Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants.

Tamara Nicolson; Elisa Bellomo; Nadeeja Wijesekara; Merewyn Loder; Jocelyn Baldwin; Armen Gyulkhandanyan; Vasilij Koshkin; Andrei Tarasov; Raffaella Carzaniga; Katrin Kronenberger; Tarvinder Taneja; Gabriela da Silva Xavier; Sarah Libert; Philippe Froguel; Raphael Scharfmann; Volodymir Stetsyuk; Philippe Ravassard; Helen Parker; Fiona Gribble; Frank Reimann; Robert Sladek; Stephen Hughes; Paul Johnson; Myriam Masseboeuf; Remy Burcelin; Stephen Baldwin; Ming Liu; Roberto Lara-Lemus; Peter Arvan; Frans Schuit; Michael Wheeler; Fabrice Chimienti; Guy Rutter

doi:10.2337/db09-0551

Journal articles

Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants.

Tamara Nicolson ¹ Elisa Bellomo ¹ Nadeeja Wijesekara ² Merewyn Loder ¹ Jocelyn Baldwin ³ Armen Gyulkhandanyan ² Vasilij Koshkin ² Andrei Tarasov ¹ Raffaella Carzaniga ⁴ Katrin Kronenberger ⁴ Tarvinder Taneja ¹ Gabriela da Silva Xavier ¹ Sarah Libert ⁵ Philippe Froguel ^{6, 7} Raphael Scharfmann ⁸ Volodymir Stetsyuk ⁸ Philippe Ravassard ⁹ Helen Parker ¹⁰ Fiona Gribble ¹⁰ Frank Reimann ¹⁰ Robert Sladek ¹¹ Stephen Hughes ¹² Paul Johnson ¹² Myriam Masseboeuf ¹³ Remy Burcelin ¹³ Stephen Baldwin ³ Ming Liu ¹⁴ Roberto Lara-Lemus ¹⁴ Peter Arvan ¹⁴ Frans Schuit ¹⁵ Michael Wheeler ³ Fabrice Chimienti ⁶ Guy Rutter ^{1, *}

* Corresponding author

1 Section of Cell Biology, Division of Medicine

2 Department of Physiology

3 Institute of Membrane and Systems Biology

4 Electron Microscopy Centre

5 Mellitech

6 Section of Genomic Medicine

7 IBL - Institut de biologie de Lille - UMS 3702

8 UMR_S 845 - Centre de recherche Croissance et signalisation

9 LGMNPN - Génétique moléculaire de la neurotransmission et des processus neurodégénératifs

10 CIMR - Cambridge Institute for Medical Research

11 Department of Human Genetics [Montréal]

12 Nuffield Department of Surgery

13 I2MR - Institut de médecine moléculaire de Rangueil

14 Division of Metabolism, Endocrinology & Diabetes

15 Gene Expression Unit

Abstract : Objective. Zinc ions are essential for the formation of hexameric insulin and hormone crystallisation. Correspondingly, a non-synonymous single nucleotide polymorphism rs13266634 in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8, is associated with type 2 diabetes. Here, we describe the effects of deleting the ZnT8 gene in mice and explore the action of the at-risk allele. Research Design and Methods. Slc30a8 null mice were generated and backcrossed at least twice onto a C57BL/6J background. Glucose and insulin tolerance were measured by intraperitoneal injection, or euglycemic clamp, respectively. Insulin secretion, electrophysiology, imaging, and the generation of adenoviruses encoding the low- (W325) or elevated- (R325) risk ZnT8 alleles, were undertaken using standard protocols. Results. ZnT8(-/-) mice displayed age, sex and diet-dependent abnormalities in glucose tolerance, insulin secretion and body weight. Islets isolated from null mice had reduced granule zinc content, and showed age-dependent changes in granule morphology, with markedly fewer dense cores but more rod-like crystals. Glucose-stimulated insulin secretion, granule fusion and insulin crystal dissolution, as assessed by total internal reflection fluorescence microscopy, were unchanged or enhanced in ZnT8(-/-) islets. Insulin processing was normal. Molecular modelling revealed that residue-325 was located at the interface between ZnT8 monomers. Correspondingly, the R325 variant displayed lower apparent Zn(2+) transport activity than W325 ZnT8 by fluorescence-based assay. Discussion and conclusions. ZnT8 is required for normal insulin crystallisation and insulin release in vivo but not, remarkably, in vitro. Defects in the former processes in carriers of the R allele may increase type 2 diabetes risk.

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Journal articles

Domain :

Life Sciences [q-bio] / Cancer

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https://www.hal.inserm.fr/inserm-00410150
Contributor : Marie Francoise Simon <>
Submitted on : Tuesday, August 18, 2009 - 10:48:12 AM
Last modification on : Saturday, December 12, 2020 - 3:16:12 AM

Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants.

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Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants.

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