metformin a pharmacological preespective
DESCRIPTION
Metformin in cancer and PCOSTRANSCRIPT
METFORMIN; A PHARMACOLOGICAL PERSPECTIVE
Dr. Asad Ullah
Department of Pharmacology
University of Veterinary and animal sciences, Lahore
INSIDESIntroductionMechanism of ActionPharmacological actionsIndication & contraindicationsMetformin and cancerNovel therapeutic perspective
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]
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]
ChREBP: carbohydrate response element binding protein SREBP-1c:sterol regulatory element-binding protein-1c gene expression
• 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
ACTIONS OF METFORMINAnti-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
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,
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]
INDICATIONS
Obese patients with type II diabetes
Alone or in combination with sulfonylureas
CONTRAINDICATIONS
ݩ Hepatic impairment
ݩ Renal impairment
ݩ Alcoholism
ݩ Heart failure
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)
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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
METFORMIN AS ANTI-CANCER
NOVEL THERAPEUTIC PERSPECTIVE
•Gestational diabetes• Diabetes prevention • Regulation of circadian clock•Metformin and pharmacogenetics
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: