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

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.

Key words： zinc; zinc transporter; pancreatic islets; β-cells; insulin secretion

References

1 Arya A, Looi CY, Cheah SC, Mustafa MR, Mohd MA (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

2 Ashcroft FM, Rorsman P (2012) Diabetes mellitus and the beta cell: the last ten years. Cell 148:1160–1171

3 Bhat A, Koul A, Rai E, Sharma S, Dhar MK, Bamezai RN (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

4 Chand S, McKnight AJ, Shabir S, Chan W, McCaughan JA, Maxwell AP, Harper L, Borrows R (2016) Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation. BBA Clin 5:41–45

5 Chimienti F (2013) Zinc, pancreatic islet cell function and diabetes: new insights into an old story. Nutr Res Rev 26:1–11

6 Cruz M, Valladares-Salgado A, Garcia-Mena J, Ross K, Edwards M, Angeles-Martinez J, Ortega-Camarillo C, de la Pena JE, Burguete-Garcia AI, Wacher-Rodarte N (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

7 Dong Y, Guo T, Traurig M, Mason CC, Kobes S, Perez J, Knowler WC, Bogardus C, Hanson RL, Baier LJ (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

8 Fellmann L, Nascimento AR, Tibirica E, Bousquet P (2013) Murine models for pharmacological studies of the metabolic syndrome. Pharmacol Ther 137:331–340

9 Franklin I, Gromada J, Gjinovci A, Theander S, Wollheim CB (2005) Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes 54:1808–1815

10 Geiser J, De Lisle RC, Andrews GK (2013) The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity. PLoS ONE 8:e82149

11 Gotoh M, Maki T, Kiyoizumi T, Satomi S, Monaco AP (1985) An improved method for isolation of mouse pancreatic islets. Transplantation 40:437–438

12 Gray JP, Eisen T, Cline GW, Smith PJ, Heart E (2011) Plasma membrane electron transport in pancreatic beta-cells is mediated in part by NQO1. Am J Physiol Endocrinol Metab 301:E113–E121

13 Gyulkhandanyan AV, Lee SC, Bikopoulos G, Dai F, Wheeler MB (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

14 Hansen JB, Tonnesen MF, Madsen AN, Hagedorn PH, Friberg J, Grunnet LG, Heller RS, Nielsen AO, Storling J, Baeyens L (2012) Divalent metal transporter 1 regulates iron-mediated ROS and pancreatic beta cell fate in response to cytokines. Cell Metab 16:449–461

15 Hardy AB, Prentice KJ, Froese S, Liu Y, Andrews GK, Wheeler MB (2015) Zip4 mediated zinc influx stimulates insulin secretion in pancreatic beta cells. PLoS ONE 10:e0119136

16 Huang L, Tepaamorndech S (2013) The SLC30 family of zinc transporters- a review of current understanding of their biological and pathophysiological roles. Mol Aspects Med 34:548–560

17 Huang L, Yan M, Kirschke CP (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

18 Hummel KP, Dickie MM, Coleman DL (1966) Diabetes, a new mutation in the mouse. Science 153:1127–1128

19 Ingalls AM, Dickie MM, Snell GD (1950) Obese, a new mutation in the house mouse. J Hered 41:317–318

20 Jeong J, Eide DJ (2013) The SLC39 family of zinc transporters. Mol Aspects Med 34:612–619

21 Li L, Bai S, Sheline CT (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

22 Li YV (2014) Zinc and insulin in pancreatic beta-cells. Endocrine 45:178–189

23 Lin S, Thomas TC, Storlien LH, Huang XF (2000) Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes Relat Metab Disord 24:639–646

24 Ling C, Del Guerra S, Lupi R, Ronn T, Granhall C, Luthman H, Masiello P, Marchetti P, Groop L, Del Prato S (2008) Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51:615–622

25 Liu Y, Batchuluun B, Ho L, Zhu D, Prentice KJ, Bhattacharjee A, Zhang M, Pourasgari F, Hardy AB, Taylor KM (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

26 Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD, Magnuson MA (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

27 Pound LD, Sarkar SA, Benninger RK, Wang Y, Suwanichkul A, Shadoan MK, Printz RL, Oeser JK, Lee CE, Piston DW (2009) Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem J 421:371–376

28 Rutter GA, Chabosseau P, Bellomo EA, Maret W, Mitchell RK, Hodson DJ, Solomou A, Hu M (2016) Intracellular zinc in insulin secretion and action: a determinant of diabetes risk? Proc Nutr Soc 75:61–72

29 Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336

30 Schwenk F, Baron U, Rajewsky K (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

31 Scott DA, Fisher AM (1938) The insulin and the zinc content of normal and diabetic pancreas. J Clin Investig 17:725–728

32 Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885

33 Sondergaard LG, Stoltenberg M, Doering P, Flyvbjerg A, Rungby J (2006) Zinc ions in the endocrine and exocrine pancreas of zinc deficient rats. Histol Histopathol 21:619–625

34 Tang X, Shay NF (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

35 Wang F, Kim BE, Petris MJ, Eide DJ (2004) The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. J Biol Chem 279:51433–51441

36 Wang X, Lei XG, Wang J (2014a) Malondialdehyde regulates glucose-stimulated insulin secretion in murine islets via TCF7L2-dependent Wnt signaling pathway. Mol Cell Endocrinol 382:8–16

37 Wang X, Vatamaniuk MZ, Roneker CA, Pepper MP, Hu LG, Simmons RA, Lei XG (2011) Knockouts of SOD1 and GPX1 exert different impacts on murine islet function and pancreatic integrity. Antioxid Redox Signal 14:391–401

38 Wang X, Yun JW, Lei XG (2014b) Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets. Antioxid Redox Signal 20:191–203

39 Wang XD, Vatamaniuk MZ, Wang SK, Roneker CA, Simmons RA, Lei XG (2008) Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice. Diabetologia 51:1515–1524

40 Wijesekara N, Dai FF, Hardy AB, Giglou PR, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano HY, Rutter GA, Wheeler MB (2010) Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53:1656–1668

41 Yang Y, Mo X, Chen S, Lu X, Gu D (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