Metformin A Pharmacological Preespective

Metformin in cancer and PCOS

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. 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. Polycystic Ovary syndrome [5]

10. Indications Obese patients with type II diabetes Alone or in combination with sulfonylureas Contraindications Hepatic impairment Renal impairment Alcoholism Heart 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: