Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells
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Metformin is the most frequently prescribed drug for treatment of type 2 diabetes. It improves insulin resistance and glycemia by reducing hepatic gluconeogenesis. In addition, diabetic patients on metformin therapy have elevated levels of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) and metformin has been shown to regulate the expression of the GLP-1R in the pancreas.
We have studied the direct long-term effects of metformin on apoptosis, and function of GLP-1-secreting L cells in vitro, using the murine GLUTag cell line as a model. The apoptosis of GLUTag cells was detected by DNA-fragment assay and caspase-3 activity determination. GLP-1 secretion was determined using ELISA and the expression of proglucagon mRNA was assessed by reverse transcription polymerase chain reaction. The activation of intracellular messengers was determined using western blotting.
Metformin significantly decreased lipotoxicity-induced apoptosis in conjunction with increased phosphorylated AMPK. Metformin also countered the JNK2 activation evoked by lipotoxicity. In addition, long-term metformin treatment stimulated GLP-1 secretion.
This study demonstrates that metformin protects against lipoapoptosis (possibly by blocking JNK2 activation), and enhances GLP-1 secretion from GLP-1-producing cells in vitro. These direct effects of the drug might explain the elevated plasma GLP-1 levels seen in diabetic patients on chronic metformin therapy. The findings may also be harnessed to therapeutic advantage in efforts aiming at enhancing endogenous GLP-1 secretion in type 2 diabetic patients.
KeywordsGlucagon-like peptide-1 Gluconeogenesis Insulinotropic Lipotoxicity L cell
AMP-activated protein kinase
c-Jun N-terminal kinase
Protein kinase A
Protein kinase C
This work was generously supported financially by Stiftelsen Olle Engkvist Byggmästare, an EFSD/Amylin research grant, and Stiftelsen Sigurd and Elsa Goljes Minne.
Conflict of interest
No conflicts of interest, financial or otherwise, are declared by the authors.
- 6.Mannucci E, Ognibene A, Cremasco F, Bardini G, Mencucci A, Pierazzuoli E, et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care. 2001;24(3):489–94.Google Scholar
- 12.Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005;11(1):90–4.Google Scholar
- 17.Saifer A, Goldman L. The free fatty acids bound to human serum albumin. J. Lipid Res. 1961;2(3):268–70.Google Scholar
- 18.Sheehan MT, Jensen MD. Metabolic complications of obesity. Pathophysiologic considerations. Med Clin North Am. 2000; 84(2): 363–85, vi.Google Scholar
- 19.Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science. 2000;288(5467):870–4.Google Scholar
- 21.Hinke SA, Martens GA, Cai Y, Finsi J, Heimberg H, Pipeleers D, et al. Methyl succinate antagonises biguanide-induced AMPK-activation and death of pancreatic beta-cells through restoration of mitochondrial electron transfer. Br J Pharmacol. 2007;150(8):1031–43.Google Scholar
- 22.Schulz E, Dopheide J, Schuhmacher S, Thomas SR, Chen K, Daiber A, et al. Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction. Circulation. 2008;118(13):1347–57.Google Scholar
- 26.Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol. 2006;26(3):611–7.Google Scholar