Therapeutic treatment for diabetes type 1 and 2 zip,herbal remedies for feline diabetes diet,how long does it take to reverse type 2 diabetes uk - PDF 2016

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Diabetes and hepatitis C infection are both prevalent diseases worldwide, and are associated with increased morbidity and mortality. A large number of studies report an increased risk for T2D in patients with chronic HCV infection (5). While insulin resistance (IR) and T2D are more frequently reported as complications of HCV infection, HCV is also known to be associated with several autoimmune manifestations, including type 1 diabetes (T1D) (12, 13).
Recently, new non-interferon-based therapeutic regimens for hepatitis C have been introduced; however, chronic HCV infection and its sequelae remain a serious public health concern especially cirrhosis and hepatocellular carcinoma (HCC) which are the leading causes of death in patients with chronic HCV (24). We systematically searched PubMed databases from 1990 to 2015.The search was limited to studies reported in English. A positive association between chronic HCV infection and T2D has been consistently demonstrated across different ethnicities and geographic regions, in both developed and developing countries.
The landmark cross-sectional NHANES III study that surveyed 9,841 US adults concluded that HCV-positive U.S.
The association between hepatitis C and T2D is also seen in the reverse direction, namely that diabetics are more prone to acquiring HCV. Hepatitis C is more common among men than women (51), and male gender is also associated with more hepatitis C disease progression to fibrosis and cirrhosis. Hepatic fibrosis and cirrhosis are not the only mechanisms leading to glucose intolerance and frank DM in HCV patients (27, 62). Another group demonstrated that mice transgenic for the HCV core protein showed decreased expression of IRS-1 and IRS-2 (85). These findings were replicated in another in vitro study using Huh-7 cells transfected with the HCV 1b or 3a core proteins (86).
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Graph shows the adjusted mean change from baseline as a repeated-measures analysis in patients who had a baseline value and at least one post-baseline value.
Data are from a post-hoc analysis of five previously reported Phase III, randomised, placebo-controlled, 24-week studies, including two studies of Onglyza as monotherapy and one study each of Onglyza as add-on therapy to metformin, a SU or a TZD. At 1 year, patients with moderate or severe renal impairment administered Onglyza or placebo had a similar risk of experiencing at least one adverse event (including hypoglycaemia; 75% vs. The majority of events were mild, although two events in two patients receiving placebo were considered severe. Data from a 1-year, placebo-controlled, randomised Phase III study of Onglyza 5 mg add-on therapy to insulin, with or without metformin, in 455 patients. FDA Advisory Panel votes 8-2 in favor of an insulin dosing label update for Dexcom's G5 CGM! Surprisingly, the research found that despite guidelines recommending metformin, only 58% of patients actually used metformin as their first diabetes medication. Our mission is to help individuals better understand their diabetes and to make our readers happier & healthier. Our mission is to help individuals better understand their diabetes and to make our readers happier and healthier. Comparative review of oral hypoglycemic agents in adults, Comparative review of oral hypoglycemic agents in adults greater reductions in hba1c with metformin any agent from the four classes of oral hypoglycemics. Reduction in glycated albumin can predict change in hba1c, Reduction in glycated albumin can predict change in hba1c: comparison of oral hypoglycaemic agent and insulin treatments. Diabetes treatment, part 2: oral agents for glycemic, It is important for clinicians to gain a broad understanding of each class of oral agents to optimize diabetes control reduction in a1c.
Treatment of type 2 diabetes – narcad, For most patients with diabetes, the target for hba1c should be can result in an average hba1c reduction of with oral agents and insulin can. How to cite this article:Ganesan D, Palaniswamy S, Palanisamy P, Ponnusha BS, Athimoolam A. 38.Weerakiet S, Tingthanatikul Y, Sophonsritsuk A, Choktanasiri W, Wansumrith S, Rojanasakul A. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button.
This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Most studies, but not all, have shown that patients with chronic hepatitis C are more prone to develop type 2 diabetes (T2D) compared to healthy controls, as well as when compared to patients with other liver diseases, including hepatitis B. The World Health Organization (WHO) reported that 170 million people are chronically infected with hepatitis C virus (HCV) globally (1), and 347 million have diabetes mellitus (DM). While a few studies could not confirm this association in the absence of liver dysfunction (6), the majority of studies strongly support this association. Therapy for chronic HCV infection, in particular interferon alpha (IFNα), can also trigger diabetes.
Numerous studies illustrate that IR and T2D have a negative impact on clinical outcomes for patients with chronic HCV infection and it is possible that insulin-sensitizing therapy with metformin might be beneficial for reducing HCV complications.
One meta-analysis of 34 studies showed a significantly higher risk for T2D in HCV patients are compared to hepatitis B virus (HBV) patients [odds ratio (OR) 1.8], matched controls, and patients with other forms of chronic liver disease infection (5). The overall prevalence of DM among chronic HCV-seropositive populations in North America, Europe, the Middle East, and Asia ranges from 13 to 33% (39, 41, 42).
Although two small cohorts from Turkey and Nigeria failed to demonstrate an increased prevalence of hepatitis C among T2D patients, the vast majority of studies do. Age has been shown to be a risk factor and an independent predictor for the development of diabetes in chronic HCV patients, although not consistently in every study. It is difficult, however, to precisely tease out the relative contribution of gender itself from confounders like fibrosis and hepatosteatosis, which are themselves markers of more severe liver disease and are associated with higher BMI, larger waist circumference, and a higher HOMA index (34). Family history of diabetes has been demonstrated to be a risk factor for the development of T2D in HCV patients as in the general population (52).
Chronic HCV infection in the absence of cirrhosis or antiviral therapy is associated with T2D (7, 31, 40, 55).
Studies have shown that non-responders to HCV treatment have a greater incidence of DM and IR (28, 58). It may be assumed that HCV infection could primarily predispose to T2D through the induction of hepatic steatosis.
The HCV genome comprises 10 mature proteins, including structural proteins (core, E1, E2, p7) and non-structural proteins (NS2–NS5). The intense inflammatory response to HCV is deemed central to the development of peripheral and hepatic IR in chronic HCV infection, primarily through disruptions in the insulin signaling pathway. This group further showed that there was an accumulation of ubiquitin-conjugated IRS-1 and IRS-2 in HepG2 human hepatic cells transfected with the HCV core protein.
Ubiquitin-mediated proteasomal degradation of IRS-1 via SOCS-7, a negative regulator of IRS expression, was found only in the cells transfected with the HCV 3a core protein. Histological evaluation of the pancreases of HCV-seropositive patients has shown evidence for pancreatic β-cells that are infected with HCV.
The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or severe renal impairment. The study was a “retroactive cohort study,” meaning that it looked back at a group of patients and analyzed their health outcomes. The study unfortunately did not include GLP-1 agonists – a common injectable drug class for treating type 2 diabetes that has been available since 2005. Chronic anovulation, hyperandrogenism, and insulin resistance (IR) are the main characteristics of this multifaceted syndrome. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: A randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome.
Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Editorial: Metformin-Comparison with Other Therapies in Ovulation Induction in Polycystic Ovary Syndrome.
Comparison of Metforminclomiphine citrate and Metformin - Letrozole effect on pregnancy rate in infertile PCOS south Indian women. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: Role of insulin sensitivity and luteinising hormone. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. A randomized study comparing dose of metformin in obese women with polycystic ovary syndrome. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: A pilot study.
Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: A randomised, double-blind, placebo controlled 6-month trial, followed by open, long-term clinical evaluation. Ovarian function and metabolic factors in women with oligomenorrhoea treated with metformin in a randomised double blind placebo-controlled trial. Effects of metformin on gonadotrophin-induced ovulation in women with polycystic ovary syndrome.
Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: A prospective randomised trial. Theimportance of IRS-1 Gly972 Argpolymorphism in evaluating the response to metformin treatment in polycystic ovary syndrome. Comparison of efficacy ofspironolactone with metformin in the management ofpolycystic ovary syndrome: An open-labeled study. Metformin and weight loss in obese women with polycystic ovary syndrome: Comparison of doses. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome.
Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Efficacy of metformin on ovulation induction in Asian women with polycystic ovary syndrome.
Prospective parallel randomized double-blind double dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in non-obese anovulatory women with polycystic ovary syndrome. The prognostic importance of the number of oocytes retrieved and estradiol levels in poor and normal responders in in vitro fertilization (IVF) treatment. A randomized double-blind comparison of the eVects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. A randomized trial of letrozole versus clomiphene citrate in women undergoing superovulation. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Use of an aromatase inhibitor in patients with polycystic ovary syndrome: A prospective randomized trial.
Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Furthermore, epidemiological studies have revealed that patients with T2D may also be at higher risk for worse outcomes of their hepatitis C infection, including reduced rate of sustained virological response, progression to fibrosis and cirrhosis, and higher risk for development of hepatocellular carcinoma. Despite decreasing prevalence of hepatitis C infection in the United States, the disease burden continues to grow due to hepatitis C-related diseases (2). This association holds even when comparing patients with chronic HCV to patients with other progressive viral liver diseases (7, 8).


Beginning with Allison’s group in 1994 (26), epidemiological studies have since specifically linked HCV and HCV cirrhosis with DM (25, 26). Perhaps due to subtle variations in HCV genotype, ethnicity, severity of liver disease, and other variables, a few studies have found no association (32–34).
It is estimated that 20% of chronic HCV patients will develop cirrhosis and as many as ~50% of these patients will have T2D (26, 40). When separated into quintiles by age, one study noted an increased frequency of diabetes in all HCV patients except in the youngest quintile that included those less than 38 years old (7).
One case-control study showed that, among 45 non-cirrhotic HCV-seropositive patients, 67% of those with T2D had a family history for diabetes versus only 7% of those without T2D (31). In North America, ~70% of HCV patients are infected with genotype 1a and 1b while a mere 4% are infected with genotypes 2a (53). This indicates that it is not the stage of liver disease alone that influences the development of T2D.
Chronic HCV infection after all carries a higher prevalence of steatosis (50%) compared to other liver diseases, including chronic HBV infection (18%) and autoimmune liver disease (16–21%) (63). Various in vitro studies have demonstrated chronic background inflammation and an increase in mitochondrial reactive oxygen species (ROS) in HCV infection. One study found that, compared to control livers, the livers of the non-obese HCV patients showed a twofold decrease in insulin-stimulated tyrosine-phosphorylation of IRS-1 and a significantly blunted activation of two downstream targets that are critical for most of the metabolic effects of insulin: phosphoinositide 3-kinase (PI3-kinase) and Akt (Protein Kinase B, a downstream target of PI3-kinase) (37).
Proteasome-mediated degradation was further suggested by the increased IRS-1 and IRS-2 expression levels after treatment with MG 132, a proteasome inhibitor (84, 85). These HCV 3a transfected cells also had significantly reduced mRNA levels of PPARγ, an insulin-sensitizing nuclear receptor, and showed an inhibition in insulin-induced Akt phosphorylation. These HCV-infected beta cells have been noted to have both morphological and functional defects, including a blunted insulin response to glucose (62). Onglyza is not recommended for patients with end-stage renal disease requiring haemodialysis.
Although currently large, prospective clinical trials evaluating the morbidity and mortality for cardiovascular disease (CVD) in PCOS patients are not available, several investigators [3],[4],[5],[6],[7],[8],[9],[10],[11] reported alterations in intermediate end points for CVD risk in this population. Moreover, hepatitis C infection and mainly its treatment, interferon α, can trigger the development of type 1 diabetes. Studies have shown that more than one-third of patients with chronic HCV infection will develop at least one extrahepatic manifestation (3, 4). There are also studies reporting T2D as a predisposing factor for HCV infection (9–11). While interferon-induced thyroiditis (IIT) is the most frequently reported autoimmune complication of IFNα therapy (14, 15), other autoimmune conditions, such as T1D (16), systemic lupus erythematosus (17), rheumatoid arthritis (18), pernicious anemia (19), optic neuritis (20), vitiligo (21), and autoimmune hemolytic anemia (22) are also associated with HCV infection [for review, see Ref. The prevalence of DM, the majority assumed to be T2D, was significantly higher among patients with HCV cirrhosis than in patients with cirrhosis due to other etiologies (26).
This translates into 47 million people worldwide and 750,000 people in the USA alone who are expected to develop HCV-associated T2D (31). By contrast, the prevalence of HBV in diabetics (0.3%) was not significantly increased compared to non-diabetics. Another study showed a positive family history for diabetes in 29% of the HCV diabetic group while only 1.8% had pertinent family history in the non-diabetic group (40). Despite these numbers, genotype 1 is relatively less associated with diabetes in the HCV population.
The presence of fibrosis and cirrhosis, however, in some studies has been shown to be an independent risk factor that contributes to the progression to T2D (31, 33, 40, 42). Viral steatosis, however, is most frequently present in chronic infections with HCV genotype 3 and yet genotype 3 is the least associated with IR. An imbalance in the levels of activating tyrosine-phosphorylated IRS-1, the inhibitory serine-phosphorylated IRS-1, and threonine-phosphorylated Akt seems to play an integral part in the development of IR in hepatitis C (79, 83, 84). The inhibition of IRS-1 may be due to mTOR activation by the HCV 2a core protein which then ultimately leads to IRS-1 degradation (84). When subsequently treated with a PPARγ agonist, not only were these effects reversed but also IRS-1 levels were noted to be increased (86). Narita’s group examined 131 chronic HCV patients with normal fasting serum glucose levels who were later diagnosed as either glucose tolerant, glucose intolerant, or overt diabetic after a 75 g oral glucose tolerance test (OGTT).
There was no imbalance in CV deaths due to heart failure (0.5% in each group according to 2-year Kaplan-Meier estimates). Data from patients who received Onglyza 5 mg or placebo in the five clinical trials were pooled and analysed using pairwise comparisons defined across CV risk-related subgroups.
In the future, we look forward to the results of the GRADE study, which aims to conclude which second-line drug for type 2 diabetes is most effective; unfortunately, however, this study will not include SGLT-2 inhibitors or any fixed dose combination drugs, which we believe will be a very limiting factor from understanding real life outcomes.
In this review, we discuss the existing data on this two-way association between diabetes and hepatitis C infection with emphasis on possible mechanisms. The highest rate of HCV infection in the world is found in Egypt where 12% of its general population and up to 40% of its older, rural population is HCV seropositive (41). A study in Taiwan that included 820 type 2 diabetics showed that HCV seropositivity was 2.8 times greater among T2D patients than in non-diabetic controls (48). This risk is comparable to the two to sixfold increased risk for T2D in the general non-HCV population who have a positive family history for diabetes (52). For instance, one US case-control analysis showed that HCV genotype 2 was present in as many as 29% of 594 HCV-positive diabetic patients versus only 3% of the local HCV control patients (7).
Various studies have shown that the rate of T2D is higher among HCV cirrhotics than in other forms of cirrhosis, including cirrhosis caused by HBV, alcohol, or cholestatic disease (5, 40). Furthermore, none of the patients with SVR developed DM while nine of the non-responders eventually developed T2D. Studies also suggest that viral steatosis may behave differently from metabolic steatosis and that the steatosis seen in non-genotype 3 HCV infections is more a marker and consequence of the underlying IR (27). Human monocytes incubated with various HCV proteins demonstrated that NS3 selectively generated ROS by activation of NADPH oxidase, Nox2 (64). CRP was higher in both diabetic groups (regardless of HCV seropositivity) while levels of IL-6 and IL-8 remained consistently low.
These results suggest that there may be genotype-specific mechanisms, although other groups have shown HCV 1b-mediated downregulation of IRS-1 by SOCS1 and SOCS3 (85). While we understand that few risks are attractive for those designing the studies, we believe SGLT-2 research could have been included as a useful arm.
Its etiology is uncertain, but current theories emphasize genetic and intrauterine origins coupled with environmental factors such as diet and altered lifestyle patterns.
It remains to be determined whether the new curative therapies for chronic hepatitis C will improve outcomes in diabetic hepatitis C patients, and conversely whether treatment with Metformin will reduce complications from hepatitis C virus infection. A recent NHANES study also had conflicting results and showed that HCV infection was only associated with ALT and GGT elevations, not diabetes.
The prevalence of DM is 25.4% among the HCV population in Egypt which indicates that chronic HCV patients are three times more likely to develop DM than the HCV seronegative population (38). When further evaluated for confounders, including ethnicity, sex, body mass index (BMI), and socioeconomic factors, the OR for T2D increased to 3.77 (43).
Across various ethnic groups (Pima Indians and populations in the US, Norway, South Africa, and the UK), the risk of developing diabetes is consistently increased among individuals with a positive family history and is up to 4.4-fold higher for individuals with a single diabetic parent (52). Seventy to eighty percent of HCV cirrhotics have been reported to have glucose intolerance (31), and 50% of these cirrhotics have developed DM compared to only 9% of the non-HCV cirrhotics (26). There is growing evidence demonstrating that specific and direct effects of the HCV itself are responsible for triggering the development of T2D. Similar upregulation of TNFα and downregulation of IL-6 were observed in hepatic tissues of chronically infected HCV patients (72). Effective treatment of PCOS remains controversial but needs to be based on the main requirements of the patient, depending on whether they are seeking cosmetic improvement, restoration of menstrual function, fertility, weight loss, or amelioration of metabolic changes. However, there was still a clear trend for higher homeostatic model assessment-estimated insulin resistance (HOMA-IR) scores in both the HCV antibody and RNA-positive groups compared to controls (35).
In Italy, the frequency of HCV infection varies depending on certain geographic regions but ranges from 3 to 15% in the general population (44). Comparable trends were also observed in Pakistan with an OR for HCV infection of 3.03 among T2D patients (50). Non-genotype 3 HCV (particularly genotypes 1, 2, and 4) has been more closely associated with the development of T2D among the hepatitis C population, and interestingly, genotype 2a in particular has been preferentially associated with extrahepatic manifestations of HCV.
It is unclear, however, if IR is simply a consequence of poor response to IFN–RBV therapy or if it, on the contrary, mechanistically contributes to treatment resistance. The structural core protein has also been demonstrated to induce an increase in ROS, mitochondrial dysfunction, and ER stress by possibly overwhelming glutathione stores and ER chaperones during viral replication (66, 67).
In recent years, so-called insulin-sensitizing agents such as metformin have found wide usage in PCOS, based on the relationship between hyperinsulinism and ovarian hyperandrogenism. Regardless, the vast majority of studies have noted a 2- to 10-fold increase of T2D in chronic HCV infection compared to other liver diseases (31, 36–38). Longer duration of hepatitis C infection has also been noted to increase the risk for diabetes. Fewer cases of IR were consistently demonstrated among HCV genotype 3 patients, even after adjusting for confounders like BMI and stage of fibrosis (52, 54). Furthermore, the rates of DM are even more increased on the background of higher grades of hepatic fibrosis, steatosis, or cirrhosis (31, 33, 40, 42, 56). Conversely, there is very strong evidence that hepatic disease progression and response to antiviral therapy are worse with concomitant DM (28, 54, 61) (see Virological Response to Antiviral Therapy).
Animal pancreatic clamp studies have linked TNFα to increased IR and decreased glucose uptake (75). The introduction of these agents has led to questioning of established therapeutic pathways for ovulation induction, which have been based on clomiphene citrate and gonadotropins such as follicle stimulating hormone (FSH). The cumulative data suggest that T2D is approximately two to threefold more prevalent in HCV than in HBV infection.
For example, the prevalence of T2D was shown to increase with every rise in the fibrosis score of HCV patients with an OR of 3.83 (51). This two-way association between hepatitis C and diabetes further supports a potential direct role of HCV in IR and T2D. Similarly, in vitro studies using cultured adipocytes stimulated with insulin showed that chronic TNFα exposure reduced tyrosine kinase activities and decreased autophosphorylation of the insulin receptor and tyrosine-phosphorylation of insulin receptor substrate 1 (IRS-1) (71, 77, 78).
Much has been written about the value of laparoscopic ovarian drilling whereby diathermy or application of laser surgery to the ovary leads to enhanced ovulation, reduction in testosterone, and increased live birth rates. We therefore believe that the risk for T2D among HCV patients is significant and is more than just coincidental or cirrhosis-dependent (5, 39, 40). These discrepancies may be due to the differences in the number of patients with available genotype data. One prospective case series with 361 HCV patients from Pakistan showed an OR for T2D of 2.0 in HCV cirrhotics compared to that of HCV non-cirrhotics. Moreover, incubation of Huh-7 hepatocytes with TNFα increased serine-phosphorylation of IRS-1 (79), also resulting in inhibition of the insulin signaling cascade. Although the procedure is less damaging to the ovary than wedge resection, concern has been expressed that adhesions may form that convert an ovulatory infertility into tubal obstruction. Conversely, DM itself has recently been demonstrated to be hasten the progression of fibrosis and cirrhosis underscoring the bidirectionality of the association between chronic HCV infection and IR in chronic HCV infection (57) (see Hepatic Fibrosis and Cirrhosis). TNFα also downregulated GLUT4 mRNA expression in muscle and adipose tissues and has been implicated in reduced expression of IRS-1 and PPARs (80, 81). Nevertheless, there is widespread use of this procedure by gynecologists who either plan a laparoscopy to perform ovarian drilling or operate on polycystic ovaries that are discovered incidentally at laparoscopic surgery. The general trend, regardless of country of origin, suggests that T2D is approximately two to threefold more prevalent in HCV than in HBV infection. The pathogenesis of PCOS is still largely unknown, and until now medical care of these subjects has been limited to symptomatic control of cosmetic concerns, menstrual dysfunction, and infertility. In this regard, several data support the hypothesis that IR and the associated hyperinsulinemia play a pathogenetic role in PCOS. Insulin has direct effects on ovarian steroidogenesis in vitro, stimulating androgen synthesis in thecal cells. It also decreases synthesis of serum sex hormone binding globulin in the liver, increasing free androgen levels.
Furthermore, in vivo studies suggest a potentiation by hyperinsulinemia of adrenocorticotropic hormone (ACTH)-stimulated adrenal androgen secretion.
Consistently, decreasing insulin secretion by diazoxide or somatostatin in these subjects has resulted in concurrent reductions of serum androgens.The PCOS is defined as the presence of both ovulatory dysfunction and hyperandrogenism. In women with PCOS, oligo- or anovulation manifests itself as irregular cycles with oligo- or amenorrhea. A third criterion for the diagnosis of PCOS is to exclude other causes of hyperandrogenism, such as nonclassic adrenal hyperplasia resulting from a 21-hydroxylase defect or an androgen-producing adrenal or ovarian tumor. The combination of hypersecretion of LH and insulin causes ovarian androgen overproduction. In turn, ovarian androgen overproduction causes hirsutism and prevents normal ovarian follicle growth, preventing regular ovulation.


PCOS can be treated by lowering LH hypersecretion [oral contraceptive pills or gonadotropin releasing hormone (GnRH) agonist analogues] or by reversing the hyperinsulinemia that is caused by IR (weight loss or metformin). Among these, metformin cloridrate, a biguanide class drug used in patients with type 2 DM, has been recognized to ameliorate IR, hyperinsulinemia, and hyperandrogenism in women with PCOS.However, to date, there are less data available regarding the effect of metformin administration on the endothelium in PCOS. The aim of the present pilot study was to evaluate the effectiveness of metformin treatment on endothelial structure and function in a group of women with PCOS.Metformin is currently being used to induce ovulation in women with PCOS.
Metformin "reverses" IR (hyperinsulinemia), thus effectively treating many diabetics.Up to 40-70% of patients with PCOS have hyperinsulinemia which leads to excess androgen (male hormones) production by the ovaries and increased production of LH by the pituitary. Clinically, this results in ovulatory irregularities (or anovulation), increased body hair, numerous small ovarian cysts, and a classic "pear-shaped" body appearance (obesity; although not always) and long-term negative health consequences such as diabetes.
Metformin is dosed at 500 mg three times per day and clomid or FSH may be added if ovulation is not established.Numerous studies indicate that metformin as the sole therapy is often effective in establishing ovulation in PCOS patients. Metformin is not without side effects and nausea is one of the most frequent.PCOS patients usually have exaggerated responses to medications such as FSH. Given the complexity of the disease, its potential long-term consequences, and difficulty in treating, PCOS patients should seek the advice of a reproductive endocrinologist. The Food and Drug Administration (FDA) has approved metformin only for the treatment of type 2 diabetes. First, it decreases the absorption of dietary carbohydrates through the intestines.Second, it reduces the production of glucose by the liver.
When the body experiences stress, the liver releases the reserve glucose to supply the brain and muscles with an immediate source of energy to cope with the stress.
Glucophage suppresses the production of this reserve fuel.Third, and perhaps most importantly, metformin increases the sensitivity of muscle cells to insulin. Insulin is the hormone that delivers glucose to our cells to be burned as a fuel, or stored. Women with PCOS frequently have "insulin resistance", a condition where excessive amounts of insulin are required in order to get blood glucose moved into cells, where it belongs.
Glucophage helps the body to transport glucose with relatively less insulin, thus lowering the insulin levels.
To minimize gastrointestinal (GI) upset or diarrhea, it is recommended to start with a low dosage and work your way up to the recommended dose.Glucophage XR, an extended-release version of Glucophage, allows the patients to take only one dose a day. In non-insulin DM cases, it exerts its effect by inhibiting glycogenesis in the liver, decreasing intestinal absorption, and by stimulating peripheral use of glucose.
Metformin increases the number of insulin receptors, but does not affect insulin concentration. Metformin is used in PCOS cases in order to decrease plasma LH, hyperinsulinemia, and ovarian androgen levels.
Metformin increases the ovulatory rate, cervical scores and pregnancy rate.Metformin decreases fasting glucose level by decreasing hepatic glucose output. Its use in PCOS patients corrects the response to oral glucose tolerance, thus decreasing insulin level. Cytochrome P450-C17a, which is a key enzyme in androgen synthesis, has an increased activity in PCOS patients due to increased levels of insulin.
Metformin decreases the activity of this enzyme, thus increasing the response to ovulation induction.These observations suggest that insulin-sensitizing agents, such as metformin ortroglitazone, should be tested for the treatment of PCOS. These drugs improve insulin sensitivity by different mechanisms, thus causing a subsequent reduction in plasma insulin levels.
Recently, some short-term studies supported this hypothesis, reporting significant reductions of serum androgens in women with PCOS given either metformin or troglitazone. Interestingly, improvements in reproductive abnormalities of these patients have also been reported in some of these studies.Treatment with the insulin-sensitizing agent, metformin, is effective in many women with PCOS, independent of changes in body weight, in attenuating IR and hyperandrogenemia and in reversing menstrual abnormalities and chronic anovulation. Insulin-sensitizing agents may prove to be an efficacious therapeutic tool in a large subset of subjects with this common disease.Metformin may lower the androgen level in follicular fluid, affecting local levels of IGFs, and may produce improved ovarian stimulation. Additionally, it leads to a decrease in hyperstimulation risk, number of cycle cancellations, and of multiple pregnancy rates.
Metformin is a supportive agent in the management of PCOS patients due to absence of teratogenic effects, lack of use during embryogenesis period, its cost-effectiveness, and tolerable side effects.
In this study, 3234 non-diabetics with elevated blood glucose were given metformin, placebo, or lifestyle recommendations.
The incidence of diabetes in the metformin group was 31% lesser than in the placebo group.Restoration of normal menstrual cycleA number of studies have shown that menstruation can be restored in many women with PCOS. For example, in a study at Jewish Hospital in Cincinnati, 43 women who were not having periods took Glucophage, and 39 of them resumed normal menses. In another study at Jewish Hospital, 11 teenage girls with PCOS were put on metformin and a high-protein, low-carbohydrate diet. Ten of the 11 girls resumed regular periods.Improved chance of pregnancyA study of 48 women with PCOS and infertility was conducted at the Baylor College of Medicine. They were first given metformin and 19 of them resumed menses and showed indications of ovulation. But 10 required clomiphene (a fertility drug) in addition to metformin in order to show evidence of ovulation.
However, 7 of the 20 miscarried.Reduced risk of miscarriageAnother aspect of PCOS-related infertility is the tendency for repeated miscarriages. A study from the Hospital de Clinicas Caracas in Venezuela looked at 65 women who received Glucophage during their pregnancies versus 31 who did not. They experience a general malaise, fatigue and occasional achiness that lasts for varying lengths of time. Malaise is a signal for the physician to closely monitor body systems affected by metformin, including liver, kidneys, and GI tract. A blood count should be taken from time to time because metformin can induce B vitamin insufficiencies that can lead to a form of anemia.GI disturbanceAbout one-third of women on metformin experience GI disturbances, including nausea, occasional vomiting and loose, more frequent bowel movements, or diarrhea.
The symptoms lessen over time; so, if the GI upset can be tolerated for a few weeks, it may go away. Starting with a very low dose and gradually increasing it has helped some women.Vitamin B12 malabsorptionOf patients who take this drug, 10-30% show evidence of reduced vitamin B12 absorption.
A substance formed in the stomach called "intrinsic factor" combines with B12 so that it can be transferred into the blood. Metformin interferes with the ability of the cells to absorb this intrinsic factor-vitamin B12 complex.Over long term, vitamin B12 insufficiency is a significant health risk. There is also a link between B12 insufficiency and CVD.At least one study raises the concern that even if metformin is withdrawn, the vitamin B12 malabsorption may continue in some people.
The apparent cause is continued problems with availability of intrinsic factor, which is required for B12 absorption.Elevated homocysteinePeople who take Glucophage tend to have higher homocysteine levels.
Women with PCOS also tend to have elevated homocysteine.Homocysteine is an amino acid in the blood. But an elevated level means that the metabolic processes are not working properly in the body. Elevated homocysteine is associated with coronary artery disease, heart attack, chronic fatigue, fibromyalgia, cognitive impairment, and cervical cancer.Vitamin B12, along with vitamin B6 and folic acid (another B vitamin), is responsible for metabolizing homocysteine into less potentially harmful substances. Therefore, when metformin reduces the absorption of vitamin B12, one of the nutrients needed to reduce homocysteine is lost and thus the risk of CVD is reduced. If left untreated, pre-eclampsia can lead to eclampsia, a serious condition that puts the mother and baby at risk. They concluded that high homocysteine levels are a risk factor for recurrent early pregnancy loss.Ovarian follicular fluid contains detectable amounts of homocysteine along with B12, B6, and folic acid.
The follicular fluid provides nourishment to the egg by facilitating transport of nutrients from blood plasma. High levels of homocysteine as well as an insufficiency of B vitamins may adversely influence the process of fertilization and early fetal development.Pregnancy warningMany women use metformin in their pursuit of a successful pregnancy.
However, Glucophage is a category B drug, meaning its safety for use while pregnant has not been established.
It is found in breast milk, so it is not advisable to breastfeed while taking Glucophage.AnemiaBy preventing optimal absorption of vitamin B12 and folic acid, metformin could induce or contribute to megaloblastic anemia. Megaloblastic anemia occurs when the bone marrow does not have enough B vitamins to manufacture red blood cells. Liver and kidney function should be assessed before starting metformin and rechecked at least once a year while taking it. A blood chemistry screen and a complete blood count would tell the physician how well the patient's system is doing with this drug.Multiple medicationsThe patient may be at risk for health problems or symptoms if metformin is taken in addition to other medications.
The more drugs the patient takes, and the higher the dosage, the greater the probability that there will be some kind of interaction between the drugs or some unexpected effect from the combined drugs. The effect of combined drugs also depends on the state of the patient's health, their genetic uniqueness, and their diet and lifestyle.
The doctor has to be consulted always if any medication is added or changed, or if there is development of any symptom.Hair lossMetformin may contribute to male pattern hair loss at the temples and top of head. Although there is nothing in the medical literature to support this linkage, some women have reported that hair loss became worse with metformin.Lactic acidosisAbout 3 of every 100,000 people who take metformin develop a medical emergency called "lactic acidosis". Lactic acid is a metabolic byproduct that can become toxic if it builds up faster than it is neutralized.
Lactic acidosis is most likely to occur in people who with diabetes, kidney or liver disease, multiple medications, dehydration, or severe chronic stress.Lactic acidosis can gradually build up.
Symptoms to watch for include a need to breathe deeply and more rapidly, a slow, irregular pulse, a feeling of weakness, muscle pain, sleepiness, and a sense of feeling very sick. The doctor has to be consulted or a visit to the hospital emergency room is a must if these symptoms are present.Bile abnormalitiesBile is produced by the liver, stored in the gallbladder, and secreted into the intestines in order to absorb fats into the bloodstream. One possible reason for the GI problems is that metformin reduces normal reabsorption of bile from the intestines back into the bloodstream, which causes elevated bile salt concentrations in the colon. Most studies suggest that colonic bile salts cause free radical damage to DNA and may contribute to colon cancer.In addition, bile acids may stimulate cells in the colon to produce leukotriene B4 (LTB4), a highly inflammatory substance. Products of bacterial action on bile salts may lead to intestinal cell damage and absorption of "foreign" molecules such as food or bacteria particles into the bloodstream, possibly causing allergies and other immune responses.Moreover, many PCOS women switch to a high-protein diet.
If the protein consists of beef and other meats, bile acid concentration in the intestines increases.
A diet high in meats is also linked to a higher risk of colon cancer.In about 25% of women, Glucophage causes side effects which may include abdominal discomfort, cramping, diarrhea and nausea. We are not aware of any serious complications resulting from Glucophage treatment.Another oral medication used for diabetes called Troglitazone has been associated with liver failure and death in rare cases.
These problems have not been associated with the use of metformin for PCOS.The most common side effects of metformin are diarrhea, nausea or vomiting, flatulence, indigestion, and abdominal discomfort. In one clinical trial of metformin at a dose of 2250 mg daily, diarrhea was reported in 53% of the patients taking metformin and 12% of patients taking placebo.
In the same study, nausea or vomiting was reported in 26% of those taking metformin and 8% of those taking placebo. However, only about 5% of patients discontinued the medication because of side effects.A rare problem caused by metformin is lactic acidosis, which is fatal in as many as 30-50% of cases.
In addition, women with conditions that increase the risk of lactic acidosis, such as congestive heart failure or sepsis, should not be prescribed metformin. Other contraindications to the use of metformin are concurrent liver disease and a previous history of lactic acidosis. Metformin therapy should be temporarily suspended for all major surgical procedures that entail restriction of fluid intake. Metformin should not be restarted until normal fluid intake has resumed and renal function has been shown to be normal. Add clomiphene to metformin treatment regimenIf the metformin does not result in ovulation and regular periods, the next step often followed is adding clomiphene to the regimen [Figure 2]. However, because of anti-estrogenic effects of clomiphene, it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. Letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects.Studies have been conducted to compare the combined effects of metformin-clomiphene citrate and metformin-letrozole on ovulation and better pregnancy rate in South Indian women patients with PCOS.
All patients between the age of 27 and 37 years who attended an infertility clinic with a suspicion of PCOS (specifically complaining of infertility, menstrual dysfunction or dermatological problems) were included in the study.The population consisted of 2000 subjects (female population) and was divided into four groups.
From them, 400 patients who were screened and found to be ideal for the study were selected. Also, administration of them in early follicular phase could be safe for ovulation induction.
While no one is quite sure exactly how the two connect, it seems that increased insulin levels lead to increased levels of androgens, also known as the male hormones. As a result, the body thinks that there is not enough insulin in the system, which triggers the production of more insulin than it really needs. In this study has reported the combined metformin treatment to improve hirsutism, induce ovulation and normalize menstrual cycle.



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