Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice.
Zinc co-crystallizes with insulin in dense core secretory granules, but its role in insulin biosynthesis, storage and secretion is unknown. In this study we assessed the role of the zinc transporter ZnT8 using ZnT8-knockout (ZnT8(-/-)) mice. Absence of ZnT8 expression caused loss of zinc release upon stimulation of exocytosis, but normal rates of insulin biosynthesis, normal insulin content and preserved glucose-induced insulin release. Ultrastructurally, mature dense core insulin granules were rare in ZnT8(-/-) beta cells and were replaced by immature, pale insulin "progranules," which were larger than in ZnT8(+/+) islets. When mice were fed a control diet, glucose tolerance and insulin sensitivity were normal. However, after high-fat diet feeding, the ZnT8(-/-) mice became glucose intolerant or diabetic, and islets became less responsive to glucose. Our data show that the ZnT8 transporter is essential for the formation of insulin crystals in beta cells, contributing to the packaging efficiency of stored insulin. Interaction between the ZnT8(-/-) genotype and diet to induce diabetes is a model for further studies of the mechanism of disease of human ZNT8 gene mutations.
Lemaire
K
K
Gene Expression Unit, Department Molecular Cell Biology, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium.
Ravier
M A
MA
Schraenen
A
A
Creemers
J W M
JW
Van de Plas
R
R
Granvik
M
M
Van Lommel
L
L
Waelkens
E
E
Chimienti
F
F
Rutter
G A
GA
Gilon
P
P
in't Veld
P A
PA
Schuit
F C
FC
D000818:Animals; D002118:Calcium / Q000378:metabolism; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003460:Crystallization; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D018149:Glucose Intolerance / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D015032:Zinc / Q000378:metabolism; D000075703:Zinc Transporter 8
D027682:Cation Transport Proteins; D007328:Insulin; C516348:Slc30a8 protein, mouse; D000075703:Zinc Transporter 8; D005947:Glucose; D015032:Zinc; D002118:Calcium
Proc Natl Acad Sci U S A. 1988 Dec;85(23):8943-7
3057496
J Clin Invest. 1992 Jan;89(1):117-25
1729264
Anal Chem. 1999 Dec 1;71(23):5263-70
10596208
Science. 2007 Jun 1;316(5829):1331-6
17463246
Diabetes. 2002 Nov;51(11):3245-53
12401716
Anal Chem. 2003 Jul 15;75(14):3468-75
14570199
Nature. 2007 Feb 22;445(7130):881-5
17293876
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17040-5
17942684
J Physiol. 2000 Dec 15;529 Pt 3:723-34
11118501
Annu Rev Nutr. 2004;24:151-72
15189117
Anal Biochem. 1996 Apr 5;236(1):173-5
8619485
Cell. 1985 Sep;42(2):671-81
3896518
Mol Med. 2007 Jul-Aug;13(7-8):337-43
17622322
Science. 2007 Jun 1;316(5829):1341-5
17463248
Nature. 1998 Jul 9;394(6689):192-5
9671304
Biometals. 2005 Aug;18(4):313-7
16158222
J Biol Chem. 2005 Mar 11;280(10):8793-9
15613469
J Biol Chem. 1995 Sep 1;270(35):20417-23
7657617
Nat Rev Neurosci. 2005 Jun;6(6):449-62
15891778
Am J Med. 1966 May;40(5):662-6
5949593
Diabetes. 1999 Dec;48(12):2374-82
10580426
Transplantation. 1988 Apr;45(4):827-30
2451869
Nat Med. 2005 Jul;11(7):757-64
15980866
Transplantation. 2008 Dec 15;86(11):1603-9
19077896
Diabetes. 1957 Jul-Aug;6(4):335-41
13447763
Biochem J. 2009 Jul 15;421(3):371-6
19450229
Biochem Soc Trans. 2008 Oct;36(Pt 5):909-15
18793160
Nat Cell Biol. 2003 Apr;5(4):330-5
12640462
Biophys J. 2004 Dec;87(6):L03-5
15516519
Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12319-24
18713856
Diabetes. 2004 Sep;53(9):2330-7
15331542
Diabetologia. 1980 Sep;19(3):174-82
6997118
Semin Cell Dev Biol. 1998 Feb;9(1):3-10
9572108
Diabetes. 2008 Oct;57(10):2693-7
18591387
Curr Opin Struct Biol. 1998 Apr;8(2):189-94
9631292
Science. 2007 Jun 1;316(5829):1336-41
17463249