Metformin Mechanism of Action

1. Metformin Mechanism of Action JaspreetNijjar, AbneetAtwal, Simran Dodd & Bipranjit Singh PHM142 Fall 2012 Instructor: Dr. Jeffrey Henderson

2. Glucose • Regular plasma glucose levels (4-7mM) are controlled by a balance between intestinal absorption, hepatic glucose production, and uptake and metabolism by peripheral tissues • Intestinal absorption of glucose inhibits endogenous glucose production

3. Insulin • Insulin is produced by β-cells in the pancreas • After carbohydrate ingestion, [insulin] rise • Insulin regulates blood glucose by: • Increasing glucose uptake by muscle and fat • Inhibiting hepatic glucose production

4. Glucose Uptake • Stimulates translocation of insulin sensitive glucose receptor (GLUT4) from intracellular sites to cell surface

5. Hepatic Glucose Inhibition • Insulin inhibits hepatic glucose production: • Blocking glycogenolysis: conversion of glycogen to glucose • Blocking gluconeogenesis: glucose synthesis from simple organic compounds • Stimulating glycogenesis: conversion of glucose to glycogen

6. Hepatic Carbohydrate Metabolism

7. Insulin Resistance • Target organs and/or tissues do not respond properly to insulin • Results in hyperglycemia and increased insulin production by pancreatic β-cells (to compensate for poor insulin response) • Results in Diabetes Mellitus (type 2)

8. TYPE 2 DIABETES • Insulin independent • Reduction of target cell responsiveness to insulin • Factors that increase risk: overweight/obese, age, fasting, family history • Readily controlled by diet and exercise

9. Metformin • Recommended in conjunction with lifestyle changes • First line of oral therapy • Decreases hepatic glucose production through a mild inhibition of the mitochondrial respiratory chain complex 1 • Other Uses: cardiovascular diseases, polycystic ovary disease and prevention and treatment of cancer

10. Anti-hyperglycemic Action • Antihyperglycemic agent • Insulin sensitizer • Positive effects on insulin receptor expression and tyrosine kinase activity • Modulation of multiple components of the incretin axis • Decrease hepatic glucose production through several mechanisms

11. Mechanisms of Metformin • Complete mechanisms of metformin’s actions at the molecular level are not yet known • Metformin does indirectly activate AMPK (AMP-activated protein kinase) which is known as the AMPK-dependent mechanism • Activation occurs through inhibition of the mitochondrial respiration chain complex 1

12. The Mitochondrial Respiration Chain Complex I

13. Activation of AMPK • AMPK is activated by: • an increase in the intracellular AMP/ATP ratio • Inhibition of complex I results in a reduction in proton-driven synthesis of ATP from ADP and Pi and alters the AMP/ATP ratio • Activated AMPK results in: • glucose, protein, lipid synthesis • fatty acid oxidation, glucose uptake

14. Activation of AMPK Pancreas

15. Mechanism of Metformin II: Metformin + GLP-1 • Metformin increases plasma levels of Glucagon-Like Peptide-1 (GLP-1) • GLP-1 is an incretin hormone • Secreted by intestinal L-cells • Short half-life (≈2 minutes) • Degraded by dipeptidylpeptidase-IV (DPP-IV) • Metformin causes sensitization of the β-cell to GLP-1 and GIP through peroxisomeproliferator-activated receptor α

16. DPP-IV Inhibition? • Ubiquitous free circulating enzyme that degrades GLP-1 • In vitro studies showed that metformin has no direct inhibition effect on DPP-IV activity (Viollet et co, 2012) • Metformin has no effect on levels of GIP, which is also inactivated by DPP-IV • Medications such as Januvia (sitagliptin) are DPP-IV inhibitors often used in conjunction with metformin

17. L-Cells • Proglucagon gene expressed in L-cells • activation of AMP Kinasein the L cell can enhance GLP-1 secretion in vitro • No definitive literature on its likelihood as a target site for metformin

18. Metformin + GLP-1 • EXACT MECHANISM OF ACTION UNKNOWN! What we do know: • GLP-1 release is through a mechanism that involves both the M3 and GRP receptor-dependent pathways • Definite link between increase GLP-1 in response to presence of metformin • Incretin effect induced by GLP-1 can therefore be attributable to metformin

19. SUMMARY • Glucose • Intestinal absorption, hepatic glucose production, uptake + metabolism by peripheral tissues, are all factors that play a role in regulating regular plasma glucose levels • Endogenous glucose production inhibited by intestinal absorption of glucose Insulin • Produced by Β-cells located within the pancreas • Insulin levels in blood increase in response to carbohydrate ingestion • Two ways Insulin regulates blood glucose levels: 1) increasing glucose uptake by muscle and fat 2) inhibiting hepatic glucose production Glucose Uptake • Translocation of GLUT4 from intracellular sites to cell surface prompted by presence of insulin • GLUT4 receptor promotes glucose transport into cells Hepatic Glucose Inhibition • Insulin causes: (-) glycogenolysis (glycogen ---> glucose) (-) gluconeogenesis (non carb simple compounds --> glucose) (+) glycogenesis (glucose --> glycogen) Insulin Resistance/Type II Diabetes • Hyperglycemia (high blood glucose levels) result of defective response to insulin by target organs/tissues • Type II diabetes characterized by the decrease in responsiveness to insulin in target cells. Type II readily controlled by diet and exercise Metformin • Predominant choice of oral therapy • Functions primarily by working as a insulin sensitizer and decreasing hepatic glucose production • Exact mechanisms at molecular level still unknown but two general mechanisms provide overview of the drug's role/actions within cell: 1) Activation of AMPK: Metformin inhibits the mitochondrial respiration chain complex 1 which results in reduction of proton-driven synthesis of ATP. This causes alterations of AMP/ATP ratios within cell which then activates AMPK. Once AMPK is activated, glucose, protein and lipid synthesis in cells is decreased while fatty acid oxidation and glucose uptake is increase. 2) Increase in GLP-1 plasma levels: Metformin has been found to increase the plasma levels of the incretin hormone GLP-1. GLP-1 found to increase insulin secretion as well increase insulin gene expression. Although exact mechanism of how metformin increases GLP-1 levels remains unknown, it is known that metformin has no effect on DPP-IV which degrades GLP-1. Possible effect on GLP-1 secreting L cells.

20. REFERENCES • Canadian Diabetes Association. (2008). Canadian journal of diabetes supplemental.32, S1. Kappe C, Patrone C, Holst JJ, Zhang Q, Sjöholm A. (2012). Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells. J Gastroenterol. • Giugliano, D., Ceriello, A., and Esposito, K. (2008). Glucose metabolism and hyperglycemia. The American Journal for Clinical Nutrition. 87(suppl):217S–22S. • Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, Ciani S, Messeri G, Rotella CM. (2001). Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 24(3):489-94 • Moore, M. C., Connolly, C. C., & Cherrington, A. (1998). Autoregulation of hepatic glucose production. European Journal of Endocrinology. 138: 240-248. • Saltiel, A. R. & Kahn, R. (2001). Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 413:799-806. • Schinner, S., Scherbaum, W. A., Bornstein, S. R., & Barthe, A. (2004). Molecular mechanisms of Insulin resistance. Diabetes UK. Diabetic Medicine, 22: 674–682 • Simon A. Hinke, Kerstin Kuhn-Wache, Torsten Hoffmann, Raymond A. Pederson,Christopher H. S. McIntosh,* and Hans-Ulrich Demuth (2002). Metformin Effects on Dipeptidylpeptidase IV Degradation of Glucagon-like Peptide-1. Biochemical and Biophysical Research Communications 291, 1302–1308 • Viollet, B., Guigas, B., Sanz Garcia, N., Leclerc, J., Foretz, M., & Andreelli, F. (2012). Cellular and molecular mechanisms of metformin: An overview. Clinical Science, 122(5-6), 253-270. doi: 10.1042/CS20110386