Skip to main content
×
Home
    • Aa
    • Aa

Zinc, pancreatic islet cell function and diabetes: new insights into an old story

  • Fabrice Chimienti (a1)
Abstract

Zn is an essential trace element, involved in many different cellular processes. A relationship between Zn, pancreatic function and diabetes was suggested almost 70 years ago. To emphasise the importance of Zn in biology, the history of Zn research in the field of diabetes along with a general description of Zn transporter families will be reviewed. The paper will then focus on the effects of Zn on pancreatic β-cell function, including insulin synthesis and secretion, Zn signalling in the pancreatic islet, the redox functions of Zn and its target genes. The recent association of two ‘Zn genes’, i.e. metallothionein (MT) and Zn transporter 8 (SLC 30A8), with type 2 diabetes at the genetic level and with insulin secretion in clinical studies offers a potential new way to identify new drug targets to modulate Zn homeostasis directly in β-cells. The action of Zn for insulin action in its target organs, as Zn signalling in other pancreatic islet cells, will be addressed. Therapeutic Zn–insulin preparations and the influence of Zn and Zn transporters in type 1 diabetes will also be discussed. An extensive review of the literature on the clinical studies using Zn supplementation in the prevention and treatment of both types of diabetes, including complications of the disease, will evaluate the overall beneficial effects of Zn supplementation on blood glucose control, suggesting that Zn might be a candidate ion for diabetes prevention and therapy. Clearly, the story of the links between Zn, pancreatic islet cells and diabetes is only now unfolding, and we are presently only at the first chapter.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Zinc, pancreatic islet cell function and diabetes: new insights into an old story
      Available formats
      ×
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Zinc, pancreatic islet cell function and diabetes: new insights into an old story
      Available formats
      ×
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Zinc, pancreatic islet cell function and diabetes: new insights into an old story
      Available formats
      ×
Copyright
Corresponding author
Corresponding author: Dr Fabrice Chimienti, email f.chimienti@mellitech.com
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

2 JJ Abel (1926) Crystalline insulin. Proc Natl Acad Sci U S A 12, 132136.

5 DA Scott & AM Fisher (1938) The insulin and the zinc content of normal and diabetic pancreas. J Clin Invest 17, 725728.

7 H Brown , F Sanger & R Kitai (1955) The structure of pig and sheep insulins. Biochem J 60, 556565.

8 MJ Adams , TL Blundell , GG Dodson , et al. (1969) Structure of rhombohedral 2 zinc insulin crystals. Nature 224, 491495.

12 RH Becker & AD Frick (2008) Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet 47, 720.

19 PD Zalewski , SH Millard , IJ Forbes , et al. (1994) Video image analysis of labile zinc in viable pancreatic islet cells using a specific fluorescent probe for zinc. J Histochem Cytochem 42, 877884.

22 RD Palmiter , TB Cole , CJ Quaife , et al. (1996) ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci U S A 93, 1493414939.

25 SC Burdette , GK Walkup , B Spingler , et al. (2001) Fluorescent sensors for Zn2+ based on a fluorescein platform: synthesis, properties and intracellular distribution. J Am Chem Soc 123, 78317841.

26 LA Lichten & RJ Cousins (2009) Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr 29, 153176.

31 O Beharier , S Dror , S Levy , et al. (2012) ZnT-1 protects HL-1 cells from simulated ischemia–reperfusion through activation of Ras-ERK signaling. J Mol Med (Berl) 90, 127138.

33 U Kiechl-Kohlendorfer , FM Fink & E Steichen-Gersdorf (2007) Transient symptomatic Zn deficiency in a breast-fed preterm infant. Pediatr Dermatol 24, 536540.

35 R Sladek , G Rocheleau , J Rung , et al. (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881885.

36 T Kambe (2011) An overview of a wide range of functions of ZnT and Zip zinc transporters in the secretory pathway. Biosci Biotechnol Biochem 75, 10361043.

38 MC Foster , RD Leapman , MX Li , et al. (1993) Elemental composition of secretory granules in pancreatic islets of Langerhans. Biophys J 64, 525532.

40 MF Dunn (2005) Zinc–ligand interactions modulate assembly and stability of the insulin hexamer – a review. Biometals 18, 295303.

43 K Smidt , J Rungby , et al. (2012) ZnT3: a zinc transporter active in several organs. Biometals 25, 18.

44 K Smidt , N Jessen , AB Petersen , et al. (2009) SLC30A3 responds to glucose- and zinc variations in β-cells and is critical for insulin production and in vivo glucose-metabolism during β-cell stress. PLoS One 4, e5684.

46 F Chimienti , S Devergnas , A Favier , et al. (2004) Identification and cloning of a β-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 53, 23302337.

47 K Smidt , SB Pedersen , B Brock , et al. (2007) Zn-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese. Mol Cell Endocrinol 264, 6873.

48 C Murgia , C Devirgiliis , E Mancini , et al. (2009) Diabetes-linked zinc transporter ZnT8 is a homodimeric protein expressed by distinct rodent endocrine cell types in the pancreas and other glands. Nutr Metab Cardiovasc Dis 19, 431439.

49 F Chimienti , S Devergnas , F Pattou , et al. (2006) In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J Cell Sci 119, 41994206.

51 TJ Nicolson , EA Bellomo , N Wijesekara , et al. (2009) Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58, 20702083.

52 J Dupuis , C Langenberg , I Prokopenko , et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42, 105116.

53 V Steinthorsdottir , G Thorleifsson , I Reynisdottir , et al. (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39, 770775.

54 H Staiger , F Machicao , N Stefan , et al. (2007) Polymorphisms within novel risk loci for type 2 diabetes determine β-cell function. PLoS ONE 2, e832.

55 ES Kang , MS Kim , YS Kim , et al. (2008) A polymorphism in the zinc transporter gene SLC30A8 confers resistance against posttransplantation diabetes mellitus in renal allograft recipients. Diabetes 57, 10431047.

56 G Pare , DI Chasman , AN Parker , et al. (2008) Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women's Genome Health Study. PLoS Genet 4, e1000312.

59 LD Pound , S Sarkar , RK Benninger , et al. (2009) Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem J 421, 371376.

60 N Wijesekara , FF Dai , AB Hardy , et al. (2010) Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53, 16561668.

61 Y Fu , W Tian , EB Pratt , et al. (2009) Down-regulation of ZnT8 expression in INS-1 rat pancreatic beta cells reduces insulin content and glucose-inducible insulin secretion. PLoS ONE 4, e5679.

63 MS Islam & T du Loots (2007) Diabetes, metallothionein, and zinc interactions: a review. Biofactors 29, 203212.

65 M Levadoux , C Mahon , JH Beattie , et al. (1999) Nuclear import of metallothionein requires its mRNA to be associated with the perinuclear cytoskeleton. J Biol Chem 274, 3496134966.

66 H Chen , EC Carlson , L Pellet , et al. (2001) Overexpression of metallothionein in pancreatic β-cells reduces streptozotocin-induced DNA damage and diabetes. Diabetes 50, 20402046.

68 W Maret & BL Vallee (1998) Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc Natl Acad Sci U S A 95, 34783482.

69 MS Stitt , KJ Wasserloos , X Tang , et al. (2006) Nitric oxide-induced nuclear translocation of the metal responsive transcription factor, MTF-1 is mediated by zinc release from metallothionein. Vascul Pharmacol 44, 149155.

71 R Giacconi , C Cipriano , E Muti , et al. (2005) Novel –209A/G MT2A polymorphism in old patients with type 2 diabetes and atherosclerosis: relationship with inflammation (IL-6) and zinc. Biogerontology 6, 407413.

73 M Seve , F Chimienti & A Favier (2002) Role of intracellular zinc in programmed cell death. Pathol Biol (Paris) 50, 212221.

74 JW Baynes (1991) Role of oxidative stress in development of complications in diabetes. Diabetes 40, 405412.

78 H Haase & L Rink (2009) Functional significance of zinc-related signaling pathways in immune cells. Annu Rev Nutr 29, 133152.

83 J Kerr-Conte , B Vandewalle , E Moerman , et al. (2010) Upgrading pretransplant human islet culture technology requires human serum combined with media renewal. Transplantation 89, 11541160.

85 L Coulston & P Dandona (1980) Insulin-like effect of zinc on adipocytes. Diabetes 29, 665667.

87 Y Yoshikawa , Y Adachi , H Yasui , et al. (2011) Oral administration of Bis(aspirinato)zinc(II) complex ameliorates hyperglycemia and metabolic syndrome-like disorders in spontaneously diabetic KK-Ay mice: structure–activity relationship on zinc–salicylate complexes. Chem Pharm Bull (Tokyo) 59, 972977.

88 Y Adachi , J Yoshida , Y Kodera , et al. (2006) Oral administration of a zinc complex improves type 2 diabetes and metabolic syndromes. Biochem Biophys Res Commun 351, 165170.

89 AR Cameron , S Anil , E Sutherland , et al. (2010) Zinc-dependent effects of small molecules on the insulin-sensitive transcription factor FOXO1a and gluconeogenic genes. Metallomics 2, 195203.

92 H Haase , W Maret , et al. (2005) Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. Biometals 18, 333338.

94 AV Gyulkhandanyan , SC Lee , G Bikopoulos , et al. (2006) The Zn2+-transporting pathways in pancreatic β-cells: a role for the L-type voltage-gated Ca2+ channel. J Biol Chem 281, 93619372.

95 J Gromada , I Franklin & CB Wollheim (2007) α-Cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28, 84116.

98 I Franklin , J Gromada , A Gjinovci , et al. (2005) β-Cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes 54, 18081815.

99 MA Ravier & GA Rutter (2005) Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic α-cells. Diabetes 54, 17891797.

103 KC de Sena , RF Arrais , M das Gracas Almeida , et al. (2005) Effects of Zn supplementation in patients with type 1 diabetes. Biol Trace Elem Res 105, 19.

104 J Jansen , E Rosenkranz , S Overbeck , et al. (2012) Disturbed zinc homeostasis in diabetic patients by in vitro and in vivo analysis of insulinomimetic activity of zinc. J Nutr Biochem 23, 14581466.

109 CB Niewoehner , JI Allen , M Boosalis , et al. (1986) Role of zinc supplementation in type II diabetes mellitus. Am J Med 81, 6368.

111 SM Hegazi , SS Ahmed , AA Mekkawy , et al. (1992) Effect of zinc supplementation on serum glucose, insulin, glucagon, glucose-6-phosphatase and mineral levels in diabetics. J Clin Biochem Nutr 12, 209215.

119 RA Anderson , AM Roussel , N Zouari , et al. (2001) Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus. J Am Coll Nutr 20, 212218.

121 JJ Garcia-Medina , MD Pinazo-Duran , M Garcia-Medina , et al. (2011) A 5-year follow-up of antioxidant supplementation in type 2 diabetic retinopathy. Eur J Ophthalmol 21, 637643.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Nutrition Research Reviews
  • ISSN: 0954-4224
  • EISSN: 1475-2700
  • URL: /core/journals/nutrition-research-reviews
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords:

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 43
Total number of PDF views: 178 *
Loading metrics...

Abstract views

Total abstract views: 333 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 23rd June 2017. This data will be updated every 24 hours.