Diabetology International

, Volume 7, Issue 2, pp 106–110 | Cite as

Is zinc an intra-islet regulator of glucagon secretion?

  • Hisamitsu IshiharaEmail author
  • Claes B. Wollheim
Review Article


More than a decade ago, zinc was suggested to have a role as an intra-islet regulator of glucagon secretion. Several lines of experimental evidence have since provided support for this hypothesis, though contradictory observations have also been reported. Meanwhile, Slc30A/ZnT8, a zinc transporter expressed in insulin and glucagon secretory granules, was identified. Furthermore, genome wide association analyses revealed it to be a candidate causative gene for type 2 diabetes mellitus. Recent progress in gene manipulation in animals yielded considerable information on the role of zinc in islet cells. In this mini-review, data pertaining the roles played by zinc in islet hormone secretion are summarized and discussed.


Glucagon Insulin Zinc Slc30A8/ZnT8 α-cells 


Compliance with ethical standards

Conflict of interest

Authors have nothing to declare related to this review.

Ethical standards

This article dose not contain any studies with human or animal subjects performed by any of the authors.


  1. 1.
    Gromada J, Franklin I, Wollheim CB. α-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocrine Rev. 2007;28:84–116.CrossRefGoogle Scholar
  2. 2.
    Gylfe E, Gilon P. Glucose regulation of glucagon secretion. Diab Res Clin Prac. 2014;103:1–10.CrossRefGoogle Scholar
  3. 3.
    Ishihara H, Maechler P, Gjinovci A, Herrera PL, Wollheim CB. Islet β-cell secretion determines glucagon release from neighbouring α-cells. Nature Cell Biol. 2003;5:330–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Marliss EB, Wollheim CB, Blondel B, Orci L, Lambert AE, Stauffacher W, Like AA, Renold AE. Insulin and glucagon release from monolayer cell cultures of pancreas from newborn rats. Eur J Clin Invest. 1973;3:16–26.CrossRefPubMedGoogle Scholar
  5. 5.
    Leclercq-Meyer V, Marchand J, Malaisse WJ. An arginine-like effect of the “fumalate + glutamate + pyruvate” mixture on glucagon release. Life Sci. 1977;20:1193–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Takahashi R, Ishihara H, Tamura A, Yamaguchi S, Yamada T, Takei D, Katagiri H, Endou H, Oka Y. Cell type specific activation of metabolism reveals that β-cell secretion suppresses glucagon release from α-cells in rat pancreatic islets. Am J Physiol. Endocrinol Metab. 2006;290:E308–16.CrossRefPubMedGoogle Scholar
  7. 7.
    Ishihara H, Wang H, Drewes LR, Wollheim CB. Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in β cells. J. Clin. Invest. 1999;104:1621–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Pullen TJ, Sylow L, Sun G, Halestrap AP, Richter EA, Rutter GA. Overexpression of monocarboxylate transporter-1 (Slc16A1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise. Diabetes. 2012;61:1719–25.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ravier MA, Rutter GA. Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic and α-cells. Diabetes. 2005;54:1789–97.CrossRefPubMedGoogle Scholar
  10. 10.
    Quoix N, Cheng-Xue R, Mattart L, Zeinoun Z, Guiot Y, Beauvois MC, Henquin JC, Gilon P. Glucose and pharmacological modulators of ATP-sensitive K channels control [Ca2+]c by different mechanisms in isolated mouse β-cells. Diabetes. 2009;58:412–21.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ramracheya R, Ward C, Shigeto M, Walker JN, Amisten S, Zhang Q, Johnson PR, Rorsman P, Braun M. Membrane potential-dependent inactivation of voltage-gated ion channels in & α-cells inhibits glucagon secretion from human islets. Diabetes. 2010;59:2198–208.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Franklin I, Gromada J, Gjinovci A, Theander S, Wollheim CB. β-cell secretory products activate and β-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes. 2005;54:1808–15.CrossRefPubMedGoogle Scholar
  13. 13.
    Le Marchand SJ, Piston DW. Glucose suppression of glucagon secretion: metabolic and calcium responses from & #x03B1;-cells in intact mouse pancreatic islets. J Biol Chem. 2010;285:14389–98.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chimienti F. Zinc, pancreatic islet cell function and diabetes: new insights into an old story. Nutri Resear Rev. 2013;26:1–11.CrossRefGoogle Scholar
  15. 15.
    Fadista J, Vikman P, Laakso EO, Mollet IG, Esguerra JL, et al. Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism. Proc Natl Acad Sci USA. 2014;111:13924–9.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, et al. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet. 2014;46:357–63.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gyulkhandanyan AV, Lu H, Lee SC, Bhattachajee A, Wijesekara N, Manning Fox JE, MacDonald PE, Chimienti F Dai FF, Wheeler MB. Investigation of transport mechanisms and regulation of intracellular Zn2+ in pancreatic α-cells. Regulation of glucagon secretion by zinc: lessons from the β cell-specific Znt8 knockout mouse model. J Biol Chem. 2008;283:10184–97.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhou H, Zhang T, Harmon JS, Bryan J, Robertson RP. Zinc, not insulin, regulates the rat α-cell response to hypoglycemia in vivo. Diabetes. 2007;56:1107–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Bancila V, Cens T, Monnier D, Chanson F, Faure C, Durant Y, Bloc A. Two SUR-1 specific histidine residues mandatory for zinc-induced activation of the rat KATP channel. J Biol Chem. 2005;280:8793–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Drobinskaya I, Neumaier F, Perverzev A, Hescheler J, Schneider T. Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion. Biochem Biophys Acta. 2015;1853:953–64.CrossRefPubMedGoogle Scholar
  21. 21.
    Hardy AB, Serino AS, Wijesekara N, Chimienti F, Wheeler MB. Regulation of glucagon secretion by zinc: lessons from the β cell-specific Znt8 knockout mouse model. Diab Obes Metab. 2011;13(Suppl. 1):112–7.CrossRefGoogle Scholar
  22. 22.
    Kawamori D, Kurpad AJ, Hu J, Liew CW, Shih JL, Ford EL, Herrera PL, Polonsky KS, McGuinness OP, Kulkarni RN. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metab. 2009;9:350–61.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Pound LD, Sarkar SA, Benninger RK, Wang Y, Suwanichkul A, et al. Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem J. 2009;421:371–6.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Nicolson TJ, Bellomo EA, Wijesekara N, Loder MK, Baldwin JM, et al. Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes. 2009;58:2070–83.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lemaire K, Ravier MA, Schraenen A, Creemers JW, Van de Plas R, et al. Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc Natl Acad Sci USA. 2009;106:14872–7.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Wijesekara N, Dai FF, Hardy AB, Giglou PR, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano HY, Rutter GA, Wheeler MB. Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia. 2010;53:1656–68.CrossRefPubMedGoogle Scholar
  27. 27.
    Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, et al. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest. 2013;123:4513–24.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Mitchell RK, Hu M, Chabosseau PL, Cane MC, Meur G, Bellomo EA, Carzaniga R, Collinson LM, Li WH, Hodson DJ, Rutter GA. Molecular Genetic regulation of Slc30a8/ZnT8 reveals a positive association with glucose tolerance. Mol Endocrinol. 2016;30:77–91.CrossRefPubMedGoogle Scholar
  29. 29.
    Solomou A, Meur G, Hodson DJ, Tomas A, Li SM, Philippe E, Herrera PL, Magnan C, Rutter GA. The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic α-cells for hypoglycemia-induced glucagon secretion. J Biol Chem. 2015;290:21432–42.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japan Diabetes Society 2016

Authors and Affiliations

  1. 1.Division of Diabetes and MetabolismNihon University School of MedicineItabashiJapan
  2. 2.Department of Cell Physiology and MetabolismUniversity Medical CentreGeneva 4Switzerland

Personalised recommendations