−2.23 ± 1.87 ng/mL, P = .008). On the other hand, the MET group, rather than the rosiglitazone group, had decreased body mass index (−0.79 ± 0.47 vs 0.56 kg/m², P = .009). The aforementioned changes in apelin and ghrelin were independently associated with HOMA-IR changes. Both rosiglitazone and metformin favorably changed glycemic indexes and apelin levels. The addition of rosiglitazone seemed to confer greater benefits in ghrelin, hs-CRP, systolic blood pressure, and HOMA-IR regulation than metformin monotherapy. Although these results reflect improvement in cardiovascular risk profile, the overall clinical importance of insulin sensitizers must be further assessed.     

Elevated serum homocysteine as a predictor for vitamin B12 or folate deficiency

Abstract: Tissue deficiency of vitamin B₁₂ and folate results in an increase in serum homocysteine (sHcy). We have measured sHcy in patients with reduced serum vitamin B₁₂ and/or red cell folate (RCF) to determine its usefulness as a discriminant for the diagnostic interpretation of reduced vitamin levels. Of 3846 patients who had serum vitamin B₁₂ and RCF assayed, 335 (9%) had reduced vitamin levels. Multivariate analysis showed a significant association between sHcy and serum creatinine (p = 0.0001), positive intrinsic factor (IF) antibody or neutrophil hypersegmentation (NHS) (p = 0.001), increased MCV (p = 0.014) and low RCF (p = 0.025) but no relationship with the level of serum vitamin B₁₂ or haemoglobin. After censoring the patients with renal impairment (n = 54), the distribution of the remaining 72 patients with elevated sHcy was 37/151 (25%) with low serum vitamin B₁₂ with or without low RCF and 35/130 (27%) with low RCF alone. sHcy correctly identified response to vitamin therapy in 33/35 (94%) patients who had adequate parameters to assess response. The positive predictive values of IF antibody/NHS, macrocytosis and/or low RCF for elevated sHcy were 100% and 34% respectively. Twenty-four percent of patients with a low serum vitamin B₁₂ and elevated sHcy had no abnormal haematologic parameters as determined by the routine laboratory staff. These data suggest that the usefulness of measuring sHcy in a routine diagnostic setting is limited and a careful review of the peripheral blood for macrocytosis and NHS plus determination of RCF may be a more cost-effective process than sHcy assay in most instances to determine the presence of tissue deficiency.     

In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations

In a recent study of older participants (age >/=60 years) in the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we showed that a combination of high serum folate and low vitamin B(12) status was associated with higher prevalence of cognitive impairment and anemia than other combinations of vitamin B(12) and folate status. In the present study, we sought to determine the joint influence of serum folate and vitamin B(12) concentrations on two functional indicators of vitamin B(12) status, total homocysteine (tHcy) and methylmalonic acid (MMA), among adult participants in phase 2 of the NHANES III (1991-1994) and the NHANES 1999-2002. Exclusion of subjects who were <20 years old, were pregnant, had evidence of kidney or liver dysfunction, or reported a history of alcohol abuse or recent anemia therapy left 4,940 NHANES III participants and 5,473 NHANES 1999-2002 participants for the study. Multivariate analyses controlled for demographic factors, smoking, alcohol use, body mass index, self-reported diabetes diagnosis, and serum concentrations of creatinine and alanine aminotransferase revealed significant interactions between serum folate and serum vitamin B(12) in relation to circulating concentrations of both metabolites. In subjects with serum vitamin B(12) >148 pmol/liter (L), concentrations of both metabolites decreased significantly as serum folate increased. In subjects with lower serum vitamin B(12), however, metabolite concentrations increased as serum folate increased starting at approximately 20 nmol/L. These results suggest a worsening of vitamin B(12)'s enzymatic functions as folate status increases in people who are vitamin B(12)-deficient.     

The effects of rosiglitazone and metformin on inflammation and endothelial dysfunction in patients with type 2 diabetes mellitus

Diabetic patients have a markedly increased risk of cardiovascular disease compared with non-diabetics. Two drug groups today target insulin resistance; biguanides and thiazolidinediones. In addition, these may have other effects on cardiovascular risk factors. The aim of this study was to evaluate the effects of metformin and rosiglitazone on non-traditional cardiovascular risk factors. Forty type 2 diabetic patients were randomized into metformin and rosiglitazone groups. After receiving the optimal doses, the patients were monitored for 12 weeks. Biochemical parameters, lipid parameters, CRP, insulin, c-peptide, and HbA1c levels were analyzed. VWF, PAI-1, ICAM-1, TNF-α, IL-6, E-selectin, and fibrinogen levels were measured in order to assess coagulation status and endothelial dysfunction. In the metformin group, body mass index, PPG, HbA1c, IL-6, ICAM-1, and TNF-α levels were significantly decreased after 12 weeks compared with the basal levels. IL-6 levels decreased from 75 pg/ml ± 20 to 42 pg/ml ± 9 (P 0.023) and TNF- α levels from 61 pg/ml ± 31 to 39 pg/ml ± 10 (P 0.018). In the rosiglitazone group, FPG, PPG, HbA1c, insulin, HOMA-IR, IL-6, and TNF-α levels decreased significantly after 12 weeks compared with the basal levels. IL-6 levels decreased from 78 pg/ml ± 21 to 41 pg/ml ± 9 (P 0.028) and TNF-α levels from 62 pg/ml ± 19 to 37 pg/ml ± 10 (P 0.012). At the end of the study, no significant differences were determined between groups. Insulin resistance and type 2 diabetes are strongly associated with low grade inflammation. Both metformin and rosiglitazone were effective in controlling inflammatory markers in addition to metabolic parameters.     

Effect of therapy with vitamin B12 and folic acid on elderly patients with low concentrations of serum vitamin B12 or erythrocyte folate but normal blood counts

To help understand the haematological significance of the low concentrations of serum vitamin B12 and erythrocyte folate occurring in elderly patients, 17 acute admissions to a geriatric unit with a low concentration of serum vitamin B12 or erythrocyte folate but a normal blood count were treated with vitamin B12 and folic acid for 3 months. Bone marrow deoxyuridine suppression was abnormal in 3 of these 17 patients, 2 of whom also had megaloblastic change in the marrow. With treatment, the MCV fell in 13 of the 17, and the average MCV fell from 90.5 to 87.9 fl (p = 0.007), but the mean Hb did not change. Ten untreated similar patients showed no change in their MCV over the same period, but the mean Hb fell from 14.0 to 13.1 g/dl (p = 0.04). Thus the low concentrations of serum vitamin B12 or erythrocyte folate found in approximately a quarter of acutely admitted elderly patients may indicate true tissue deficiency of these vitamins, even when the blood count is normal.     

Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes

AIM: This study assessed the efficacy and safety of rosiglitazone and metformin (RSG/MET) fixed-dose combination (AVANDAMET) as initial therapy in patients with uncontrolled type 2 diabetes compared with monotherapy with either RSG or MET after 32 weeks of treatment. METHODS: A total of 468 drug-naive patients with uncontrolled type 2 diabetes were recruited for this multicentre, double-blind trial if their glycated haemoglobin (A1c) was greater than 7.5%, but less than or equal to 11%, and their fasting plasma glucose (FPG) was less than or equal to 15 mmol/l. Patients were randomized to 32 weeks of blinded treatment with either RSG/MET fixed-dose combination (n = 155), MET (n = 154) or RSG (n = 159). The groups were comparable at baseline, with mean A1c of 8.8% and FPG of 11 mmol/l. RSG/MET was initiated with a total daily dose of 2 mg/500 mg and could be increased up to 8 mg/2000 mg; MET therapy began with a total daily dose of 500 mg and could be increased up to 2000 mg; and RSG treatment began with a total daily dose of 4 mg and could be increased up to 8 mg. Medication was uptitrated during on-therapy visits based on failure to attain glycaemic target of mean daily glucose less than or equal to 6.1 mmol/l (unless at maximum tolerated dose). Patients were assessed for efficacy and safety at nine visits over a 32-week treatment period. This was a trial designed to show greater efficacy of RSG/MET combination therapy compared with MET or RSG monotherapy. The primary end point was change in A1c from baseline to week 32. Secondary end points included the proportion of patients achieving recommended A1c and FPG targets for glycaemic control and change from baseline in FPG, free fatty acid, lipids, insulin, insulin sensitivity, C-reactive protein and adiponectin. Safety evaluations included adverse-event (AE) monitoring, changes in weight and clinical laboratory evaluations. RESULTS: At week 32, RSG/MET showed significant improvements in A1c from a baseline of 8.9 +/- 1.1% to 6.6 +/- 1.0% at study end, and this 2.3% reduction was significantly greater than the reductions achieved individually with MET (-1.8%; p = 0.0008) and RSG (-1.6%; p < 0.0001). The greatest mean decrease in FPG was seen with RSG/MET (-4.1 mmol/l) and was significant compared with MET (-2.8 mmol/l; p < 0.0001) and RSG (-2.6 mmol/l; p < 0.0001). Target A1c of less than or equal to 6.5% and less than 7% were achieved in more patients in the RSG/MET group (60% and 77%) than with MET (39% and 57%) or RSG (35% and 58%) respectively. Treatment was well tolerated, with nausea, vomiting and diarrhoea as the most commonly reported AEs. Oedema was comparable between RSG/MET (6%) and RSG (7%) and lower in the MET group (3%). No new safety and tolerability issues were observed in the RSG/MET group. CONCLUSIONS: As first-line therapy in patients with uncontrolled type 2 diabetes, RSG/MET fixed-dose combination therapy achieved significant reductions in A1c and FPG compared with either RSG or MET monotherapy. RSG/MET was generally well tolerated as initial therapy, with no new tolerability issues identified with the fixed-dose combination.     

Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy

AIM: This double-blind study evaluated the efficacy and safety of metformin-glibenclamide tablets vs. metformin plus rosiglitazone therapy in patients with type 2 diabetes inadequately controlled on metformin monotherapy. SUBJECTS AND METHODS: After an open-label, metformin lead-in phase, 318 patients were randomly assigned to treatment based on metformin-glibenclamide 500/2.5 mg tablets (initial daily dose 1000/5 mg) or metformin 500 mg plus rosiglitazone 4 mg (initial daily dose 1000-2000 mg + 4 mg, depending on previous treatment) for 24 weeks. Doses were titrated to achieve the therapeutic glycaemic target. The primary efficacy variable was the change in HbA1C. RESULTS: At week 24, metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C (-1.5%) and fasting plasma glucose [-2.6 mmol/l (-46 mg/dl)] than metformin plus rosiglitazone [-1.1%, p < 0.001; -2 mmol/l (-36 mg/dl), p = 0.03]. More patients receiving metformin-glibenclamide attained HbA1C <7.0% than did those in the metformin plus rosiglitazone group (60 vs. 47%) and had fasting plasma glucose levels <7 mmol/l (<126 mg/dl) by week 24 (34 vs. 25%). Both treatments were well tolerated. Frequency of adverse gastrointestinal events was comparable between groups. Four per cent of patients receiving metformin-glibenclamide withdrew because of symptomatic hypoglycaemia contrasted with 3% of patients receiving metformin plus rosiglitazone who withdrew because of persistent hyperglycaemia. Hypoglycaemic events were mild or moderate in intensity and were easily self-managed. CONCLUSIONS: Metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C and fasting plasma glucose compared with metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.     

Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy

Aims/hypotheses

Despite oral hypoglycaemic medications being the most commonly used pharmacological treatments for type 2 diabetes, research is limited on their comparative safety, particularly their effects on overall mortality. We compared mortality risk with monotherapy initiation of four oral hypoglycaemic medications in a nationwide cohort of US veterans with type 2 diabetes.

Methods

We identified new users of oral hypoglycaemic medication monotherapy between 2004 and 2009 who received care for at least 1 year from the Veterans Health Administration. Patients were followed until initial monotherapy discontinuation, addition of another diabetes pharmacotherapy, death or end of follow-up. Mortality HRs were estimated using Cox regression adjusted for potential confounding factors.

Results

Among new users of metformin, sulfonylureas and rosiglitazone (185,360 men, 7,812 women), 4,256 (2.2%) died during follow-up. Average duration of medication use ranged from 1.4 to 1.7 years. Significantly higher mortality risk was seen for glibenclamide (known as glyburide in the USA and Canada) (HR 1.38, 95% CI 1.27, 1.50) or glipizide (HR 1.55, 95% CI 1.43, 1.67) compared with metformin monotherapy, and for glipizide compared with rosiglitazone (HR 1.27, 95% CI 1.01, 1.59) or glibenclamide monotherapy (HR 1.12, 95% CI 1.02, 1.23). A significant sex–rosiglitazone interaction was seen (p?=?0.034) compared with metformin monotherapy, with women having a higher HR (HR 4.36, 95% CI 1.34, 14.20) than men (HR 1.19, 95% CI 0.95, 1.49).

Conclusions/interpretations

Significantly higher mortality was associated with glibenclamide, glipizide and rosiglitazone use compared with metformin, and with glipizide use compared with rosiglitazone or glibenclamide. The potential for residual confounding by indication should be considered in interpreting these results.     

吡格列酮和二甲双胍对2型糖尿病胰岛素抵抗的影响

目的　观察吡格列酮和二甲双胍治疗对 2型糖尿病患者胰岛素抵抗 (IR)的影响。方法 5 0例血糖控制不良的 2型糖尿病患者在原治疗方案下 ,随机给予盐酸吡格列酮片 3 0mg(2片 ) 1次 /日和模拟二甲双胍片 (1片 ) 2次 /日 ,即吡格列酮组 ;或随机给予盐酸二甲双胍片 5 0 0mg(1片 ) 2次 /日和模拟吡格列酮片 (2片 ) 1次 /日 ,即二甲双胍组 ,所有治疗疗程 12周。结果　在两组患者取得相当降糖疗效基础上 ,二甲双胍组和吡格列酮组在治疗后空腹和馒头餐后C肽水平均较用药前有明显降低、IR稍有降低 ,β细胞功能明显改善。吡格列酮在减低餐后胰岛素、改善IR方面优于二甲双胍。两种药物治疗前后血游离脂肪酸水平则差异未见显著性。结论　吡格列酮和二甲双胍均能有效地降低IR和改善 β细胞功能。在改善IR方面 ,吡格列酮稍优于二甲双胍。     

Effect of berberine and metformin on serum lipids of type 2 diabetes mellitus patients

目的 探讨小檗碱和二甲双胍治疗对2型糖尿病患者血脂的影响.方法 入选初发2型糖尿病伴血脂异常患者50例,随机分为小檗碱组和二甲双胍组,治疗随访6个月,治疗前后测定患者血脂、血糖、胰岛素和糖化血红蛋白(HbA1c)等指标.结果 治疗6个月小檗碱组和二甲双胍组患者总胆固醇(TC)、低密度脂蛋白-胆固醇(LDL-C)、甘油三脂(TG)均明显降低(P＜0.05),组间比较差异无统计学意义.两组HbA1c、胰岛素抵抗指数(HOMA-IR)和胰岛β细胞功能指数(HOMA-β)均明显改善,二甲双胍组改善HOMA-IR较小檗碱组明显(P＜0.05).结论 小檗碱可能通过多种机制降糖降脂,对伴有血脂异常的2型糖尿病患者小檗碱效果可能优于二甲双胍.     

Circulating homocysteine levels in patients with type 2 diabetes mellitus

Background and aimPrevious studies have shown conflicting results regarding circulating homocysteine levels in patients with type 2 diabetes.Methods and resultsThis observational study included 2121 patients with angiographically proven coronary artery disease (507 patients with type 2 diabetes and 1614 patients without diabetes). Circulating homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, renal function, presence of coronary artery disease (CAD) diagnosed by coronary angiography, and circulating folate and vitamin B₁₂ status were assessed. Plasma homocysteine levels [median (25th; 75th percentile)] were significantly higher in patients with diabetes than in those without [12.4 μmol/L (9.9 μmol/L; 15.9 μmol/L) versus 11.7 μmol/L (9.6 μmol/L; 14.5 μmol/L), P = 0.011]. Diabetes affected homocysteine levels only in patients with a glomerular filtration rate <90 mL/min [13.0 μmol/L (10.5 μmol/L; 16.7 μmol/L) in patients with diabetes versus 12.2 μmol/L (10.1 μmol/L; 15.2 μmol/L) in patients without diabetes, P = 0.006] but not in those with a glomerular filtration rate ≥90 mL/min [10.1 μmol/L (8.1 μmol/L; 12.4 μmol/L) versus 10.2 μmol/L (8.8 μmol/L; 12.3 μmol/L), P = 0.267]. Multivariable analysis did not show an independent association between diabetes and homocysteine level (P = 0.342).ConclusionCirculating homocysteine levels are increased in patients with type 2 diabetes compared with non-diabetic patients due to a more diabetes-associated adverse risk profile rather than to diabetes itself.     

罗格列酮对2型糖尿病患者C反应蛋白的影响

目的观察罗格列酮（RSG）治疗2型糖尿病（T2DM）前后血清高敏C反应蛋白（hsC-RP）的变化。方法采用随机、双盲、安慰剂平行对照法将120例已合用磺脲类和双胍类药物的T2DM患者随机分为安慰剂组和RSG组,治疗12周。结果安慰剂组的HbA1c明显下降（P〈0.05）,其他指标均无显著变化;RSG组与基线比较FPG、2hPG、HbA1c、胰岛素抵抗指数、hsC-RP均明显下降（P均〈0.01）。结论RSG治疗T2DM,除能改善胰岛素抵抗,降低血糖,还有明显的抗炎症作用,使hsC-RP下降。