Disease relevance of metformin

• Lactic acidosis in patients with diabetes treated with metformin [1].
• Efficacy of metformin in non-insulin-dependent diabetes mellitus [2].
• Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus [3].
• CONCLUSIONS: In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism [4].
• Metformin-induced hemolysis with jaundice [5].
• Breast cancer cells can be protected against metformin-induced growth inhibition by small interfering RNA against AMP kinase [6].
• These data, and the epidemiological and retrospective data supporting the antineoplastic effects of metformin, provide the rationale to study the role of metformin for breast cancer therapy in a variety of clinical settings [7].
• Our finding that metformin use was associated with improved outcome of patients with diabetes and pancreatic cancer should be confirmed in independent studies [8].

Psychiatry related information on metformin

• Long-term vascular risk reduction has been demonstrated only with sulfonylureas and metformin [9].
• This newer formulation may enhance patient compliance with oral therapy and improve long-term control of diabetes compared with the conventional immediate-release formulation of metformin (MIR) [10].
• Metformin therapy in a transgenic mouse model of Huntington's disease [11].
• There was a significant improvement in hirsutism at the end of the metformin phase compared with placebo: F-G score 15.8+/-1.4 vs 17.5+/-1.2 (P=0.025) and patient self-assessment 2.4+/-0.1 vs 3.3+/-0.3 (P=0.014) [12].
• The risk factors to metformin included advanced coronary heart disease in 51%, atrial fibrillation in 9.8%, chronic alcohol abuse in 3.3%, advanced peripheral vascular disease in 2%, and pregnancy in 0.7% [13].

High impact information on metformin

• CONCLUSIONS: The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin [14].
• CONCLUSIONS: Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis [15].
• 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 [16].
• Metformin improved fatty liver disease, reversing hepatomegaly, steatosis and aminotransferase abnormalities [17].
• Metformin reverses fatty liver disease in obese, leptin-deficient mice [17].

Chemical compound and disease context of metformin

• Effects of metformin or gemfibrozil on the lipodystrophy of HIV-infected patients receiving protease inhibitors [18].
• We propose that metformin improves diabetes-associated vascular disease both by lowering blood glucose and by its effect on PTP regulation [19].
• Body weight decreased in the metformin (84 +/- 4 vs. 82 +/- 4 kg, P < 0.05) but not the rosiglitazone group [20].
• Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells [21].
• Glyburide/metformin dose was maintained or reduced by 2.5/500 mg for symptomatic hypoglycemia [22].
• Metformin therapy is safe and effective in abrogating weight gain, decreased insulin sensitivity, and abnormal glucose metabolism resulting from treatment of children and adolescents with atypicals [23].

Biological context of metformin

• Metabolic effects of metformin in non-insulin-dependent diabetes mellitus [15].
• To evaluate this possibility, insulin-resistant ob/ob mice with fatty livers were treated with metformin, an agent that improves hepatic insulin-resistance [17].
• In a high percentage of patients, treatment with metformin is followed by regularization of menstrual cycle, reduction in hyperandrogenism and in cardiovascular risk factors, and improvement in response to therapies for induction of ovulation [24].
• RESULTS: Patients treated with metformin demonstrated significant reductions in mean (SEM) insulin AUC 120 minutes after OGTT (-2930 [912] vs -414 [432] microIU/mL [-20349 6334 vs -2875 3000 pmol/L]; P =.01), weight (-1.3 [0.6] vs 1.1 [0.4] kg; P =.005), and diastolic blood pressure (-5 [4] vs 5 [2] mm Hg; P =.009) vs controls, respectively [25].
• Instead, the protective effects of metformin correlated with complete prevention of the upregulation of plasminogen activator inhibitor (PAI)-1 caused by ethanol [26].

Anatomical context of metformin

• Metformin therapy was associated with a decrease in visceral abdominal fat (VAT; -1115 [819] vs 1191 [699] mm(2); P =.08) and a proportional reduction in subcutaneous abdominal fat (SAT); the VAT-SAT ratio was unchanged in metformin-treated vs placebo-treated patients [25].
• In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation [27].
• Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin [28].
• Regulation of glucose transport and insulin signaling by troglitazone or metformin in adipose tissue of type 2 diabetic subjects [29].
• Isolated rat adipocytes were incubated with or without metformin (1-100 micrograms/ml) for 2 h at 37 degrees C followed by an incubation with or without insulin (1.72 nM) [30].

Associations of metformin with other chemical compounds

• 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 [16].
• BACKGROUND & AIMS: The biguanide drug metformin has recently been found to improve steatosis and liver damage in animal models and in humans with nonalcoholic steatohepatitis [26].
• The effect of metformin or rosiglitazone monotherapy versus placebo on insulin signaling and gene expression in skeletal muscle of patients with newly diagnosed type 2 diabetes was determined [31].
• These data demonstrate that, unlike glyburide, metformin provides cardioprotection against HG-induced abnormalities in myocyte relaxation, perhaps through tyrosine kinase-dependent changes in intracellular Ca2+ handling, independent of its insulin sensitizing action [32].
• To determine whether improving S(I) in subjects with impaired glucose tolerance (IGT) was associated with decreased CD68 expression, IGT subjects were treated for 10 weeks with pioglitazone or metformin [33].
• The insulin sensitivity index increased with metformin but did not change with Diane(35) Diario [34].
• At 6 and 12 months after treatment suspension, in the metformin group, insulin sensitivity index significantly (P < 0.05) worsened in comparison with that observed at baseline and during treatment and with that observed in the placebo and control groups [35].
• Metformin dose-dependently suppressed IL-1beta-induced IL-8 production, cAMP-induced mRNA expression and aromatase activity, and 5-bromo-2'-deoxyuridine incorporation in ESCs [36].
• In therapy naïve women, we found no evidence of a difference in live birth rate when comparing metformin with clomifene citrate (CC) [relative risks (RR) 0.73; 95% confidence interval (CI) 0.51-1.1] or comparing metformin plus CC with CC (RR 1.0; 95% CI 0.82-1.3) [37].
• The inhibition of metformin renal tubular secretion by cimetidine also appeared to be dependent on this mutation [38].
• The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway [39].

Gene context of metformin

• Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin [40].
• In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters [40].
• Metformin also increased mRNA expression of the MEF2 isoforms [41].
• The effect of metformin was completely blocked by an IR inhibitor [42].
• Metformin was also associated with lower insulin resistance and leptin and IGF-I levels and higher SHBG and IGF-binding protein-1 levels and with a more favorable lipid profile [43].
• In peripheral tissues, injection of metformin leads to mPer2 degradation and a phase advance in the circadian expression pattern of clock genes in wild-type mice but not in AMPK alpha2 knock-out mice [44].

Analytical, diagnostic and therapeutic context of metformin

• METHODS: We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome [14].
• METHODS: Patients on stable antiretroviral therapy containing protease inhibitors, with abdominal obesity defined by increased waist-to-hip ratio, and plasma triglycerides >200 mg/dl, were randomized to receive blind medication consisting of metformin 850 mg, gemfibrozil 600 mg or placebo every 12 h for 1 year [18].
• Insulin receptor binding to monocytes, insulin secretion, and glucose tolerance following metformin treatment. Results of a double-blind cross-over study in type II diabetics [45].
• After treatment of the impaired glucose-tolerant subjects with insulin sensitizers for 10 weeks, pioglitazone (but not metformin) resulted in a 60% increase in the insulin sensitivity index (S(i)) and a 32% decrease in IMCLs (both P < 0.01), along with an increase in lipin-beta (but not lipin-alpha) expression by 200% (P < 0.005) [46].
• Because metformin improves peripheral insulin sensitivity, we examined the acute effect of metformin and placebo on glucose and lipid metabolism in nine insulin-resistant first-degree relatives of NIDDM patients with the euglycemic insulin-clamp technique combined with indirect calorimetry and infusion of [3-3H]glucose [47].

References