Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats

Nature Medicine

Volumn 21, Issue 5, 2015, Pages 506-511

  Duca, Frank A ^a   Côté, Clémence D ^a,b   Rasmussen, Brittany A ^a,b   Zadeh Tahmasebi, Melika ^a,b   Rutter, Guy A ^c   Filippi, Beatrice M ^a   Lam, Tony K T ^a,b,d  

^a UNIVERSITY HEALTH NETWORK   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c HAMMERSMITH HOSPITAL   (United Kingdom)

^d UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

GLUCAGON RECEPTOR; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; GLUCOSE; GLUCOSE BLOOD LEVEL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; INSULIN; METFORMIN; NICOTINAMIDE;

ANIMAL; BLOOD; CHEMISTRY; DRUG EFFECTS; DUODENUM; ENZYMOLOGY; GENE EXPRESSION REGULATION; GLUCOSE BLOOD LEVEL; GLUCOSE CLAMP TECHNIQUE; HEK293 CELL LINE; HUMAN; INSULIN RESISTANCE; LIVER; MALE; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; RAT; SIGNAL TRANSDUCTION; SPRAGUE DAWLEY RAT;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; DUODENUM; GENE EXPRESSION REGULATION, ENZYMOLOGIC; GLUCOSE; GLUCOSE CLAMP TECHNIQUE; HEK293 CELLS; HUMANS; INSULIN; INSULIN RESISTANCE; LIVER; MALE; METFORMIN; NIACINAMIDE; OBESITY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, GLUCAGON; SIGNAL TRANSDUCTION;

EID: 84929177057     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3787     Document Type: Article

References (45)

1. Foretz, M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355-2369 (2010).
2. Fullerton, M.D. et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19, 1649-1654 (2013).
3. Madiraju, A.K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542-546 (2014).
4. Miller, R.A. et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494, 256-260 (2013).
5. Shaw, R.J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642-1646 (2005).
6. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167-1174 (2001).
7. Lam, T.K. Neuronal regulation of homeostasis by nutrient sensing. Nat. Med. 16, 392-395 (2010).
8. Taylor, S.I. Deconstructing type 2 diabetes. Cell 97, 9-12 (1999).
9. Hundal, R.S. et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49, 2063-2069 (2000).
10. Radziuk, J., Zhang, Z., Wiernsperger, N. & Pye, S. Effects of metformin on lactate uptake and gluconeogenesis in the perfused rat liver. Diabetes 46, 1406-1413 (1997).
11. Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G. & Gerich, J.E. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 333, 550-554 (1995).
12. Salpeter, S.R., Buckley, N.S., Kahn, J.A. & Salpeter, E.E. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am. J. Med. 121, 149 e2-157 e2 (2008).
13. Owen, M.R., Doran, E. & Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607-614 (2000).
14. Hawley, S.A. et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554-565 (2010).
15. Wang, P.Y. et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 452, 1012-1016 (2008).
16. Cheung, G.W., Kokorovic, A., Lam, C.K., Chari, M. & Lam, T.K. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab. 10, 99-109 (2009).
17. Rasmussen, B.A. et al. Jejunal leptin-PI3K signaling lowers glucose production. Cell Metab. 19, 155-161 (2014).
18. Breen, D.M. et al. Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nat. Med. 18, 950-955 (2012).
19. Stepensky, D., Friedman, M., Raz, I. & Hoffman, A. Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect. Drug Metab. Dispos. 30, 861-868 (2002).
20. Maida, A., Lamont, B.J., Cao, X. & Drucker, D.J. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia 54, 339-349 (2011).
21. Shin, N.R. et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727-735 (2014).
22. Vardarli, I., Arndt, E., Deacon, C.F., Holst, J.J. & Nauck, M.A. Effects of sitagliptin and metformin treatment on incretin hormone and insulin secretory responses to oral and "isoglycemic" intravenous glucose. Diabetes 63, 663-674 (2014).
23. Harmel, E. et al. AMPK in the small intestine in normal and pathophysiological conditions. Endocrinology 155, 873-888 (2014).
24. Bain, J. et al. The selectivity of protein kinase inhibitors: a further update. Biochem. J. 408, 297-315 (2007).
25. He, G. et al. AMP-activated protein kinase induces p53 by phosphorylating MDMX and inhibiting its activity. Mol. Cell. Biol. 34, 148-157 (2014).
26. Rasmussen, B.A. et al. Duodenal activation of cAMP-dependent protein kinase induces vagal afferent firing and lowers glucose production in rats. Gastroenterology 142, 834 e3-843.e3 (2012).
27. Richards, P. et al. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 63, 1224-1233 (2014).
28. Yusta, B. et al. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 4, 391-406 (2006).
29. Samuel, V.T. et al. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes. Proc. Natl. Acad. Sci. USA 106, 12121-12126 (2009).
30. Viollet, B. et al. Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. (Lond.) 122, 253-270 (2012).
31. Shackelford, D.B. et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143-158 (2013).
32. Pollak, M. Overcoming drug development bottlenecks with repurposing: repurposing biguanides to target energy metabolism for cancer treatment. Nat. Med. 20, 591-593 (2014).
33. Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4, 2192 (2013).
34. Wilcock, C. & Bailey, C.J. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24, 49-57 (1994).
35. Habib, A.M. et al. Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology 153, 3054-3065 (2012).
36. Mulherin, A.J. et al. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology 152, 4610-4619 (2011).
37. Ono, H. et al. Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J. Clin. Invest. 118, 2959-2968 (2008).
38. Wang, J. et al. Overfeeding rapidly induces leptin and insulin resistance. Diabetes 50, 2786-2791 (2001).
39. Filippi, B.M., Yang, C.S., Tang, C. & Lam, T.K. Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab. 16, 500-510 (2012).
40. Kokorovic, A. et al. Duodenal mucosal protein kinase C-delta regulates glucose production in rats. Gastroenterology 141, 1720-1727 (2011).
41. da Silva Xavier, G. et al. Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem. J. 371, 761-774 (2003).
42. Choi, Y.H., Kim, S.G. & Lee, M.G. Dose-independent pharmacokinetics of metformin in rats: hepatic and gastrointestinal first-pass effects. J. Pharm. Sci. 95, 2543-2552 (2006).
43. Graham, G.G. et al. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 50, 81-98 (2011).
44. Sakamoto, K. et al. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 24, 1810-1820 (2005).
45. Dale, S., Wilson, W.A., Edelman, A.M. & Hardie, D.G. Similar substrate recognition motifs for mammalian Amp-activated protein kinase, higher-plant HMG-CoA reductase kinase-A, yeast SNF1, and mammalian calmodulin-dependent protein kinase I. FEBS Lett. 361, 191-195 (1995).