Metformin and male reproduction: effects on Sertoli cell metabolism

Background and Purpose

Metformin is commonly used to treat type 2 diabetes (T2D). While new clinical applications have been ascribed to metformin, including treatment of anovulatory infertility, its effects on male reproduction have not been investigated. The Sertoli cell (SC) is crucial for germ cell development, exerting metabolic control of spermatogenesis, therefore, we investigated the effects of metformin on SC metabolism.

Experimental Approach

Rat SCs were cultured in the absence and presence of metformin (5, 50 and 500 μM). mRNA and protein levels of glucose transporters (GLUT1 and GLUT3), phosphofructokinase 1 (PFK 1), lactate dehydrogenase (LDH) and monocarboxylate transporter 4 (MCT4) were determined by quantitative PCR and Western blot respectively. LDH activity was assessed and metabolite production/consumption determined by ¹H-NMR.

Key Results

Metformin (50 μM) decreased mRNA and protein levels of GLUT1, GLUT3, MCT4 and PFK 1 but did not affect LDH mRNA or protein levels. However, although glucose consumption was maintained in metformin-treated cells, LDH activity, lactate and alanine production were increased, indicating an enhanced glycolytic flux. No metabolic cytotoxicity was detected in SCs exposed to supra-pharmacological concentration of metformin.

Conclusions and Implications

Our results indicate that metformin: (i) decreases mRNA and protein levels of glycolysis-related transporters in SCs but increases their activity; and (ii) stimulates alanine production, which induces antioxidant activity and maintains the NADH/NAD⁺ equilibrium. The increased lactate in metformin-treated SCs provides nutritional support and has an anti-apoptotic effect in developing germ cells. Thus, metformin can be considered as a suitable antidiabetic drug for male patients of reproductive age with T2D.     

Metformin may produce antidepressant effects through improvement of cognitive function among depressed patients with diabetes mellitus

Diabetes mellitus and depressive disorders are both common chronic diseases that increase functional disability and social burden. Cognitive impairment is a potentially debilitating feature of depression. Previous evidence indicates that the antidiabetic drug metformin could be suitable for diabetic patients with cognitive impairment. However, there is no direct evidence from clinical studies that metformin treatment improves cognitive function in diabetic patients suffering from depression. In the present study, 58 participants diagnosed with depression and type 2 diabetes mellitus (T2DM) were recruited and divided into two groups, one treated with metformin and the other treated with placebo for 24 weeks. Cognitive function, depressive behaviour and diabetes improvement were evaluated. Chronic treatment with metformin for 24 weeks improved cognitive performance, as assessed by the Wechsler Memory Scale–Revised, in depressed patients with T2DM. In addition, metformin significantly improved depressive performance and changed the glucose metabolism in depressed patients with diabetes. Depressive symptoms were negatively correlated with cognitive performance in metformin‐treated participants. Furthermore, associations were observed between the parameters of blood glucose metabolism and the depression phenotype. These findings suggest that chronic treatment with metformin has antidepressant behavioural effects and that improved cognitive function is involved in the therapeutic outcome of metformin. The results of the present study also raise the possibility that supplementary administration of antidiabetic medications may enhance the recovery of depression, comorbid with T2DM, through improvements in cognitive performance.     

甘精胰岛素联合二甲双胍治疗糖尿病合并高脂血症40例临床观察

目的:观察甘精胰岛素联合二甲双胍治疗糖尿病合并高脂血症的临床疗效。方法:将符合诊断标准的40例患者按随机数字表法分为治疗组和对照组,每组各20例,对照组单用甘精胰岛素治疗,治疗组在甘精胰岛素治疗基础上加服二甲双胍片,共治疗12周后检测各项指标。结果:经治疗后2组患者HbA1c均有改善,但对血脂水平的影响各有不同。治疗组血清TG及LDL-C降低明显,而对照组与治疗前相比变化不明显。结论:甘精胰岛素联合二甲双胍治疗糖尿病合并高脂血症效果优于单纯胰岛素治疗,值得临床推广。     

吡格列酮联合二甲双胍治疗2型糖尿病效果的meta分析

目的：系统评价吡格列酮联合二甲双胍治疗2型糖尿病的疗效和安全性。方法：检索Cochrane Library、PubMed、EMbase、CBM、CNKI、VIP、WanFang Data共7个数据库,收集主题为吡格列酮联合二甲双胍治疗2型糖尿病的文献;根据排除标准筛选确定最终文献,并根据Cochrane手册评价纳入研究质量,最后提取结局指标数据运用RevMan 5.2进行meta分析。结果：纳入15篇文献,包含T2DM患者1881例,其中联合组941例,二甲双胍单用组940例。结果显示,联合组更能有效降低血糖和糖化血红蛋白,改善胰岛素及血脂,但体质指数无显著差异;不良反应方面,两组在胃肠道事件发生率方面无显著差异;但联合组的水肿发生率略高于单用组。结论：联合用药效果优于二甲双胍单用,且安全性良好。     

Early combination versus initial metformin monotherapy in the management of newly diagnosed type 2 diabetes: An East Asian perspective

Type 2 diabetes (T2D) in the East Asian population is characterized by phenotypes such as low body mass index, an index of β-cell dysfunction, and higher percentage of body fat, an index of insulin resistance. These phenotypes/pathologies may predispose people to early onset of diabetes with increased risk of stroke and renal disease. Less than 50% of patients with T2D in East Asia achieve glycaemic targets recommended by national or regional guidelines, which may be attributable to knowledge and/or implementation gaps. Herein, we review the latest evidence with special reference to East Asian patients with T2D and present arguments for the need to use early combination therapy to intensify glycaemic control. This strategy is supported by the 5-year worldwide VERIFY study, which reported better glycaemic durability in newly diagnosed patients with T2D with a mean HbA1c of 6.9% treated with early combination therapy of vildagliptin plus metformin versus those treated with initial metformin monotherapy followed by addition of vildagliptin only with worsening glycaemic control. This paradigm shift of early intensified treatment is now recommended by the American Diabetes Association and the European Association for the Study of Diabetes. In order to translate these evidence to practice, increased awareness and strengthening of the healthcare system are needed to diagnose and manage patients with T2D early for combination therapy.     

Effects of insulin-sensitising agents in mice with hepatic insulin resistance

Aims/hypothesis The metabolic abnormalities of insulin resistance are ameliorated by insulin sensitisers via different mechanisms. Metformin decreases hepatic glucose output, whereas rosiglitazone (RSG) is an agonist for peroxisome proliferator activated receptor (PPAR), highly expressed in fat. To gain insight into the mechanisms of action of these drugs, we compared their actions in two models of insulin resistance: the obese, hyperglycaemic ob/ob mouse and the liver specific insulin receptor knockout (LIRKO) mouse.Methods Control, ob/ob, and LIRKO mice were divided into three groups that received metformin (300 mg/kg body weight/day), RSG (3 mg/kg body weight/day), or placebo for 3 weeks.Results In the presence of the severe hepatic insulin resistance of the LIRKO mouse, neither metformin nor RSG had any significant effect on glucose or insulin tolerance tests. On the other hand, RSG decreased serum concentrations of total cholesterol, LDL, and HDL in LIRKO mice. Adipocyte PPAR gene and protein expression, and adipocyte size were all increased in LIRKO mice treated with RSG, whereas fat-cell size in control animals was decreased by RSG.Conclusion/interpretation TZDs probably improve some lipid parameters of the dysmetabolic syndrome associated with diabetes mellitus even in the presence of absolute hepatic insulin resistance, but both metformin and TZDs require an operating insulin signalling system in the liver for their effects in glucose homeostasis.Abbreviations TZD Thiazolidinedione - RSG rosiglitazone - LIRKO liver specific insulin receptor knockout     

Canagliflozin,a sodium glucose co-transporter 2 inhibitor,reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial

Objective

Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin.

Materials/Methods

Patients (N = 37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods. Patients received Treatments (A) placebo/placebo, (B) canagliflozin 300 mg/placebo, (C) canagliflozin 300 mg/canagliflozin 300 mg, or (D) canagliflozin 300 mg/canagliflozin 150 mg on Day 2/Day 3 in one of four treatment sequences (similar urinary glucose excretion [UGE] expected for Treatments B–D). A mixed-meal tolerance test (MMTT) was given 20 minutes post-dose on Day 3 of each period.

Results

A single dose of canagliflozin 300 mg reduced both fasting and postprandial PG compared with placebo, with generally similar effects on fasting PG and UGE observed for Treatments B–D. An additional dose of canagliflozin 300 mg (Treatment C), but not 150 mg (Treatment D), prior to the MMTT on Day 3 provided greater postprandial PG reduction versus placebo (difference in incremental glucose AUC_0–2h, − 7.5% for B vs A; − 18.5% for C vs A; − 12.0% [P = 0.012] for C vs B), leading to modestly greater reductions in total glucose AUC_0–2h with Treatment C versus Treatment B or D. Canagliflozin was generally well tolerated.

Conclusions

These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.