Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets

Huang,Chenghu; Yuan,Li; Cao,Shuyi

doi:10.3892/ijmm.2015.2207

Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets

Authors:
- Chenghu Huang
- Li Yuan
- Shuyi Cao
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Affiliations: Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: May 12, 2015 https://doi.org/10.3892/ijmm.2015.2207
Pages: 173-185
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.

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1	Kusminski CM, Shetty S, Orci L, Unger RH and Scherer PE: Diabetes and apoptosis: Lipotoxicity. Apoptosis. 14:1484–1495. 2009. View Article : Google Scholar : PubMed/NCBI
2	Kim JW and Yoon KH: Glucolipotoxicity in pancreatic β-cells. Diabetes Metab J. 35:444–450. 2011. View Article : Google Scholar : PubMed/NCBI
3	Rial E, Rodríguez-Sánchez L, Gallardo-Vara E, Zaragoza P, Moyano E and González-Barroso MM: Lipotoxicity, fatty acid uncoupling and mitochondrial carrier function. Biochim Biophys Acta. 1797:800–806. 2010. View Article : Google Scholar : PubMed/NCBI
4	Kim W and Egan JM: The role of incretins in glucose homeo-stasis and diabetes treatment. Pharmacol Rev. 60:470–512. 2008. View Article : Google Scholar : PubMed/NCBI
5	Buteau J: GLP-1 receptor signaling: Effects on pancreatic beta-cell proliferation and survival. Diabetes Metab. 34(Suppl 2): S73–S77. 2008. View Article : Google Scholar : PubMed/NCBI
6	Lamont BJ and Andrikopoulos S: Hope and fear for new classes of type 2 diabetes drugs: Is there preclinical evidence that incretin-based therapies alter pancreatic morphology? J Endocrinol. 221:T43–T61. 2014. View Article : Google Scholar : PubMed/NCBI
7	Yang Y, Tong Y, Gong M, Lu Y, Wang C, Zhou M, Yang Q, Mao T and Tong N: Activation of PPARβ/δ protects pancreatic β cells from palmitate-induced apoptosis by upregulating the expression of GLP-1 receptor. Cell Signal. 26:268–278. 2014. View Article : Google Scholar
8	Kemp DM and Habener JF: Insulinotropic hormone glucagon-like peptide-1 (GLP-1) activation of insulin gene promoter inhibited by p38 mitogen-activated protein kinase. Endocrinology. 142:1179–1187. 2001.PubMed/NCBI
9	Lotfy M, Singh J, Rashed H, Tariq S, Zilahi E and Adeghate E: Mechanism of the beneficial and protective effects of exenatide in diabetic rats. J Endocrinol. 220:291–304. 2014. View Article : Google Scholar
10	Chen LN, Lyu J, Yang XF, Ji WJ, Yuan BX, Chen MX, Ma X and Wang B: Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice. Int J Mol Med. 32:892–900. 2013.PubMed/NCBI
11	Hendarto H, Inoguchi T, Maeda Y, Ikeda N, Zheng J, Takei R, Yokomizo H, Hirata E, Sonoda N and Takayanagi R: GLP-1 analog liraglutide protects against oxidative stress and albu-minuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism. 61:1422–1434. 2012. View Article : Google Scholar : PubMed/NCBI
12	Liu Z, Stanojevic V, Avadhani S, Yano T and Habener JF: Stromal cell-derived factor-1 (SDF-1)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis activation induces intra-islet glucagon-like peptide-1 (GLP-1) production and enhances beta cell survival. Diabetologia. 54:2067–2076. 2011. View Article : Google Scholar : PubMed/NCBI
13	Pugazhenthi U, Velmurugan K, Tran A, Mahaffey G and Pugazhenthi S: Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: Potential therapeutic benefits in diabetic patients. Diabetologia. 53:2357–2368. 2010. View Article : Google Scholar : PubMed/NCBI
14	Marchetti P, Lupi R, Bugliani M, Kirkpatrick CL, Sebastiani G, Grieco FA, Del Guerra S, D’Aleo V, Piro S, Marselli L, et al: A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia. 55:3262–3272. 2012. View Article : Google Scholar : PubMed/NCBI
15	Habener JF and Stanojevic V: Alpha cells come of age. Trends Endocrinol Metab. 24:153–163. 2013. View Article : Google Scholar
16	Habener JF and Stanojevic V: α-cell role in β-cell generation and regeneration. Islets. 4:188–198. 2012. View Article : Google Scholar : PubMed/NCBI
17	Nie Y, Nakashima M, Brubaker PL, Li QL, Perfetti R, Jansen E, Zambre Y, Pipeleers D and Friedman TC: Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. J Clin Invest. 105:955–965. 2000. View Article : Google Scholar : PubMed/NCBI
18	Zhang Y, Zhang Y, Bone RN, Cui W, Peng JB, Siegal GP, Wang H and Wu H: Regeneration of pancreatic non-β endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin. PLoS One. 7:e366752012. View Article : Google Scholar
19	Yano T, Liu Z, Donovan J, Thomas MK and Habener JF: Stromal cell derived factor-1 (SDF-1)/CXCL12 attenuates diabetes in mice and promotes pancreatic beta-cell survival by activation of the prosurvival kinase Akt. Diabetes. 56:2946–2957. 2007. View Article : Google Scholar : PubMed/NCBI
20	Thyssen S, Arany E and Hill DJ: Ontogeny of regeneration of beta-cells in the neonatal rat after treatment with streptozotocin. Endocrinology. 147:2346–2356. 2006. View Article : Google Scholar : PubMed/NCBI
21	Lau T, Carlsson PO and Leung PS: Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia. 47:240–248. 2004. View Article : Google Scholar : PubMed/NCBI
22	Wang HW, Mizuta M, Saitoh Y, Noma K, Ueno H and Nakazato M: Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic β-cells. Metabolism. 60:1081–1089. 2011. View Article : Google Scholar : PubMed/NCBI
23	Jaksch C and Thams P: A critical role for CK2 in cytokine-induced activation of NFκB in pancreatic β cell death. Endocrine. 47:117–128. 2014. View Article : Google Scholar :
24	Yuan L, Lu CL, Wang Y, Li Y and Li XY: Ang (1-7) protects islet endothelial cells from palmitate-induced apoptosis by AKT, eNOS, p38 MAPK, and JNK pathways. J Diabetes Res. 2014:3914762014. View Article : Google Scholar : PubMed/NCBI
25	Fraulob JC, Ogg-Diamantino R, Fernandes-Santos C, Aguila MB and Mandarim-de-Lacerda CA: A mouse model of metabolic syndrome: Insulin resistance, fatty liver and non-alcoholic fatty pancreas disease (NAFPD) in C57BL/6 mice fed a high fat diet. J Clin Biochem Nutr. 46:212–223. 2010. View Article : Google Scholar : PubMed/NCBI
26	Davidson HW: (Pro)Insulin processing: A historical perspective. Cell Biochem Biophys. 40(Suppl 3): 143–158. 2004.PubMed/NCBI
27	Portela-Gomes GM, Grimelius L and Stridsberg M: Prohormone convertases 1/3, 2, furin and protein 7B2 (Secretogranin V) in endocrine cells of the human pancreas. Regul Pept. 146:117–124. 2008. View Article : Google Scholar
28	Kieffer TJ, McIntosh CH and Pederson RA: Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 136:3585–3596. 1995.PubMed/NCBI
29	Mondragon A, Davidsson D, Kyriakoudi S, Bertling A, Gomes-Faria R, Cohen P, Rothery S, Chabosseau P, Rutter GA and da Silva Xavier G: Divergent effects of liraglutide, exendin-4, and sitagliptin on beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia. PLoS One. 9:e1048732014. View Article : Google Scholar : PubMed/NCBI
30	Gloire G, Legrand-Poels S and Piette J: NF-kappaB activation by reactive oxygen species: Fifteen years later. Biochem Pharmacol. 72:1493–1505. 2006. View Article : Google Scholar : PubMed/NCBI
31	Quan W, Jo EK and Lee MS: Role of pancreatic β-cell death and inflammation in diabetes. Diabetes Obes Metab. 15(Suppl 3): 141–151. 2013. View Article : Google Scholar
32	O’Malley TJ, Fava GE, Zhang Y, Fonseca VA and Wu H: Progressive change of intra-islet GLP-1 production during diabetes development. Diabetes Metab Res Rev. 30:661–668. 2014. View Article : Google Scholar
33	Hansen AM, Bödvarsdottir TB, Nordestgaard DN, Heller RS, Gotfredsen CF, Maedler K, Fels JJ, Holst JJ and Karlsen AE: Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus - an adaptive response to hyperglycaemia? Diabetologia. 54:1379–1387. 2011. View Article : Google Scholar : PubMed/NCBI
34	Talchai C, Xuan S, Lin HV, Sussel L and Accili D: Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 150:1223–1234. 2012. View Article : Google Scholar : PubMed/NCBI
35	Wang Z, York NW, Nichols CG and Remedi MS: Pancreatic β cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. 19:872–882. 2014. View Article : Google Scholar : PubMed/NCBI
36	Tortosa F and Dotta F: Incretin hormones and beta-cell mass expansion: What we know and what is missing? Arch Physiol Biochem. 119:161–169. 2013. View Article : Google Scholar : PubMed/NCBI
37	Evans JL, Goldfine ID, Maddux BA and Grodsky GM: Oxidative stress and stress-activated signaling pathways: A unifying hypothesis of type 2 diabetes. Endocr Rev. 23:599–622. 2002. View Article : Google Scholar : PubMed/NCBI
38	Yuzefovych LV, LeDoux SP, Wilson GL and Rachek LI: Mitochondrial DNA damage via augmented oxidative stress regulates endoplasmic reticulum stress and autophagy: Crosstalk, links and signaling. PLoS One. 8:e833492013. View Article : Google Scholar :
39	Gehrmann W, Elsner M and Lenzen S: Role of metabolically generated reactive oxygen species for lipotoxicity in pancreatic β-cells. Diabetes Obes Metab. 12(Suppl 2): 149–158. 2010. View Article : Google Scholar
40	Erdogdu O, Eriksson L, Xu H, Sjöholm A, Zhang Q and Nyström T: Exendin-4 protects endothelial cells from lipo-apoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. J Mol Endocrinol. 50:229–241. 2013. View Article : Google Scholar : PubMed/NCBI
41	Jin L, Lim SW, Doh KC, Piao SG, Jin J, Heo SB, Chung BH and Yang CW: Dipeptidyl peptidase IV inhibitor MK-0626 attenuates pancreatic islet injury in tacrolimus-induced diabetic rats. PLoS One. 9:e1007982014. View Article : Google Scholar : PubMed/NCBI
42	Tomas E, Stanojevic V and Habener JF: GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes. Regul Pept. 167:177–184. 2011. View Article : Google Scholar : PubMed/NCBI
43	Liu Z, Stanojevic V, Brindamour LJ and Habener JF: GLP1-derived nonapeptide GLP1(28-36)amide protects pancreatic β-cells from glucolipotoxicity. J Endocrinol. 213:143–154. 2012. View Article : Google Scholar : PubMed/NCBI