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Metformin beyond Dysglycemia Metformin beyond Dysglycemia
Beatrice Anne. M, Post Doctoral Fellow
Sujoy Ghosh, Associate Professor
Department of Endocrinology, IPGMER, Kolkata receptor substrate 2 (IRS-2) and enhances glucose uptake Metformin, an oral antidiabetic drug belongs to the via increased translocation of glucose transporters, biguanide class of drugs. It is one of the most widely used such as GLUT-1 to the plasma membrane. As a result, drugs for treatment of diabetes and is one of only two metformin enhances the insulin-mediated suppression of oral antidiabetic drugs on the World Health Organization gluconeogenesis.   Furthermore,   and   possibly   of   greater   (WHO) list of essential medicines. The antidiabetic importance, metformin opposes the gluconeogenic action effect  of  metformin  was  first  reported  by  Jean  Sterne,  a   of the peptide hormone glucagon. The net effect of the French  physician  in  1957.  The  popularity  of  metformin   interactions is that metformin inhibits gluconeogenic gained momentum when it was found to be an effective enzymes and stimulates glycolysis by altering the activity alternative to the only available treatment then, insulin. of multiple enzymes in these pathways. The uptake of Further  studies  done  in  this  aspect  showed  that  metformin   gluconeogenic substrates, such as alanine and lactate is was  as  promising  as  Sterne's  first  report  showed.  More   reduced in the presence of metformin, possibly owing than 50 years after its discovery, metformin has stood to depolarization of the hepatocyte membrane through the test of time and its multifaceted therapeutic effect metformin-stimulated Cl"  efflux.1 has broadened its scope in the treatment of not only Metformin improves insulin sensitivity and insulin- type 2 diabetes, but also diseases like polycystic ovarian mediated glucose uptake in skeletal muscle through an syndrome, gestational diabetes mellitus, prediabetes, increase in the tyrosine kinase activity of the insulin non-alcoholic fatty liver disease and cancer. This review receptor and through enhanced activity and translocation attempts to explore the potential value of this valuable of glucose transporters, such as GLUT-4 to the plasma drug in these diseases and study its role beyond control of hyperglycemia.
Studies on autoptic pancreatic tissue have revealed that the islets in type 2 diabetes may have decreased beta cell Metformin in Diabetes
mass as well as functional defects. A recent study3 reported data on the characteristics of pancreatic islets isolated from The molecular mechanisms underlying the antidiabetic type 2 diabeticorgan donors, in which reduced insulin actions of metformin is a matter of debate. The content, decreased amount of mature insulin granules, antihyperglycaemic action of biguanides is mainly due impaired glucose-induced insulin secretion, reduced to the reduced glucose output owing to inhibition of insulin mRNA expression, and increased apoptosis with liver gluconeogenesis and possibly to a lesser extent, enhanced activity of caspase-3 and -8 were found. These increased insulin-mediated glucose uptake in the alterations were associated with evidence of increased skeletal muscle. Metformin also slightly delays the oxidative stress. It was found in this study that metformin glucose absorption process in the gastrointestinal tract. It can reverse most of the alterations found in type 2 diabetes increases the activity of the insulin receptor and of insulin JOURNAL OF CLINICAL DIABETOLOGYAn  Official  Publication  of  the  Association  of  Clinical  Diabetology islets and it was proposed to be due to improved islet Prevention Program Outcomes Study (DPPOS), it may redox  balance.  This  finding  is  supported  by  studies  that   be cost-saving over a 10-year period.7 It was as effective have shown that metformin can enter the mitochondria, as  lifestyle  modification  in  participants  with  a  BMI  e"35   accumulate within these organelles, and inhibit complex kg/m2.The ADA recommends consideration of metformin 1 of the respiratory chain4. Therefore, when isletcells are use in those with impaired glucose tolerance, impaired exposed to the drug, a lower amount of reactive oxygen fasting  glucose  or  an  A1C  5.7–6.4%,  especially  for  those   species of mitochondrial origin is likely to be produced, with BMI >35 kg/m2,  aged  <60  years  and  women  with   which restores a sort of vicious circle, leading to reduced prior Gestational Diabetes Mellitus (GDM).
oxidative stress.
The effectiveness of metformin in the treatment of Metformin in Polycystic Ovarian Syndrome
type 2 diabetes mellitus has been proven by various studies   and   it   is   advocated   as   the   first   line   treatment   PCOS affects 5 to 10% of women of child bearing age for newly diagnosed type 2 diabetics by the American and is the most common cause of an ovulatory infertility Diabetic Association (ADA) because of its low risk of in developed countries. It is characterized by menstrual hypoglycemia, the likelihood of modest weight loss, the irregularities and signs of androgen excess such as reasonable durability of its antihyperglycemic effects and hirsutism, acne and alopecia. Insulin resistance plays a its long-term general and cardiovascular safety record. central pathogenic role in PCOS and can explain most of There are reservations regarding use of metformin in the the features of the syndrome as well as the predisposition presence of chronic kidney disease and the guidelines to develop type 2 diabetes, metabolic syndrome and endorsed by the various bodies (ADA, AACE, UK-NICE guidelines,   US   guidelines)   recommend   different   eGFR   As the ovaries of women with polycystic ovary cut-offs for metformin use.
syndrome remain sensitive to insulin in contrast to tissues   A   Swedish   study   in   which   51   675   men   and   women   like muscle and fat, the hyperinsulinemic environment with type 2 diabetes, registered in the Swedish National favors the ovarian production of excess androgen by Diabetes Register and on continuous glucose-lowering activating its homologous receptor. Hyperinsulinemia treatment with oral hypoglycaemic agents (OHAs) or inhibits the hepatic production of sex hormone–binding insulin were studied, found that metformin showed lower globulin, thereby increasing circulating free testosterone risk than insulin for cardiovascular disease (CVD) and levels. Hyperinsulinemia also inhibits the hepatic secretion all-cause mortality and slightly lower risk for all-cause of  the  IGF  binding  protein  (IGFBP)-­1,  leading  to  increased   mortality compared with other OHAs. Patients with renal bioactivity   of   IGF-­Iand   -­II,   two   important   regulators   impairment showed no increased risk of CVD, all-cause of ovarian follicular maturation and steroidogenesis. mortality or acidosis/serious infection in this study.5The The   IGF-­I   and   -­II   systemic   increase   augments   ovarian   question whether current contraindications are too androgen  production  from  the  cacells  by  acting  on  IGF-­I   restrictive still remains and standardisation of prescribing receptors.8Finally,   insulin   impedes   ovulation,   either   by   advice and consensus on use are required.
directly affecting follicular development or by indirectly increasing intraovarian androgen levels or altering Metformin in Prediabetes
The Diabetes Prevention Program (DPP) was a 27-   Further   evidence   to   the   pathogenic   role   of   center randomized clinical trial to determine whether hyperinsulinemia is provided by the fact that measures to lifestyle intervention or pharmacological therapy lower the insulin levels result in increased frequency of (metformin) would prevent or delay the onset of diabetes ovulation or menses and may also lead to reduced serum in individuals with impaired glucose tolerance (IGT) testosterone levels. Metformin effect on hyperandrogenism who are at high risk for the disease. It was found that has been explained by the reduced ovarian and adrenal both lifestyle intervention and metformin were effective secretion of androgens, a reduced pituitary secretion of in decreasing the incidence of diabetes. Lifestyle LH and an increased liver SHBG production.9 intervention decreased the incidence of type 2 diabetes   Studies  done  in  PCOS  have  confirmed  the  ability  of   by 58% compared with 31% in the metformin-treated metformin to reduce insulin and androgen levels. This group.6Although metformin was less effective than translates into an increased frequency of ovulation and lifestyle  modification  in  the  DPP  and  the  U.S.  Diabetes   improved menstrual cyclicity, apart from a reduction Metformin beyond Dysglycemia of the hyperandrogenic features. A meta-analysis by this regard. One such study15 investigated the effect of Lord et al,10 in which 13 trials were included and > 500 metformin on human prostate cancer cell proliferation in women with PCOS were studied, revealed that metformin vitro and in vivo. The results showed that metformin is effective in achieving ovulation in women with affects the expression and the phosphorylation of key polycystic  ovary  syndrome  with  odds  ratios  of  3.88  (95%   proteins of the cell cycle and leads to an arrest in G /G in confidence  interval  2.25  to  6.69)  for  metformin  compared   human prostate cancer cells which is correlated with a with placebo and 4.41 (2.37 to 8.22) for metformin and decrease of expression of cyclin D1 and phosphorylation clomifene compared with clomifene alone. An analysis of   pRb.   The   cyclin   D1   gene   is   amplified   and/or   over   of   pregnancy   rates   shows   a   significant   treatment   effect   expressed  in  several  types  of  human  cancer.  Furthermore,   for   metformin   and   clomifene   (odds   ratio   4.40,   1.96   to   increased expression of cyclin D1 enhanced cell growth 9.85).   Metformin   was   also   found   to   reduce   the   fasting   and tumorigenicity. This study also revealed that insulin concentrations, blood pressure and low density apoptosis is not implicated in the antiproliferative effects of metformin. Although the effects of metformin have   In  order  to  evaluate  the  efficacy  of  metformin  in  the   been essentially attributed to its ability to activate the treatment of PCOS, various head to head comparisons have AMPK pathway, this series of experiments demonstrated been  done  with  clomiphene  citrate  (CC)  with  conflicting   that at the protein and cellular level, the AMPK pathway results. In the study by Palombaet al.,11 the cumulative plays no role in the effect of metformin on cell cycle.
ovulation rate was similar in women treated with CC or Another study 16reported that the anti neoplastic activity metformin(62.0   vs. 84.0%, respectively), whereas the of metformin was by down-regulation of mammalian pregnancy  rate  was  significantly  higher  (32.0  vs. 62.0%,   Target Of Rapamycin (mTOR) signaling through respectively) in women treated with metformin compared activation of AMP-activated protein kinase (AMPK). with those treated with CC although this did not translate mTOR is a serine–threonine protein kinase which is into   significant   number   of   live   births   (18.0   vs. 5.2%, up-regulated in many cancer cells as a result of genetic respectively) in women treated with CC vs. metformin, alterations or aberrant activation of the components of although a trend favoring the metformin group was PI3-k/Akt pathway, contributing to dysregulation of cell present. Another study by Legroet al. 12 reported that proliferation, growth, differentiation and survival. In CC was superior to metformin in increasing cumulative breast cancer cells this occurs through the stimulation ovulation (75.1 vs. 55.3%,  respectively),  pregnancy(29.7   of   epidermal   growth   factor   receptor   (EGFR),   the   vs. 12.0%, respectively) and live-birth (22.5 vs.7.2%, estrogen  receptor  (ER),  as  well  as  the  insulin  and  IGF1R,   respectively) rates. Lastly, in the study by Zain et al.13, which in turn enhance cell proliferation and cancer the   cumulative   ovulation   rate   was   significantly   higher   progression. AMPK is an energy-sensing/signaling in   CC   than   metformin   (59.0   vs. 23.7%, respectively), intracellular protein which is activated in response to whereas there were no statistical differences in the cellular stresses that deplete cellular energy levels and rates of pregnancies (15.4 vs. 7.9%,   respectively)   and   increase the AMP/ATP ratio.
live births(15.4 vs. 7.9%,   respectively).  The   conflicting   The activity of this protein ensures that cell division, results of these studies could be due to the heterogeneity which is a highly energy-consuming process, only of the population studied. Nevertheless, metformin is still proceeds   if   cells   have   sufficient   metabolic   resources   to   considered   one   of   the   first   line   drugs   for   the   treatment   support cell proliferation. AMPK activation by metformin of the polycystic ovary syndrome, although it is not yet is not only necessary for inhibition of gluconeogenesis approved  by  the  Food  and  Drug  Administration  for  this   in hepatocytes and reduction of Acetyl-CoA carboxylase purpose. The safety data for metformin in pregnancy (ACC) activity and hence fatty acid oxidation, but also is reassuring in that multiple studies14 have repeatedly for its growth-inhibitory effect in epithelial cells, an effect confirmed  that  there  is  no  evidence  of  an  increased  risk   associated with decreased mTOR activation. Several for major malformations.
studies have now demonstrated that activation of AMPK suppresses mTOR signaling induced by growth factors Metformin and Cancer
and amino acids.
Recent studies suggest that metformin may reduce the There is yet another proposed mode of action of risk of cancer, but its mode of action in cancer remains metformin through which it may exert its anti-cancer unclear. Various experimental studies have been done in effect.   Fatty   acid   synthesis   is   markedly   increased   de JOURNAL OF CLINICAL DIABETOLOGYAn  Official  Publication  of  the  Association  of  Clinical  Diabetology novo in many cancer cells including breast cancer, as a development. Other studies19-­24 on metformin in pregnancy result   of   high   expression   of   fatty   acid   synthase   (FAS),   have also shown favorable outcomes except for one a key enzyme for fatty acid synthesis. High levels small, retrospective cohort study25 that showed increased of   FAS   appear   to   be   associated   with   the   malignant   rates of perinatal loss and preeclampsiaas compared with phenotype of breast and ovarian cancers, and inhibition insulin treatment. Nevertheless, metformin has emerged of   FAS   suppresses   cancer   proliferation   and   induces   as a safe and acceptable drug in treatment of diabetes in cell   death   through   apoptosis.   FAS   expression   has   also   pregnancy, alone or in combination with insulin.
been   correlated   with   Her-­2   over   expression,   and   FAS  inhibition repressed Her2 expression at the transcriptional Metformin and Nonalcoholic Fatty Liver
level. Phosphorylation and activation of AMPK by metformin  leads  to  suppression  of  FAS  gene  expression   NAFLD  has  been  strongly  linked  to  diabetes  and  insulin   and inactivation of ACC, and this causes reduction in resistance and it can also predict the development of lipogenesis and synthesis of the ACC product malonyl- diabetes. A higher incidence of vascular complications of CoA, resulting in increased fatty acid oxidation.
diabetes  have  been  noted  in  those  with  NAFLD  .26Studies have shown that metformin improves the insulin resistance Metformin and Gestational Diabetes
associated  with  NAFLD  and  probably  the  liver  enzymes   as well but did not show consistent results in improving The Endocrine Society recommends use of metformin the liver histology.27-31 The TONIC trial32 in which a therapy only for those women with GDM who do not head to head comparison of metformin and vitamin E have satisfactory glycemic control despite medical was  done  in  biopsy  proven  NAFLD  in  173  children  (age   nutrition therapy, refuse or cannot use insulin or glyburide 8–17   years)   without   diabetes   demonstrated   significant   and  are  not  in  the  first  trimester.  Breast  feeding  women   improvement in hepatocellular ballooning only in the with overt diabetes successfully using metformin during metformin  group  compared  with  placebo.  No  significant   pregnancy should continue to use metformin according to differences were found between metformin and placebo these recommendations. Metformin is a more acceptable when examining other histological features or the primary form of treatment than insulin in women with gestational outcome of sustained improvement in ALT over time. diabetes although its use in pregnancy is controversial.
Despite  inconsistent  results  on  NAFLD  itself,  metformin   The Metformin in Gestational DiabetesTrial17 studied use   may   be   beneficial   in   minimizing   the   increased   risk   751 women with gestational diabetes mellitus at 20 to of hepatocellular carcinoma (HCC). The inhibitory effect 33 weeks of gestation who were subjected to open of metformin on cancer cell growth has been discussed treatment with metformin (with supplemental insulin if earlier. Case-control studies have shown that the Odds required)  or  insulin.  There  was  no  significant  difference   ratio of developing HCC in patients with diabetes treated in the incidence of neonatal complications in the groups. with metformin reduces to 0.3 when compared with those Severe  hypoglycemia  (glucose  level  <1.6  mmol  per  liter)   without this therapy .33,34 was less common in the metformin group, but preterm birth (before 37 weeks of gestation) was more common Metformin and Cardiovascular Disease
in the metformin group although the increased rate of Various studies have examined the effects of metformin preterm birth was not associated with higher rates of other on cardiovascular disease, both in diabetics as well as non- complications. Glucose targets were reached sooner in the diabetics. In patients with type 2 DM, the UK Prospective metformin group and the rates of maternal hypertensive Diabetes Study (UKPDS) showed that metformin may complications  did  not  differ  significantly  between  the  two   be   cardioprotective   in   that   metformin   significantly   decreased all-cause mortality and stroke end-points.35A Although uncertainties exist regarding the effect on recent experimental study36 demonstrated that a very off springs, data from a study,18   in   which   126   infants   low dose of metformin exerteda cardioprotective effect of women with polycysticovarian syndrome who were in a nondiabetic murinemodel of myocardial ischemia- treated with metformin were reassessed at 18 months of reperfusion injury, improving AMPK activation, already age, have provided preliminary reassurance of a lack of activated by myocardialischemia as an endogenous effect of metformin on growth and on motor and social protective signaling mechanism, and increasing Metformin beyond Dysglycemia endothelial nitric oxide synthase phosphorylation. The GIPS III trial 37was a double-blind, placebo-controlled To conclude, the therapeutic actions of metformin study conducted among 380 non diabetic patients who encompass a wide variety of disease pathologies centering underwent primary percutaneous coronary intervention around insulin resistance and the effect of metformin (PCI) for ST segment elevation myocardial infarction goes way beyond control of hyperglycemia. It should (STEMI) to evaluate the effect of metformin treatment be emphasized that metformin should be considered on preservation of left ventricular function after STEMI. as an adjunct and not a replacement to the more potent The trial showed that the use of metformin compared with treatment  options,  namely  lifestyle  modifications  like  diet   placebo  did  not  result  in  improved  LVEF  after  4  months   and exercise. Although metformin is not advocated as the in these patients.
first  line  therapy  for  the  conditions  described,  except  type   A meta-analysis of randomized clinical trials by 2 diabetes, each of these therapeutic avenues remains to Lamannaet al.38to assess the effects of metformin on be explored and future studies will probably guide us in the incidence of cardiovascular events and mortality these directions.
showed that overall metformin was not associated with significant  harm  or  benefit  on  cardiovascular  events.  In   trials  versus  placebo/no  therapy,  a  significant  benefit  was   Pernicova I, Korbonits M. Nat. Rev. Endocrinol. 2014; 10: 143– observed but not in active-comparator trials. Although metformin monotherapy was shown to be associated with Fischer,  Y.,  Thomas,  J.,  Rosen,  P.  &  Kammermeier,  H.  Action  of  metformin on glucose transport and glucose transporter GLUT1 improved survival, concomitant use with sulphonylureas and GLUT4 in heart muscle cells from healthy and diabetic was associated with reduced survival. AMPK plays a rats. Endocrinology 136,  412–420  (1995).
key role in the regulation of cellular lipid metabolism Piero Marchetti, Silvia del Guerra, Lorella Marselli, Roberto increasing  the  rate  of  fatty  acidoxidation  (FAO),39,40 and Lupi, Matilde Masini, Maria Pollera et al. Pancreatic Islets from Type  2  Diabetic  Patients  Have  Functional  Defects  and  Increased   metformin could act as lipid lowering agent activating Apoptosis That Are Ameliorated by Metformin. The Journal of AMPK   and   thus   increasing   FAO.   Metformin   treatment   Clinical  Endocrinology  &  Metabolism;;  89(11):5535–5541.
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"Sometimes you put walls up not to keep people out,
but to see who cares enough to break them down."

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