Diabetes Mellitus (DM) and insulin resistant (IR) are highly prevalent among heart failure (HF) patients. There is now increasing evidence to suggest a bidirectional relationship between IR and HF. DM and IR not only lead to heart failure, but heart failure can also lead to the development of DM or IR. The degree of IR also correlates with the severity and mortality of CHF. The pathophysiology of IR in CHF has yet to be fully defined. Activation of sympathetic nervous system, abnormal regulation of adipocytokines systems, activation of inflammatory and coagulation cascade, accumulation of glycated products, endothelial dysfunction and hyperinsulinaemia are potential explanations of the development of IR in CHF. Additionally, it remains to be determined if IR is merely a marker reflecting the severity of CHF or whether it contributes to the disease in CHF. If IR is truly a culprit that worsens CHF, reversing IR may potentially be a new target for treatment in CHF, which may result in an improvement in symptoms and even mortality in patients with CHF. However, there are concerns over the use of certain insulin sensitizers, most notably, the thiazolidinediones (TZDs), which has been linked with increased risk of hospitalizations for CHF and concerns regarding its association with increased myocardial infarction. Despite previous concerns of lactic acidosis, there is now evidence that metformin may not only be safe but could potentially be useful in the setting of CHF. We have conducted a randomised double-blind, placebo-controlled trial testing the hypothesis of reversing IR with metformin in insulin-resistant CHF will have beneficial effects. If IR is a possible target for the treatment of CHF, what are the new and potential treatment modalities? We have now had better understandings of the adipocytokines systems, which may prove to be a therapeutic option to improve IR in CHF. AMP-activated protein kinase (AMPK) pathway has become the focus of research as a novel therapeutic target in cardio-metabolic disease. It has been shown to mediate, at least in part, the effects of a number of physiological and pharmacological factors that improve IR. It also exerts beneficial effects on the vasculature and the heart. There have been some new AMPK activators that are currently being tested in vivo setting or phase 1-2 trials, and the early results are somewhat promising. Increased understandings and refreshed insights of IR and CHF have opened a new horizon and encouraged us to explore more therapeutics options in CHF.

Prior research has suggested that life style factors, such as diet and physical activity, influence prostate cancer (PCa) progression. Metformin intake has been shown to be associated with decreased cancer risk in type II diabetic patients. We hypothesize that a low carbohydrate diet, prolonged aerobic exercise and metformin treatment can all independently slow prostate tumor development and a combination regimen will have an additive benefit. We used LNCaP xenografts to test this hypothesis. Results revealed that a diet low in carbohydrate reduced food consumption and a combination with exercise significantly reduced animal body weights. Ten weeks of metformin did not significantly alter tumor growth rate compared to control animals. Ten weeks of exercise significantly inhibited tumor growth. Out results suggest that dietary carbohydrate alteration or the administration of metformin alone cannot significantly influence prostate tumor progression. A suitable sustained exercise regimen may offer a more protective effect against PCa progression.

Prior research has suggested that life style factors, such as diet and physical activity, influence prostate cancer (PCa) progression. Metformin intake has been shown to be associated with decreased cancer risk in type II diabetic patients. We hypothesize that a low carbohydrate diet, prolonged aerobic exercise and metformin treatment can all independently slow prostate tumor development and a combination regimen will have an additive benefit. We used LNCaP xenografts to test this hypothesis. Results revealed that a diet low in carbohydrate reduced food consumption and a combination with exercise significantly reduced animal body weights. Ten weeks of metformin did not significantly alter tumor growth rate compared to control animals. Ten weeks of exercise significantly inhibited tumor growth. Out results suggest that dietary carbohydrate alteration or the administration of metformin alone cannot significantly influence prostate tumor progression. A suitable sustained exercise regimen may offer a more protective effect against PCa progression.

Endometrial cancer (EC) is the most common gynaecological cancer affecting women in developed countries. Improving outcomes for women who are unfit for primary surgery or have advanced disease remains a challenge. Metformin use is associated with reduced cancer risk in several observational studies of patients with type 2 diabetes. Pre-clinical studies in EC show that metformin reduces cellular proliferation. The work described in this thesis tests the hypothesis that metformin reduces cellular proliferation in vitro and in vivo in type I EC through actions on the PI3K/AKT/mTOR pro-proliferative pathway. First, an in vitro model of EC using cell lines was established to determine the effect of metformin on cellular proliferation. Metformin was found to be cytostatic in a dose-dependent manner; these effects were potentiated in combination with carboplatin and paclitaxel. Metformin was shown to modulate mTOR phosphorylation proteins by immunoblot. Flow cytometric and metabolic assays found metformin to increase mitochondrial mass, but conversely, reduce mitochondrial function. These in vitro findings varied according to glucose concentration and were attenuated in hypoxia. Next, staining and scoring protocols for Ki-67, a marker of cellular proliferation, were established using semi-automated scoring on archived EC tumours. Ki-67 correlated with age, tumour grade and myometrial invasion; high Ki-67 expression was associated with an increased risk of disease recurrence, and was thus a prognostic marker. Finally, a presurgical window study of metformin versus no drug in women with EC demonstrated a 17% reduction in tumour Ki-67 with short-term metformin. Ki-67 response varied positively with increased average daily dose of metformin and negatively with increased BMI. High grade tumours were more hypoxic, according to baseline HIF-1alpha and the Ki-67 response to metformin was lower in hypoxic tumours. The effect on tumour mTOR phosphorylation events varied, but was not significant after adjusting for changes in controls. In conclusion, these results demonstrated that short-term oral metformin was associated with reduced cellular proliferation in women with EC. The findings from this study require corroboration with a placebo-controlled trial prior to the introduction of metformin as treatment for EC, both as a sole agent and in combination with existing adjuvant therapy. The response to metformin was heterogeneous; tumour hypoxia and metabolic adaptations of cancer cells may lead to metformin-resistance. Future studies should take these modulating effects into account to help identify patients likely to derive clinical benefit from metformin.

Pharmaceutically Active Compounds include metformin, the most often prescripted drug for a treatment of the diabetes mellitus type 2. Metformin is used in high daily doses (up to 3000 mg per day) and it is eliminated by kidneys in its original non - metabolized form. Metformin is degraded in the wastewater treatment plants to guanylurea. The wastewater treatment plants aren't able to clean the waste water, so metformin and guanylurea enter the environment, especially surface water. This diploma thesis deals with the ability to remove metformin and its environmental metabolite guanylurea via phytoextraction technologies. First experiment was focused on phytoextraction of metformin using 5 plant species - Zea mays L., Pisum sativum L., Avena sativa L., Alternanthera reineckii Mini L. and Staurogyne repens L. Second experiment studied phytoextraction of guanylurea using Zea mays L. and Pisum sativum L. The third experiment deals with the phytoextraction of metformin and guanylurea together using Zea mays L. The media of all plants were contaminated by metformin or guanylurea at different concentration levels. The samples of media were taken in 24 hours intervals during the plant cultivation and the decrease of its concentration were studied by HPLC with UV detection at 233 nm for metformin and 210 nm...

Abstract The polycystic ovary syndrome, described first as the association of bilateral polycystic ovaries and amenorrhoea, oligomenorrhoea, hirsutism and obesity, was later shown to be a complex metabolic syndrome. The first purpose of this study was to investigate the occurrence of hyperinsulinaemia and the severity of insulin resistance and glucose tolerance disorders in polycystic ovary syndrome by means of the oral glucose tolerance test and the euglycaemic hyperinsulinaemic clamp. The next goal was to investigate whether women with polycystic ovary syndrome would benefit from insulin-sensitising drugs, and in particular to compare the effects of metformin and a contraceptive pill containing ethinyl oestradiol and cyproterone acetate. Altogether, 81 women with polycystic ovary syndrome and 34 healthy control subjects were involved in the study. Marked impairment of insulin sensitivity in obese subjects with polycystic ovary syndrome, including a decrease of both cellular oxidative and non-oxidative utilisation of glucose, and a slight non-significant decrease of insulin sensitivity in non-obese subjects was observed. Both non-obese and obese subjects with polycystic ovary syndrome exhibited increased abdominal obesity compared with the controls, confirming the fact that obesity, in particular abdominal obesity, is an important contributor in the development of insulin resistance in this syndrome. Metformin alleviated hyperandrogenism by essentially decreasing ovarian, but not adrenal androgen secretion. The improvement of hyperandrogenism and ovarian function seemed to be mediated by the improvement of hyperinsulinaemia, which resulted itself from subtle improvements in both hepatic insulin extraction and insulin sensitivity. Metformin decreased abdominal obesity and the release of free fatty acids from adipose tissue, and improved ovarian cyclicity and fertility. The transient decrease in serum leptin levels observed may have some role in the improvement of ovarian function. The contraceptive pill significantly improved hyperandrogenism and hirsutism, and it slightly affected glucose metabolism. Thus, it could be the treatment of choice in women with hirsutism problems and no fertility hopes. Metformin could be the drug of choice for women with polycystic ovary syndrome who wish to conceive. Because of its beneficial metabolic effects, the value of metformin in reducing the risk of cardiovascular diseases in polycystic ovary syndrome needs to be further studied.

Class of 2014 Abstract / Specific Aims: To assess appropriate use or cessation of metformin therapy in the presence of renal impairment. Methods: A retrospective chart review was conducted on 785 charts of patients at El Rio Community Health Center between June 2011 and December 2012. Eligibility criteria were adults aged 18 years or older with a diagnosis of Type 2 Diabetes Mellitus (DM), a history of metformin therapy, and renal function data. Data was accessed through the electronic medical record (EMR) at El Rio and metformin history, presence of contraindications, renal function, weight, age, gender, and race/ethnicity were collected. Group 1 were patients who were currently taking metformin and Group 2 were patients with a history of taking metformin. Main Results: A larger proportion of patients had renal impairment (eGFR 30-60 ml/min/1.73 m2) in Group 1 than Group 2 (Yates’ p = 0.002). Only one patient in the entire study had severe renal impairment (eGFR < 30 ml/min/1.73 m2). There was a greater proportion of inappropriate cessation in Group 2 than inappropriate use or cessation in Group 1 (Yates’ p < 0.001). Conclusion: Most patients were found to have normal renal function. Group 2 had a greater proportion of inappropriate metformin cessation than inappropriate use or cessation in Group 1.

Class of 2008 Abstract / Objectives: To assess the effect of metformin usage and lifestyle modifications in women with polycystic ovary syndrome (PCOS) in achieving conception and live birth. Methods: A retrospective chart review of patients at a southwest reproductive health center was performed. Patients given a diagnosis of PCOS, treated with metformin alone, with at least 12 weeks of outcome data were enrolled. Diagnostic, reproductive history, and baseline endocrine and metabolic data were collected. All available metformin use, menstrual cyclycity, ovulation, pregnancy, pregnancy outcome, and alternative treatment data were captured. Results: A total of 1250 charts were reviewed and 103 patients were enrolled. Pre-treatment, a significant relationship between BMI and HDL, triglycerides/HDL, and fasting glucose (P <0.001, 0.018, 0.016) was noted with leaner patients having better metabolic profiles. The pregnancy, miscarriage, and live birth rates with metformin treatment were 55.3 %, 18.2 %, and 35.0 % respectively. Patients (40/103) that did not conceive with metformin attempted alternative fertility treatment; 55% became pregnant and 30% had a live birth. One third of all patients experienced minor adverse events, primarily gastrointestinal in nature. Logistic regression analyses comparing responders to nonresponders did not identify any baseline patient characteristics useful as significant predictors of success with metformin treatment. Conclusions: For the population under study, metformin use and lifestyle modifications resulted in conception and live birth for as many as 35 % of patients. Contrary to recent publications, it appears that this method of fertility treatment remains a viable option to treat infertility in patients with polycystic ovary syndrome.

Background and objective: Childhood obesity is a serious global health problem and it is associated with insulin resistance and significantly increased risk for development of type 2 diabetes and cardiovascular disease. Metformin reduces the risk of developing T2D in adult patients with obesity and insulin resistance. However there is limited and inconclusive data in obese non diabetic children and adolescents. The objective of the Metformin in Obese Children and Adolescents (MOCA trial) was to assess the effect of metformin on body composition, metabolic risk factors and adipokines. Design and methods: The MOCA trial was a six month multi-centre randomized, double-blind placebo-controlled trial of metformin (1.5g daily) in children and adolescents (8-18 years) with insulin resistance and/or impaired glucose tolerance. Auxology, blood pressure measurement and fasting blood tests (insulin, glucose, fasting lipids, ALT, bilirubin, CRP, lactate, resistin, adiponectin, leptin) were performed at baseline, three and six months. A prolonged oral glucose tolerance test was performed at baseline and after six months. Measures of insulin resistance/sensitivity were calculated including HOMA-IR and the adiponectin: leptin (A/L) ratio. Results: 151 obese children participated in the trial (metformin:77, placebo:78). 102 (67.5%) female, 99 (65.6%) post-pubertal, 115 (76.2%) White British and 36 (23.8%) British Asian or Afro-Caribbean. Mean age of participants was 13.7 ±2.3 year and mean BMI-SDS 3.4 (0.5). In regression analysis, controlling for baseline values, sex, ethnicity and pubertal status, metformin had a greater treatment effect over placebo for BMI at three months, that was sustained at six months (-0.25 kg/m2, p=0.01, 95% CI 0.29 to 1.86) and BMI-SDS (-0.1, p=0.01, 95% CI 0.02 to 0.19). Fasting glucose reduced (-0.03 mmol/l, p=0.03) and A/L ratio increased at three months (+0.04, p=0.03), but the improvements were lost at six months. The other measures of insulin sensitivity, metabolic risk factors and concentrations of adipokines did not change with metformin treatment. Conclusions: Metformin therapy for obese children with abnormal insulin glucose status is safe, well tolerated and has a small beneficial treatment effect over placebo for BMI, BMI-SDS, fasting glucose and A/L ratio at three months, with the changes in body composition sustained at six months. A three month course of metformin should be considered by Paediatricians to halt the inexorable rise in BMI-SDS in these children, improve insulin glucose status and act as catalyst and support for more radical change in lifestyle in the individual. Trial register number: ISRCTN 19517475.

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Obesity is a growing public health concern globally, particularly in developed countries such as the United States (US). More than 30% of Americans are considered obese. In the past 20 years in America, incidence of obesity has increased significantly (Mokdad et al., 2003). As a consequence, the Centers for Disease Control (CDC) anticipates that 1 in 3 American adults will be diabetic by 2050 (Boyle et al., 2001; Hedley et al., 2004). The most important cause of obesity is poor nutrition, absence of physical exercise and unfavourable lifestyle changes (James et al., 2001).