Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion.
OBJECTIVE
Zinc is highly concentrated in pancreatic beta cells, is critical for normal insulin storage and may regulate glucagon secretion from alpha cells. Zinc transport family member 8 (ZnT8) is a zinc efflux transporter that is highly abundant in beta cells. Polymorphisms of ZnT8 (also known as SLC30A8) gene in man are associated with increased risk of type 2 diabetes. While global Znt8 knockout (Znt8KO) mice have been characterised, ZnT8 is also present in other islet cell types and extra-pancreatic tissues. Therefore, it is important to find ways of understanding the role of ZnT8 in beta and alpha cells without the difficulties caused by the confounding effects of ZnT8 in these other tissues.


METHODS
We generated mice with beta cell-specific (Znt8BKO) and alpha cell-specific (Znt8AKO) knockout of Znt8, and performed in vivo and in vitro characterisation of the phenotypes to determine the functional and anatomical impact of ZnT8 in these cells. Thus we assessed zinc accumulation, insulin granule morphology, insulin biosynthesis and secretion, and glucose homeostasis.


RESULTS
Znt8BKO mice are glucose-intolerant, have reduced beta cell zinc accumulation and atypical insulin granules. They also display reduced first-phase glucose-stimulated insulin secretion, reduced insulin processing enzyme transcripts and increased proinsulin levels. In contrast, Znt8AKO mice show no evident abnormalities in plasma glucagon and glucose homeostasis.


CONCLUSIONS
This is the first report of specific beta and alpha cell deletion of Znt8. Our data indicate that while, under the conditions studied, ZnT8 is absolutely essential for proper beta cell function, it is largely dispensable for alpha cell function.
Wijesekara
N
N
Department of Physiology, University of Toronto, 1 King's College Circle Room 3352, Toronto, ON, Canada M5S 1A8.
Dai
F F
FF
Hardy
A B
AB
Giglou
P R
PR
Bhattacharjee
A
A
Koshkin
V
V
Chimienti
F
F
Gaisano
H Y
HY
Rutter
G A
GA
Wheeler
M B
MB
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000235:genetics / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D020133:Reverse Transcriptase Polymerase Chain Reaction; 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