Protein kinase C pathway mediates the protective effects of glucagon-like peptide-1 on the apoptosis of islet β-cells

Zhang,Lihai; Wang,Yuesheng; Wang,Jiao; Liu,Yinglan; Yin,Yanbin

doi:10.3892/mmr.2015.4355

Protein kinase C pathway mediates the protective effects of glucagon-like peptide-1 on the apoptosis of islet β-cells

Authors:
- Lihai Zhang
- Yuesheng Wang
- Jiao Wang
- Yinglan Liu
- Yanbin Yin
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Affiliations: Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China, Department of Pediatrics, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang 154002, P.R. China
Published online on: September 24, 2015 https://doi.org/10.3892/mmr.2015.4355
Pages: 7589-7594

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Abstract

The incidence of diabetes has been increasing over previous years. It is hypothesized that promoting the survival of islet β-cells is a key direction for the treatment of diabetes. Although gastric bypass surgery improves certain types of diabetes and attenuates its progression, there are certain associated disadvantages (including intestinal obstruction and anastomotic leakage), and quality of life and physical status (such as malnutrition) are significantly affected by gastric bypass surgery. Therefore, it is important to determine the mechanisms underlying the improvement of diabetes by gastric bypass surgery and identify novel gene targets for diabetes therapeutics. In the present study, glucagon‑like peptide‑1 (GLP‑1), whose secretion was markedly increased following gastric bypass surgery, increased the activity of protein kinase C (PKC) in islet β‑cells in a dose‑dependent manner. Additionally, treatment with GLP‑1 boosted cell viability and decreased cell death in starved islet β‑cells, and inhibited mitochondria‑dependent apoptosis by regulating the expression levels of Bcl‑2/Bax. These effects were reversed by inhibiting the PKC pathway using hypericin. Therefore, the present study concluded that GLP‑1 may promote the survival and inhibit the apoptosis of islet β‑cells at least in part by activating the PKC pathway, which is an important underlying mechanism and may be exploited in the treatment of diabetes.

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1	Shirazi R, Palsdottir V, Collander J, Anesten F, Vogel H, Langlet F, Jaschke A, Schürmann A, Prévot V, Shao R, et al: Glucagon-like peptide 1 receptor induced suppression of food intake and body weight is mediated by central IL-1 and IL-6. Proc Natl Acad Sci USA. 110:16199–16204. 2013. View Article : Google Scholar
2	Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, Bertolotto C, Di Mario U, Harlan DM and Perfetti R: Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 144:5149–5158. 2003. View Article : Google Scholar : PubMed/NCBI
3	Madsbad S and Holst JJ: GLP-1 as a mediator in the remission of type 2 diabetes after gastric bypass and sleeve gastrectomy surgery. Diabetes. 63:3172–3174. 2014. View Article : Google Scholar : PubMed/NCBI
4	Mentlein R, Gallwitz B and Schmidt WE: Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 214:829–835. 1993. View Article : Google Scholar : PubMed/NCBI
5	Peters A: Incretin-based therapies: Review of current clinical trial data. Am J Med. 123(3 Suppl): S28–S37. 2010. View Article : Google Scholar : PubMed/NCBI
6	Newton AC: Regulation of the ABC kinases by phosphorylation: Protein kinase C as a paradigm. Biochem J. 370:361–371. 2003. View Article : Google Scholar
7	Steinberg SF: Structural basis of protein kinase C isoform function. Physiol Rev. 88:1341–1378. 2008. View Article : Google Scholar : PubMed/NCBI
8	Nishizuka Y: Protein kinase C and lipid signaling for sustained cellular responses. FASEB J. 9:484–496. 1995.PubMed/NCBI
9	Newton AC: Regulation of protein kinase C. Curr Opin Cell Biol. 9:161–167. 1997. View Article : Google Scholar : PubMed/NCBI
10	Mellor H and Parker PJ: The extended protein kinase C super-family. Biochem J. 332:281–292. 1998. View Article : Google Scholar
11	Onoda K, Hagiwara M, Hachiya T, Usuda N, Nagata T and Hidaka H: Different expression of protein kinase C isozymes in pancreatic islet cells. Endocrinology. 126:1235–1240. 1990. View Article : Google Scholar : PubMed/NCBI
12	Knutson KL and Hoenig M: Identification and subcellular characterization of protein kinase-C isoforms in insulinoma beta-cells and whole islets. Endocrinology. 135:881–886. 1994.PubMed/NCBI
13	Tian YM, Urquidi V and Ashcroft SJ: Protein kinase C in beta-cells: Expression of multiple isoforms and involvement in cholinergic stimulation of insulin secretion. Mol Cell Endocrinol. 119:185–193. 1996. View Article : Google Scholar : PubMed/NCBI
14	Pinton P, Tsuboi T, Ainscow EK, Pozzan T, Rizzuto R and Rutter GA: Dynamics of glucose-induced membrane recruitment of protein kinase C beta II in living pancreatic islet beta-cells. J Biol Chem. 277:37702–37710. 2002. View Article : Google Scholar : PubMed/NCBI
15	Mogami H, Zhang H, Suzuki Y, Urano T, Saito N, Kojima I and Petersen OH: Decoding of short-lived Ca²⁺ influx signals into long term substrate phosphorylation through activation of two distinct classes of protein kinase C. J Biol Chem. 278:9896–9904. 2003. View Article : Google Scholar : PubMed/NCBI
16	Schapiro SA and Everitt JI: Preparation of animals for use in the laboratory: issues and challenges for the Institutional Animal Care and Use Committee (IACUC). ILAR J. 47:370–375. 2006. View Article : Google Scholar : PubMed/NCBI
17	Wang SJ, Gao Y, Chen H, Kong R, Jiang HC, Pan SH, Xue DB, Bai XW and Sun B: Dihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo. Cancer Lett. 293:99–108. 2010. View Article : Google Scholar : PubMed/NCBI
18	Matsumura T, Sakai M, Kobori S, Biwa T, Takemura T, Matsuda H, Hakamata H, Horiuchi S and Shichiri M: Two intracellular signaling pathways for activation of protein kinase C are involved in oxidized low-density lipoprotein-induced macrophage growth. Arterioscler Thromb Vasc Biol. 17:3013–3020. 1997. View Article : Google Scholar : PubMed/NCBI
19	Narang AS and Mahato RI: Biological and biomaterial approaches for improved islet transplantation. Pharmacol Rev. 58:194–243. 2006. View Article : Google Scholar : PubMed/NCBI
20	Maclean PS, Bergouignan A, Cornier MA and Jackman MR: Biology's response to dieting: the impetus for weight regain. Am J Physiol Regul Integr Comp Physiol. 301:R581–R600. 2011. View Article : Google Scholar : PubMed/NCBI
21	Jayadev S, Liu B, Bielawska AE, Lee JY, Nazaire F, Pushkareva MYu, Obeid LM and Hannun YA: Role for ceramide in cell cycle arrest. J Biol Chem. 270:2047–2052. 1995. View Article : Google Scholar : PubMed/NCBI
22	Howard MK, Burke LC, Mailhos C, Pizzey A, Gilbert CS, Lawson WD, Collins MK, Thomas NS and Latchman DS: Cell cycle arrest of proliferating neuronal cells by serum deprivation can result in either apoptosis or differentiation. J Neurochem. 60:1783–1791. 1993. View Article : Google Scholar : PubMed/NCBI
23	Bai J and Cederbaum AI: Cycloheximide protects HepG2 cells from serum withdrawal-induced apoptosis by decreasing p53 and phosphorylated p53 levels. J Pharmacol Exp Ther. 319:1435–1443. 2006. View Article : Google Scholar : PubMed/NCBI
24	Hengartner MO: The biochemistry of apoptosis. Nature. 407:770–776. 2000. View Article : Google Scholar : PubMed/NCBI
25	Samraj AK, Sohn D, Schulze-Osthoff K and Schmitz I: Loss of caspase-9 reveals its essential role for caspase-2 activation and mitochondrial membrane depolarization. Mol Biol Cell. 18:84–93. 2007. View Article : Google Scholar :
26	Li Y, Li Q, Wang Z, Liang D, Liang S, Tang X, Guo L, Zhang R and Zhu D: 15-HETE suppresses K(+) channel activity and inhibits apoptosis in pulmonary artery smooth muscle cells. Apoptosis. 14:42–51. 2009. View Article : Google Scholar
27	Wang Z, Tang X, Li Y, Leu C, Guo L, Zheng X and Zhu D: 20-Hydroxyeicosatetraenoic acid inhibits the apoptotic responses in pulmonary artery smooth muscle cells. Eur J Pharmacol. 588:9–17. 2008. View Article : Google Scholar : PubMed/NCBI