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)

LAC

TIC

AC

IDO

SIS

M

EC

HA

NIS

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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: