This document discusses metformin, a first-line oral therapy for treating hyperglycemia. It is prescribed to over 120 million people worldwide. Metformin works by decreasing hepatic glucose production and intestinal glucose absorption. It also has anti-oxidative and anti-inflammatory properties. The document outlines metformin's mechanisms of action, pharmacological actions including its effects on weight, lipids, and insulin sensitivity, as well as its indications for treating conditions like diabetes and polycystic ovary syndrome. Potential side effects and contraindications are also presented. The document concludes by discussing metformin's potential role in cancer prevention and its novel therapeutic applications.

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.

11. INDICATIONS
Obese patients with type II diabetes
Alone or in combination with sulfonylureas
CONTRAINDICATIONS
‫ݩ‬Hepatic impairment
‫ݩ‬Alcoholism
‫ݩ‬Renal impairment
‫ݩ‬Heart failure

12. 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)

13. LACTIC ACIDOSIS
MECHANISM

14. 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

15. METFORMIN AS ANTI-CANCER

16. NOVEL THERAPEUTIC PERSPECTIVE
• Gestational diabetes
• Diabetes prevention
• Regulation of circadian clock
• Metformin and pharmacogenetics

17. 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: