Metformin A Pharmacological Preespective

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Metformin in cancer and PCOS

Metformin in cancer and PCOS

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  •  Interestingly, it has been recently shown that metformin, by contrast to rotenone, also exerts an inhibitory effect on mitochondrial ROS production by selectively blocking the reverse electron flow through the respiratory-chain complex 1
  • ACC producemelonyl CoA ,which is a inhibitor of carnitine shuttle responsible for entry of free fatty acid into mitochondria for Beta oxidation.AMP allosterically inhibit the Fructose 1,6 bisphosphatese,a main regulatory enzyme of gluconeogeneisi.Phosphoryaltion activate these two enzymes1-Hormone sensitive lipase, regulatory enzyme of lipolysis, 2- Glycogen phosphorylase, regulatory enzyme for glycogenolysis.
  • GLP-1 is a physiological regulator of appetite and food intake. metformin induces a fast regulation of the two major intestinal glucose transporters SGLT-1 and GLUT2, through a rapid AMPK phosphorylation. We further demonstrate that mucosal metforminmarkedly increased the phosphorylation of the catalytic subunitα2 of AMPK in enterocyte. Moreover, metformin effect onglucose transporters can be blocked by compound C, a classicalinhibitor of AMPK phosphorylation
  • Lipolysis produce triglyceride.
  •  However, the current and more likely explanation for metformin-induced vitamin B12 malabsorption and deficiency is that metformin has an effect on calcium-dependent membrane action in the terminal ileum. Absorption of the vitamin B12-intrinsic factor complex is calcium dependent and metformin interferes with this absorption. In support of this hypothesis is evidence that dietary calcium supplementation reverses metformin-induced vitamin B12 malabsorption
  • NAD/NADH is the critical criteria for the conversion of lactate into pyruvate. Metformin shift this balance to NADH/NAD ,hence stop this conversion.
  • IGF-1Insulin growth factor
  • Gestational diabetes The risk of gestational diabetes (GD) is increasing in obese women and is associated with adverse pregnancy outcomes [143]. Recently, data accumulated from case control studies [144] or the Metformin in Gestational Diabetes Trial [145] suggested that women treated with metformin had less weight gain and improved neonatal outcomes compared with those treated with insulin. Although no significant adverse events were observed when metformin was administered during pregnancy, its use in overweight women with GD has to be confirmed by additional studies and new guidelines.Circadin clock:  metformin markedly enhanced expression of the core clock components CLOCK, BMAL1 and PER2 through induction of AMPK-NAMPT-SIRT1 signaling and was associated with reduction of hyperglycemia and hyperinsulinemia in db/db mice.

Transcript

  • 1. METFORMIN; A PHARMACOLOGICAL PERSPECTIVE Dr. Asad Ullah Department of Pharmacology University of Veterinary and animal sciences, Lahore
  • 2. INSIDES Introduction Mechanism of Action Pharmacological actions Indication & contraindications Metformin and cancer Novel therapeutic perspective
  • 3. INTRODUCTION • Metformin (1,1-dimethylbiguanide), a biguanide derivate, • First line oral therapy in the recent guidelines of the American Diabetes Association • Most widely prescribed drug to treat hyperglycemia, at least 120 million user worldwide[3] • Insulin sensitizer[4] • Monotherapy & in combination with all antidiabetic[1]
  • 4. MECHANISM OF ACTION • Decrease hepatic glucose production through a mild inhibition of the mitochondrial respiratory-chain complex 1.[2] • Decrease intestinal absorption of glucose • anti-oxidative properties of metformin on endothelial cells[2]
  • 5. ChREBP: carbohydrate response element binding protein SREBP-1c: sterol regulatory element-binding protein-1c gene expression
  • 6. • activation of AMPK is the direct consequence of a transient reduction in cellular energy status induced by the mild and specific inhibition of the respiratory-chain complex 1
  • 7. ACTIONS OF METFORMIN Anti-obesity effects: • Decreased appetite • Increased GLP-1 secretion Anti-hyperglycemic effects: • Decreased intestinal carbohydrate absorption • Inhibition of hepatic gluconeogenesis • Enhancement of insulin-stimulated glucose transport in skeletal muscle: increased activity of GLUT-4
  • 8. Anti-lipidemic effects: • Inhibition of lipolysis in adipose tissue Anti-diabetic protective effects: • Protection of β-cells from glucose toxicity and lipotoxicity Hepatoprotective effects: • Decreased hepatic insulin resistance and improved lipemia levels Cardioprotective effects: • Cumulative effects of decreased weight gain and better lipid profile GLP-1 – glucagon-like peptide-1, AMPK – AMP-activated protein kinase, GLUT-4 – glucose transporter type 4,
  • 9. POLYCYSTIC OVARY SYNDROME[5] PCOS is a common endocrinopathy, 5 to 15% women . • Menstrual disturbance , Hyperandrogenism , polycystic ovary on ultrasound. • Insulin resistance, obesity • Insulin sensitizer e.g. Metformin by alleviation of insulin excess acting upon ovary and through direct ovarian effects.
  • 10. INDICATIONS Obese patients with type II diabetes Alone or in combination with sulfonylureas CONTRAINDICATIONS ‫ݩ‬Hepatic impairment ‫ݩ‬Alcoholism ‫ݩ‬Renal impairment ‫ݩ‬Heart failure
  • 11. SIDE EFFECT • 1.Metallic taste in the mouth • 2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea, abdominal discomfort) • 3. Vitamin B 12 deficiency (prolonged use) • 4. Lactic acidosis ( rare – 01/ 30,000-exclusive in renal & hepatic failure)
  • 12. LACTIC ACIDOSIS MECHANISM
  • 13. METFORMIN AS ANTI-CANCER • T2DM increase risk of cancer • Insulin resistance, Hyperglycemia and increase level of IGF-I due to hyperinsulinemia promote carcinogenesis • metformin reduce serum insulin and IGF-1 levels • LKB1/AMPK pathway controlling cellular proliferation • Apoptotic pathways by both caspase-dependent and caspase-independent mechanisms
  • 14. METFORMIN AS ANTI-CANCER
  • 15. NOVEL THERAPEUTIC PERSPECTIVE • Gestational diabetes • Diabetes prevention • Regulation of circadian clock • Metformin and pharmacogenetics
  • 16. REFERENCES: • 1. Gallagher EJ, LeRoith D. Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. Annals of the New York Academy of Sciences 2011;1243:54-68 doi: 10.1111/j.1749-6632.2011.06285.x[published Online First: Epub Date]|. • 2. Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clinical science 2012;122(6):253-70 doi: 10.1042/CS20110386[published Online First: Epub Date]|. • 3. Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diabetes & vascular disease research : official journal of the International Society of Diabetes and Vascular Disease 2008;5(3):157-67 doi: 10.3132/dvdr.2008.027[published Online First: Epub Date]|. • 4. Hundal RS, Inzucchi SE. Metformin: new understandings, new uses. Drugs 2003;63(18):1879-94 • 5. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. nsulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev.2010: