The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2

doi:10.1007/s13238-018-0580-1

Protein Cell

2019, Vol. 10

Issue (6) : 436-449 https://doi.org/10.1007/s13238-018-0580-1

RESEARCH ARTICLE

The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2

Xinhui Wang¹, Hong Gao¹, Wenhui Wu¹, Enjun Xie¹, Yingying Yu¹, Xuyan He¹, Jin Li¹, Wanru Zheng¹, Xudong Wang¹, Xizhi Cao², Zhuoxian Meng³, Ligong Chen²(

), Junxia Min¹(

), Fudi Wang¹(

)

¹. School of Public Health, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
². School of Pharmaceutical Sciences, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
³. Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China

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Abstract

Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover, β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.

Keywords zinc zinc transporter pancreatic islets β-cells insulin secretion

Corresponding Author(s): Ligong Chen,Junxia Min,Fudi Wang

Issue Date: 19 June 2019

Cite this article:

Xinhui Wang,Hong Gao,Wenhui Wu, et al. The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2[J]. Protein Cell, 2019, 10(6): 436-449.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-018-0580-1
https://academic.hep.com.cn/pac/EN/Y2019/V10/I6/436

1	A Arya, CY Looi, SC Cheah, MR Mustafa, MA Mohd (2012) Antidiabetic effects of Centratherum anthelminticumseeds methanolic fraction on pancreatic cells, beta-TC6 and its alleviating role in type 2 diabetic rats. J Ethnopharmacol 144:22–32 https://doi.org/10.1016/j.jep.2012.08.014
2	FM Ashcroft, P Rorsman (2012) Diabetes mellitus and the beta cell: the last ten years. Cell 148:1160–1171 https://doi.org/10.1016/j.cell.2012.02.010
3	A Bhat, A Koul, E Rai, S Sharma, MK Dhar, RN Bamezai (2007) PGC-1alpha Thr394Thr and Gly482Ser variants are significantly associated with T2DM in two North Indian populations: a replicate case-control study. Hum Genet 121:609–614 https://doi.org/10.1007/s00439-007-0352-0
4	S Chand, AJ McKnight, S Shabir, W Chan, JA McCaughan, AP Maxwell, L Harper, R Borrows (2016) Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation. BBA Clin 5:41–45 https://doi.org/10.1016/j.bbacli.2015.12.004
5	F Chimienti (2013) Zinc, pancreatic islet cell function and diabetes: new insights into an old story. Nutr Res Rev 26:1–11 https://doi.org/10.1017/S0954422412000212
6	M Cruz, A Valladares-Salgado, J Garcia-Mena, K Ross, M Edwards, J Angeles-Martinez, C Ortega-Camarillo, JE de la Pena, AI Burguete-Garcia, N Wacher-Rodarteet al. (2010) Candidate gene association study conditioning on individual ancestry in patients with type 2 diabetes and metabolic syndrome from Mexico City. Diabetes Metab Res Rev 26:261–270 https://doi.org/10.1002/dmrr.1082
7	Y Dong, T Guo, M Traurig, CC Mason, S Kobes, J Perez, WC Knowler, C Bogardus, RL Hanson, LJ Baier (2011) SIRT1 is associated with a decrease in acute insulin secretion and a sex specific increase in risk for type 2 diabetes in Pima Indians. Mol Genet Metab 104:661–665 https://doi.org/10.1016/j.ymgme.2011.08.001
8	L Fellmann, AR Nascimento, E Tibirica, P Bousquet (2013) Murine models for pharmacological studies of the metabolic syndrome. Pharmacol Ther 137:331–340 https://doi.org/10.1016/j.pharmthera.2012.11.004
9	I Franklin, J Gromada, A Gjinovci, S Theander, CB Wollheim (2005) Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes 54:1808–1815 https://doi.org/10.2337/diabetes.54.6.1808
10	J Geiser, RC De Lisle, GK Andrews (2013) The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. PLoS ONE 8:e82149 https://doi.org/10.1371/journal.pone.0082149
11	M Gotoh, T Maki, T Kiyoizumi, S Satomi, AP Monaco (1985) An improved method for isolation of mouse pancreatic islets. Transplantation 40:437–438 https://doi.org/10.1097/00007890-198510000-00018
12	JP Gray, T Eisen, GW Cline, PJ Smith, E Heart (2011) Plasma membrane electron transport in pancreatic beta-cells is mediated in part by NQO1. Am J Physiol Endocrinol Metab 301:E113–E121 https://doi.org/10.1152/ajpendo.00673.2010
13	AV Gyulkhandanyan, SC Lee, G Bikopoulos, F Dai, MB Wheeler (2006) The Zn2+-transporting pathways in pancreatic beta-cells: a role for the L-type voltage-gated Ca2+ channel. J Biol Chem 281:9361–9372 https://doi.org/10.1074/jbc.M508542200
14	JB Hansen, MF Tonnesen, AN Madsen, PH Hagedorn, J Friberg, LG Grunnet, RS Heller, AO Nielsen, J Storling, L Baeyenset al. (2012) Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic beta cell fate in response to cytokines. Cell Metab 16:449–461 https://doi.org/10.1016/j.cmet.2012.09.001
15	AB Hardy, KJ Prentice, S Froese, Y Liu, GK Andrews, MB Wheeler (2015) Zip4 mediated zinc influx stimulates insulin secretion in pancreatic beta cells. PLoS ONE 10:e0119136 https://doi.org/10.1371/journal.pone.0119136
16	L Huang, S Tepaamorndech (2013) The SLC30 family of zinc transporters- a review of current understanding of their biological and pathophysiological roles. Mol Aspects Med 34:548–560 https://doi.org/10.1016/j.mam.2012.05.008
17	L Huang, M Yan, CP Kirschke (2010) Over-expression of ZnT7 increases insulin synthesis and secretion in pancreatic beta-cells by promoting insulin gene transcription. Exp Cell Res 316:2630–2643 https://doi.org/10.1016/j.yexcr.2010.06.017
18	KP Hummel, MM Dickie, DL Coleman (1966) Diabetes, a new mutation in the mouse. Science 153:1127–1128 https://doi.org/10.1126/science.153.3740.1127
19	AM Ingalls, MM Dickie, GD Snell (1950) Obese, a new mutation in the house mouse. J Hered 41:317–318 https://doi.org/10.1093/oxfordjournals.jhered.a106073
20	J Jeong, DJ Eide (2013) The SLC39 family of zinc transporters. Mol Aspects Med 34:612–619 https://doi.org/10.1016/j.mam.2012.05.011
21	L Li, S Bai, CT Sheline (2017) hZnT8 (Slc30a8) transgenic mice that overexpress the R325W polymorph have reduced islet Zn2+ and proinsulin levels, increased glucose tolerance after a high-fat diet, and altered levels of pancreatic zinc binding proteins. Diabetes 66:551–559 https://doi.org/10.2337/db16-0323
22	YV Li (2014) Zinc and insulin in pancreatic beta-cells. Endocrine 45:178–189 https://doi.org/10.1007/s12020-013-0032-x
23	S Lin, TC Thomas, LH Storlien, XF Huang (2000) Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes Relat Metab Disord 24:639–646 https://doi.org/10.1038/sj.ijo.0801209
24	C Ling, S Del Guerra, R Lupi, T Ronn, C Granhall, H Luthman, P Masiello, P Marchetti, L Groop, S Del Prato (2008) Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51:615–622 https://doi.org/10.1007/s00125-007-0916-5
25	Y Liu, B Batchuluun, L Ho, D Zhu, KJ Prentice, A Bhattacharjee, M Zhang, F Pourasgari, AB Hardy, KM Tayloret al. (2015) Characterization of zinc influx transporters (ZIPs) in pancreatic beta cells: roles in regulating cytosolic zinc homeostasis and insulin secretion. J Biol Chem 290:18757–18769 https://doi.org/10.1074/jbc.M115.640524
26	C Postic, M Shiota, KD Niswender, TL Jetton, Y Chen, JM Moates, KD Shelton, J Lindner, AD Cherrington, MA Magnuson (1999) Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem 274:305–315 https://doi.org/10.1074/jbc.274.1.305
27	LD Pound, SA Sarkar, RK Benninger, Y Wang, A Suwanichkul, MK Shadoan, RL Printz, JK Oeser, CE Lee, DW Pistonet al. (2009) Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem J 421:371–376 https://doi.org/10.1042/BJ20090530
28	GA Rutter, P Chabosseau, EA Bellomo, W Maret, RK Mitchell, DJ Hodson, A Solomou, M Hu (2016) Intracellular zinc in insulin secretion and action: a determinant of diabetes risk? Proc Nutr Soc 75:61–72 https://doi.org/10.1017/S0029665115003237
29	R Saxena, BF Voight, V Lyssenko, NP Burtt, PI de Bakker, H Chen, JJ Roix, S Kathiresan, JN Hirschhorn, MJ Dalyet al. (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336 https://doi.org/10.1126/science.1142358
30	F Schwenk, U Baron, K Rajewsky (1995) A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res 23:5080–5081 https://doi.org/10.1093/nar/23.24.5080
31	DA Scott, AM Fisher (1938) The insulin and the zinc content of normal and diabetic pancreas. J Clin Investig 17:725–728 https://doi.org/10.1172/JCI101000
32	R Sladek, G Rocheleau, J Rung, C Dina, L Shen, D Serre, P Boutin, D Vincent, A Belisle, S Hadjadjet al. (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885 https://doi.org/10.1038/nature05616
33	LG Sondergaard, M Stoltenberg, P Doering, A Flyvbjerg, J Rungby (2006) Zinc ions in the endocrine and exocrine pancreas of zinc deficient rats. Histol Histopathol 21:619–625
34	X Tang, NF Shay (2001) Zinc has an insulin-like effect on glucose transport mediated by phosphoinositol-3-kinase and Akt in 3T3-L1 fibroblasts and adipocytes. J Nutr 131:1414–1420 https://doi.org/10.1093/jn/131.5.1414
35	F Wang, BE Kim, MJ Petris, DJ Eide (2004) The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. J Biol Chem 279:51433–51441 https://doi.org/10.1074/jbc.M408361200
36	X Wang, XG Lei, J Wang (2014a) Malondialdehyde regulates glucose-stimulated insulin secretion in murine islets via TCF7L2-dependent Wnt signaling pathway. Mol Cell Endocrinol 382:8–16 https://doi.org/10.1016/j.mce.2013.09.003
37	X Wang, MZ Vatamaniuk, CA Roneker, MP Pepper, LG Hu, RA Simmons, XG Lei (2011) Knockouts of SOD1 and GPX1 exert different impacts on murine islet function and pancreatic integrity. Antioxid Redox Signal 14:391–401 https://doi.org/10.1089/ars.2010.3302
38	X Wang, JW Yun, XG Lei (2014b) Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets. Antioxid Redox Signal 20:191–203 https://doi.org/10.1089/ars.2013.5361
39	XD Wang, MZ Vatamaniuk, SK Wang, CA Roneker, RA Simmons, XG Lei (2008) Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice. Diabetologia 51:1515–1524 https://doi.org/10.1007/s00125-008-1055-3
40	N Wijesekara, FF Dai, AB Hardy, PR Giglou, A Bhattacharjee, V Koshkin, F Chimienti, HY Gaisano, GA Rutter, MB Wheeler (2010) Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53:1656–1668 https://doi.org/10.1007/s00125-010-1733-9
41	Y Yang, X Mo, S Chen, X Lu, D Gu (2011) Association of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene polymorphisms and type 2 diabetes mellitus: a meta-analysis. Diabetes Metab Res Rev 27:177–184 https://doi.org/10.1002/dmrr.1158

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