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  • ISSN: 2333-6692
    Special Issue on Antidiabetic Drug-Metformin
    Ling He
    Division of Metabolism
    Department of Pediatrics
    Johns Hopkins University School of Medicine
    Mini Review
    Ariane Germeyer1* and Edison Capp1,2,3
    Objective: About 10% of European couples are suffering infertility problems. The underlying cause is evenly distributed. In the female polycystic ovaries, often associated with anovulatory cycles, contribute to a high extend of underlying problems. Despite the anovulation many of these have an underlying insulin resistance and increased risk of ovarian hyperstimulation syndrome when ovarian hyperstimulation is performed. Last but not least, when conception is achieved the prevalence of recurrent abortion, as well as increased gestational complications are increased in women with polycystic ovaries and /or insulin resistence. Therefore the Off-label use of the anti-diabetic drug metformin has been tested as a treatment option in combination with different reproductive procedures. Last, but not least, since many advantages could be noted in women with PCOS under the metformin therapy, the range of application has been widened. This review will shed some light on the different potential implication of Off-label metformin therapy in reproductive medicine.
    Review Article
    Bodo C Melnik1* and Gerd Schmitz21
    Abstract: Recent progress in molecular medicine has identified the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1) as the central regulator of protein and lipid synthesis, cell growth, proliferation, energy metabolism and autophagy. Age-related diseases of Western civilization such as obesity, diabetes mellitus, neurodegenerative diseases, and cancer are associated with enhanced mTORC1 signaling. According to the current opinion, metformin’s primary mode of action is the alteration of cellular energy metabolism stimulating 5-AMP-Activated Protein Kinase (AMPK). However, the notion that AMPK primarily mediates metformin´s anti-hyperglycemic action has recently been challenged, thrusting AMPK-independent effects into the focus of interest. We provide a new viewpoint on metformin´s mode of action as an inhibitor of mTORC1. Metformin´s insulin-lowering and AMPK-activating effects decrease RHEB-mediated stimulation of mTORC1. Independent of AMPK metformin inhibits mTORC1 in a RAG GTPase-dependent manner. Thus, metformin interferes with the two major pathways required for mTORC1 activation: 1) energy- and cell stress-mediated activation of AMPK attenuating the activity of the GTPase RHEB and 2) suppression of amino acid signaling down regulating the activity of lysosomal RAG GTPases. Both RHEB- and RAG GTPase activation, which are required for mTORC1 activation at the lysosomal membrane, are thus suppressed by metformin. Metformin-induced suppression of mTORC1 subsequently decreases S6K1 activity and S6K1-mediated insulin resistance as well as AKT-FoxO1-mediated hepatic gluconeogenesis. Metformin represents an ideal, save and cheap drug targeting the pathogenesis of mTORC1-driven anabolic and hyperproliferative diseases of civilization.
    Shumei Meng*
    Abstract: Metformin as the first line therapy for type 2 diabetes mellitus has its unique attraction for its weight loss and possible macrovascular benefit. In addition, recent accumulating epidemiological and clinical evidence suggests metformin maybe a potential anticancer medication as an adjuvant therapy or a chemoprevention given the increased prevalence of obesity and diabetes mellitus in cancer patients and the low cost and safety of the drug. Metformin may work through multiple pathways to inhibit cancer cell growth and proliferation. Epidemiological and clinical data were summarized in this review. More carefully designed longer and larger randomized controlled trials in selected cancer population in the future are needed.
    Daniela Jakubowicz1* and Markku Seppala2
    Abstract: Polycystic Ovary Syndrome (PCOS) is characterized by ovulatory disturbances, hyperandrogenaemia and hyperinsulinemia secondary to increased insulin resistance. In PCOS, hyperinsulinemic insulin resistance is of interest because skeletal muscle may be resistant to insulin in terms of glucose metabolism, while the ovaries remain sensitive to insulin with regard to stimulation of testosterone biosynthesis. Insulin resistance and hyperinsulinemia are associated with reproductive failure such as early pregnancy loss, and cardiovascular risk and the development of diabetes mellitus later in life. Insulin-sensitizing agents such as metformin improve insulin sensitivity, thereby improving ovulatory cycles and fertility in women with PCOS. Metformin has also been shown to retard progression to type 2 diabetes in PCOS. This review addresses the effects of metformin on reproduction.
    Battsetseg Batchuluun1, Noriyuki Sonoda1,2*, Ryoichi Takayanagi1 and Toyoshi Inoguchi1,2
    Metformin, a first-line agent for type 2 diabetes pharmacotherapy, is one of the most prescribed drugs worldwide. Its glucose lowering effect is mediated through suppressing the hepatic production of glucose, decreasing intestinal glucose absorption and improving glucose uptake and utilization [1].
    Joselyn Rojas*, Mervin Chávez-Castillo, Wheeler Torres, Nailet Arraiz, Mayela Cabrera and Valmore Bermúdez
    Abstract: Dimethylbiguanide (Metformin) is an anti-hyperglycemic drug used in the management of insulin resistance-related diseases like type 2 diabetes mellitus for over 40 years. The molecular mechanisms of action related to its metabolic effects are linked to dependent and independent AMP-dependent kinase (AMPK) activation. Epidemiological evidence has suggested that metformin administration has been associated to lower cancer risk and cancer-related mortality in patients with type 2 diabetes mellitus. Anti-tumoral properties have been described via AMPK-dependent and independent pathways. Metformin is a cationic molecule capable of copper sequestration and subsequent mitochondrial electron transport inhibition, compromising oxidative phosphorylation. Moreover, metformin has also been confirmed to modulate pluripotency in cancer stem cells, blunting their survival and proliferation. Finally, the reduction of vitamin B12 availability has also been suggested to control one-carbon metabolism, DNA synthesis and cytostatic effects. The purpose of this review is to examine the AMPK-independent related mechanisms concerning tumor expansion control and survival.
    Winston Crasto*, Pallavi Rao and Helena Gleeson
    Abstract: Reproductive health is an important domain of women’s health care and broadly encompasses conditions which impact fertility, conception or birth of a healthy infant. Although numerous factors or conditions are associated with infertility, polycystic ovary disease is a well recognised cause. In this regard, metformin which belongs to the biguanide group of drugs and is commonly used as first line treatment in type 2 diabetes has also been commonly employed in the management of infertile women with PCOS with beneficial results. This review examines the evidence base of the utility of metformin in PCOS on ovulation and reproductive outcomes and discusses its role in different aspects of management and in future research.
    Research Article
    Chen-Pin Wang1,2*, Carlos Lorenzo3 and Sara E Espinoza3,4,5,6
    Objective: To determine whether the protective effect of metformin against death is modified by frailty status in older adults with type 2 diabetes.
    Research Design and Methods: We conducted a cohort study during October 1, 1999-September 30, 2006 among veterans aged 65-89 years old with type 2 diabetes but without history of liver, renal diseases, or cancers, who had sulfonylureas or metformin as the sole antidiabetic drug for ≥180 days. The Cox proportional hazard model was used to compare hazard rates of all-cause mortality between the metformin and sulfonylurea users adjusting for the propensity score of metformin use and covariates: age, race/ethnicity, diabetes duration, Charlson comorbidity score, statin use, smoking status, BMI, LDL, and HbA1c.
    Results: In this cohort of 2,415 veterans, 307 (12.7%) were metformin users, 2,108 (87.3%) were sulfonylurea users, the mean age was 73.7±5.2 years, the mean study period was 5.6±2.3 years, the mean HbA1c at baseline was 6.7±1.0%, 23% had diabetes for ≥10 years, and 43.6% (N=1,048) died during the study period. For patients with and without frailty, the adjusted hazard ratio (HR) of death for metformin vs. sulfonylurea use were 0.92 (95% CI=0.90-1.31, p-value=0.19) and 0.69 (95% CI = 0.60-0.79, p-value<0.001), respectively. Logistic regression analyses showed that metformin (vs. sulfonylurea) was significantly associated with a decreased odds of frailty (OR: 0.66, 95% CI: 0.61-0.71, p-value <.0001)
    Conclusion: Our study suggests that metformin could potentially promote longevity via preventing frailty in older adults with type 2 diabetes.
    Birsen Unsal Koyuncu1 and Mustafa Kemal Balcı2*
    Abstract: In Type 2 Diabetes Mellitus, incretin axes play an important role in terms of progressive beta abnormalities. It was found that enteroendocrin cells in the small bowel have T1R2 and T1R3 taste receptors. Artificial sweeteners and glucose have significant effects on secretion of GLP-1 and GIP hormones from intestine. Recent research studies worked on healthy people showed that glucose triggers release of these hormones by the taste receptors in the L cells. The aim of this study was evaluation of the metabolic effects of dissolved aspartame in the mouth taken before meals in prediabetic patients.
    This cross-over study was done in Akdeniz University, Endocrinology and Metabolism Unit. 54 prediabetic patients were included to this study. Patients were randomly separated to two groups. At the beginning of the study, patients interviewed with specialized diabetes dietitians. The first group was initiated with diet for three months and continued with diet and aspartame during second three months. Diet and aspartame were started in the second group for the first three months. Aspartame was discontinued after three months and patients continued with only diet during the second three months. Two tablets of aspartame (1 tablet equal to 18 mg) before meals were taken by dissolving on the tongue.In the two groups weight, height, BMI, waist circumference, fasting and postprandial blood glucose, hemoglobin A1c (HbA1c), fructosamine, alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, LDL cholesterol, HDL cholesterol, triglycerides and insulin were evaluated at 0, 3 and 6 months.
    In the first group, diet was found effective on losing weight at the end of the third month. After aspartame was added, weight loss continued till the end of the 6 month. In the second group, weight loss was detected with aspartame and diet during the first three months. However; in the second three months, weight gain occurred after aspartame was discontinued. Both groups were compared regarding weight loss in the first and second period. Weight loss in the first group was greater than in the second group during second period (p=0.027). The changes in the other parameters were not found significantly different.
    In conclusion, aspartame has additional effect on weight loss in prediabetic patients. We need long term studies to investigate the relation between weight change and incretins.
    Kamran MA Aziz*
    Abstract: Metformin is currently considered a first line therapy for managing type-2 diabetes for targeting insulin resistance and obesity. However, in usual busy clinical practice, the importance of metformin is sometimes ignored and patients are prescribed directly OHA or shifted to insulin therapy without metformin. Metformin has been shown to counteract dyslipidemia and as a drug for cardiac and renal protection as well. Current research was planned to enroll type-2 patients who were additionally prescribed metformin (with other OHA/insulins) compared to those who were not on metformin; and to compare HbA1c lipids, creatinine, spot urine protein and spot urine protein/creatinine between these two groups of patients. Study included 1590 patients and data were collected for the period of 5 years (January 2009 till January 2014) in the diabetology clinic ofAseer Diabetes Center at initial visits by standardized methodology. Type-1 DM, children (<13 years), pregnant, chronic renal failure, ESRD, and patients intolerant to metformin were excluded from the study. It was observed that 581 (36.6%) type-2 DM subjects were not prescribed metformin. Levels of HbA1c and BMI were lower in the metformin group compared to those without metformin (9.47 ± 2and 27.35versus 9.74± 2.4 and 30.25 ± 5.72; p-values 0.004 and < 0.0001 respectively). Non-HDL-C values were higher for the metformin group (152.6 ± 48 versus 140.4 ± 44; p<0.0001). Levels of creatinine, spot urine protein and spot urine protein/creatinine was higher for the group without metformin therapy (1.1 ± 0.31, 95.23 ± 138, 1.143 ± 3.39 versus 0.89 ± 0.2, 38.92 ± 82.17, 0.425 ± 1.25 with p-values <0.0001, 0.017 and 0.015 respectively). In the current study, metformin provided unique Glycemic and lipid control and cardio-renal protection among type-2 DM patients and should be prescribed to type-2 DM patients while managing diabetes to prevent complications of diabetes.
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