Beneficial Effects Of Metformin Research Articles

Relationship between abnormal glucose tolerance test and history of previous recurrent miscarriages, and beneficial effect of metformin in these patients: a prospective clinical study

To determine the incidence of an abnormal glucose tolerance test in patients with recurrent spontaneous abortion and whether metformin would safely reduce the rate of first trimester spontaneous abortions in patients without polycystic ovary syndrome (PCOS) as well as with PCOS and an abnormal glucose tolerance test. Prospective control clinical trial. Shiraz University-affiliated hospital. Patients with a history of recurrent spontaneous abortion and women with a history of normal full term pregnancy. The incidence of abnormal carbohydrate metabolism was determined. Metformin and placebo were given to women with an abnormal glucose tolerance test and who had recurrent spontaneous abortions. Continuation of pregnancy beyond the first trimester in all groups and presence or absence of teratogenicity in the delivered baby after metformin therapy. Twenty-nine of the patients in the group with recurrent spontaneous abortion were found to have an abnormal glucose tolerance test result compared with just four (5.4%) patients in the normal pregnancy group. The abortion rate was significantly reduced after metformin therapy in patients without PCOS in comparison to the placebo group (15% vs. 55%). This study indicates an important link between an abnormal glucose tolerance test and a history of recurrent abortion. It was also found that metformin therapy improves the chances of a successful pregnancy in patients with an abnormal glucose tolerance test.

Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin

Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin

O-298: In vitro maturation, in vitro fertilization and embryo transfer (IVM-IVF) combined with low dose FSH over Metformin pretreatment and frozen-thawed cycles should be a routine ART option for polycystic ovarian syndrome (PCOS) patients

O-298: In vitro maturation, in vitro fertilization and embryo transfer (IVM-IVF) combined with low dose FSH over Metformin pretreatment and frozen-thawed cycles should be a routine ART option for polycystic ovarian syndrome (PCOS) patients

Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

Metformin has been shown to increase fatty acid oxidation, an effect mediated by AMP activated protein kinase (AMPK). We hypothesised that metformin could prevent both caspase-3 activation and apoptosis when induced by palmitic acid. Cardiomyocytes were incubated with 1 mmol/l palmitic acid, in the absence or presence of metformin (1-5 mmol/l). Following 1 to 16 h, cell damage was evaluated by measuring lactate dehydrogenase released into the incubation medium, and Hoechst staining. To investigate the mechanism of metformin's effect on cardiomyocytes, substrate utilisation and phosphorylation of AMPK and acetyl-CoA carboxylase were measured. Intracellular mediators of apoptosis were also evaluated. Incubation of myocytes with palmitic acid for 16 h increased apoptosis, an effect that was partly blunted by 1 and 2 mmol/l metformin. This beneficial effect of metformin was associated with increased AMPK phosphorylation, palmitic acid oxidation and suppression of high-fat-induced increases in (1) long chain base biosynthesis protein 1 levels, (2) ceramide levels, and (3) caspase-3 activity. Unexpectedly, 5 mmol/l metformin dramatically increased apoptosis in myocytes incubated with high fat. This effect was associated with a robust increase in glycolysis, lactate accumulation, and a significant drop of pH in the myocyte incubation medium. Our study demonstrates that metformin reduces high-fat-induced cardiac cell death, probably through inhibition of ceramide synthesis. However, at high concentrations, metformin causes proton and lactate accumulation, leading to cell damage that is independent of caspase-3.

Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin

Women with polycystic ovary syndrome (PCOS) have an increased prevalence of insulin resistance (IR) and related disorders. Elevated serum levels of cellular adhesion molecules (CAMs) reflect low-grade chronic inflammation and have been associated with several insulin-resistant states. The objective of this study is to investigate whether soluble inflammatory markers [soluble intercellular adhesion molecule-1 (sICAM-1), soluble endothelial leukocyte adhesion molecule-1 (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1) and C-reactive protein (CRP)] are altered in PCOS and to further elucidate the effect of metformin treatment on their levels. Two young populations were studied [62 women with PCOS and 45 normal women of similar age, BMI and waist-to-hip ratio (WHR)]. Plasma levels of sICAM-1, sVCAM-1, sE-selectin and high-sensitivity CRP (hsCRP) were measured in both groups. Additionally, the effect of metformin on these molecules was investigated in 22 women with PCOS who accepted to metformin protocol (1700 mg daily for a 6-month period). In the total population studied, plasma levels of hsCRP (mg/l), sICAM-1 (ng/ml) and sE-selectin (ng/ml) were higher in the PCOS group compared with those in controls (hsCRP 1.31 +/- 0.22 versus 0.92 +/- 0.27, P = 0.014, sICAM-1 301.21 +/- 24.80 versus 209.86 +/- 17.05, P = 0.025, sE-selectin 57.37 +/- 4.08 versus 45.67 +/- 4.62, P = 0.045, respectively). sVCAM-1 (ng/ml) did not differ statistically among the two groups (P = 0.896). A significant reduction in hsCRP and sVCAM-1 was achieved after 6 months of metformin administration: PCOS pretreatment hsCRP 1.92 +/- 0.60 versus PCOS post-treatment hsCRP 0.52 +/- 0.26, P = 0.005; PCOS pretreatment sVCAM-1 668.09 +/- 98.38 versus PCOS post-treatment sVCAM-1 365.82 +/- 99.77, P = 0.039. These findings imply the presence of chronic inflammation in women with PCOS. Metformin decreases the levels of plasma inflammatory indices. Further investigation is required to determine whether these findings may prove to be of clinical significance for PCOS patients.

Beneficial effect of metformin on pregnancy outcome in women with polycystic ovary syndrome is not associated with major changes in C-reactive protein levels or indices of coagulation

In women with polycystic ovary syndrome, C-reactive protein levels and D-dimer, antithrombin III, activated protein C resistance, and activated partial thromboplastin time were unaffected by metformin treatment throughout pregnancy. Protein C levels increased slightly in the metformin group compared with the placebo group.

Metformin reduces abortion in pregnant women with polycystic ovary syndrome

Background. Women with polycystic ovary syndrome (PCOS) are considered to be at increased risk of miscarriage. Since metformin has beneficial effects on the risk factors contributing to first-trimester abortion in PCOS patients, we hypothesized that metformin – owing to its metabolic, endocrine, vascular and anti-inflammatory effects – may reduce the incidence of first-trimester abortion in PCOS women.Materials and methods. A prospective cohort study was set up to determine the beneficial effects of metformin on PCOS patients during pregnancy. Two hundred non-diabetic PCOS patients were evaluated while undergoing assisted reproduction. One hundred and twenty patients became pregnant while taking metformin, and continued taking metformin at a dose of 1000–2000 mg daily throughout pregnancy. Eighty women who discontinued metformin use at the time of conception or during pregnancy comprised the control group.Results. Both groups were similar with respect to all background characteristics (age, body mass index, waist/hip ratio, follicle-stimulating hormone, luteinizing hormone, estradiol and dehydroepiandrosterone sulfate levels). Rates of early pregnancy loss in the metformin group were 11.6% compared with 36.3% in the control group (p < 0.0001; odds ratio = 0.23, 95% confidence interval 0.11–0.42).Conclusions. Administration of metformin throughout pregnancy to women with PCOS was associated with a marked and significant reduction in the rate of early pregnancy loss.

Low Dose FSH Administration Over Metformin Pretreatment on Polycystic Ovarian Syndrome (PCOS) Patients Improves the Clinical Outcome of In Vitro Maturation and In Vitro Fertilization and Embryo Transfer (IVM-IVF) Treatment

In vitro maturation of immature oocytes obtained from non-stimulated patients and in vitro fertilization and embryo transfer (IVM-IVF) is a relatively new option of assisted reproductive technologies (ART). Although IVM-IVF is not only a promising method to avoid the potential side effects of gonadotropins, ovarian hyperstimulation syndrome (OHSS), especially with polycystic ovarian syndrome (PCOS) patients, but also has so many advantages such as less medication, lower cost, and less stress, pregnancy rates are still inferior to conventional IVF-ET with ovarian stimulation. A beneficial effect of Metformin on IVM-IVF has been reported at last ASRM meeting (Fertil Steril 2004; 82, Suppl; O-123). The present study was conducted to determine whether administration of low dose FSH over Metformin pretreatment further improved the clinical outcomes of IVM-IVF treatment. Retrospective clinical study at private setting fertility clinic IVM-IVF was performed on 66 cycles, non pretreatment (Group A: 28 cycles), pretreatment with 1000-1500 mg/day Metformin at least for 4 weeks before oocyte retrievals (Group B: 26 cycles) or total dose of 450 units of FSH administration over Metformin pretreatment (Group C: 12 cycles). Follicular monitoring began from cycle day-7 and follicles were aspirated when at least 2 follicles reached more than 7mm in diameter before dominant follicle (>13.5mm) appeared. Human chorionic gonadotropin (hCG) of 10,000units was administered 36hours before retrieval. In group C, 150 units per day of FSH were administered for 3 days before hCG administration. Immature oocytes retrieved were cultured in TCM-199 medium supplemented with 20% of donor follicular fluid for 28hours and ICSI was performed on matured oocytes. Fertilization was confirmed by the presence of 2 pronuclei and 2 polar bodies 18hours after ICSI. Day-3 embryos were transferred after assisted hatching. Clinical pregnancy was identified by the appearance of gestational sac. Totally 855 (group A: 286, group B: 408, and group C: 161) immature oocytes were retrieved and used for analysis. Number of retrieved immature oocytes per cycle in group A (10.2 ± 7.2) was significantly lower (P<0.01) than either group B (15.7 ± 8.1) or group C (13.4 ± 10.0). However, there were no significant differences in either maturation rates (48.9%, 47.3% and 41.0%) or fertilization rates (81.4%, 87.6% and 83.3%) among group A, B and C, respectively. The rates of embryo transfer per retrieval were similar in group A (64.3%), B (80.8%) and C (66.7%). The pregnancy rates were highest in group C (50%), second in group B (26.7%) and lowest in group A (22.2%). Either Metformin alone or low dose FSH combined with Metformin pretreatment increased the number of immature oocyte retrieved. Combination of Metformin pretreatment with low dose FSH achieved highest pregnancy rate per transfer (50%) and second highest was Metformin pretreatment alone (26.7%). The pregnancy rate of IVM-IVF without any pretreatment was the lowest (22.2%). The present study suggests that pretreatment of PCOS patients with not only Metformin but also low dose FSH combined with Metformin enhances the clinical outcomes of IVM-IVF treatment.

0267 Hyperinsulinemia and beneficial effects of metformin in myotonic dystrophy type I (DM1)

0267 Hyperinsulinemia and beneficial effects of metformin in myotonic dystrophy type I (DM1)

Effect of Metformin in Asian Indian Women with Polycystic Ovarian Syndrome

This study was conducted to study the therapeutic benefits of metformin and to determine the correction of insulin resistance on 25 patients of polycystic ovarian syndrome (PCOS) attending the Department of Obstetrics and Gynaecology, S.C.B. Medical College and Hospital, Cuttack, India, for varying complaints. Twenty-five women diagnosed as having PCOS received metformin in doses of 500 mg every 8 h for 6 months. Periodical evaluation with respect to clinical improvement was done after months 3 and 6, while evaluations of changes in biochemical parameters and hormone levels were done at the end of month 6. Out of 23 cases (92%) women who presented with menstrual disturbances, the cycles were regularized in 21 (91%). Fourteen women complained of infertility, and five (35.7%) of them conceived within the span of treatment. In six (24%) cases with complaints of hirsutism, there was improvement in three cases (50%). Twelve (91.6%) of obese patients with PCOS had weight loss with significant changes in waist-to-hip ratio (WHR) after metformin therapy. Of the three patients with low FSH, the level became normal in two cases. Polycystic changes in ovary regressed in 12 (85.7%) cases. Of the 13 patients with elevated serum testoterone level, normalization of values was seen in 12 cases. Abnormal LH/FSH ratio and impaired glucose tolerance were normalized, and insulin resistance was significantly reduced in all the cases studied, with mean HOMA values decreasing from 3.34 to 1.82. This study conclusively points out the beneficial effects of metformin in cases of PCOS in Asian women, both in the adolescent and the reproductive age. This mode of treatment is successful and has an etiological rationale behind its use. The additional benefits are a relatively low cost of therapy and diminished hazards associated with surgical intervention.

Beneficial effects of metformin on haemostasis and vascular function in man

Type 2 diabetes is characterised by insulin resistance in association with clustering of atherothrombotic risk factors (dysglycaemia, hyperinsulinaemia, hypertension, raised triglyceride, low HDL cholesterol and increased levels of plasminogen activator inhibitor-1 (PAI-1) and clotting factor VII). There is a 3-5 fold increase in risk of myocardial infarction rising to 10-20 fold in the presence of microalbuminuria and overall around 70-75% of subjects with type 2 diabetes die of cardiovascular disease. However, classical risk factors which associate with insulin resistance do not account for all the increased burden of vascular disease in diabetic subjects. Metformin is a biguanide compound which is antihyperglycaemic, reduces insulin resistance and has cardioprotective effects on lipids, thrombosis and blood flow. Metformin has a weight neutral/weight lowering effect and reduces hypertriglyceridaemia, elevated levels of PAI-1, factor VII and C-reactive protein. In addition recent studies indicate that metformin has direct effects on fibrin structure/function and stabilises platelets, two important components of arterial thrombus. The United Kingdom Prospective Diabetes Study (UKPDS) reported that metformin was associated with a 32% reduction in any diabetes related endpoint (p<0.002), a 39% reduction in myocardial infarction (p<0.01) and a non-significant 29% fall in microvascular complications. The figures for macrovascular complications compare favourably for those described for other cardioprotective agents such as ACE inhibitors and statins. These findings confirm metformin as first line therapy in the management of obese insulin resistant type 2 diabetes and in the prevention of the vascular complications of this common condition.

Do effects on blood pressure contribute to improved clinical outcomes with metformin?

Hyperinsulinaemia and hypertension commonly coexist, and a large body of evidence points to a common pathogenesis based on the presence of underlying insulin resistance (the "insulin hypothesis" of hypertension). Metformin improves insulin sensitivity in liver and muscle as its primary antihyperglycaemic mechanism of action, and intensive glycaemic management with metformin significantly reduced the risk of macrovascular diabetic complications in the UK Prospective Diabetes Study. The clinical outcome benefits in the metformin group included a significant reduction in the risk of stroke (- 41% vs + 14% with sulphonylurea or insulin treatment, p=0.032), which is well known to be highly sensitive to changes in blood pressure. Furthermore, a placebo-controlled study has shown that metformin significantly improved endothelial function, a key regulator of vascular tone and blood pressure, in type 2 diabetic patients. However, clinical studies have shown that metformin treatment is not associated with clinically relevant reductions in blood pressure in man. These apparently conflicting observations are difficult to reconcile. Either the beneficial vascular actions of metformin involve physiological systems not involved in the control of blood pressure, or counter-regulatory mechanisms prevent beneficial effects of metformin on the vasculature being translated into a clinically meaningful antihypertensive effect. Further research will be required to resolve this paradox.

The importance of insulin resistance in polycystic ovary syndrome

The most widely accepted criteria for the diagnosis of polycystic ovary syndrome (PCOS) are hyperandrogenism and/or hyperandrogenemia and oligo-ovulation, with the exclusion of other hyperandrogenic disorders (1). Thus, androgen elevation defines the syndrome. This definition permits a wide range of presentations and clinical appearances, that is, a continuum of patients with PCOS. Androgen excess, of ovarian and often also adrenal origin, underlies the symptoms of hirsutism, acne, alopecia, and seborrhea, and treatment with anti-androgens is the most effective method of reducing these complaints. Hyperandrogenemia may also be responsible for the weight gain present in about 50% of cases. What has been increasingly recognized is that PCOS is associated with insulin resistance and compensatory hyperinsulinemia. While not required for the diagnosis of PCOS, insulin resistance appears to cause or exacerbate hyperandrogenemia in many patients, as evidenced by the reduction in ovarian and adrenal androgen levels with insulin-sensitizing therapy (2‐ 6). More importantly, insulin resistance leads to hypertension, diabetes, and cardiovascular disease, the most significant complications of PCOS.