The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance.
Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.
Motoyuki
M
Tamaki
Yoshio
Y
Fujitani
Akemi
A
Hara
Toyoyoshi
T
Uchida
Yoshifumi
Y
Tamura
Kageumi
K
Takeno
Minako
M
Kawaguchi
Takahiro
T
Watanabe
Takeshi
T
Ogihara
Ayako
A
Fukunaka
Tomoaki
T
Shimizu
Tomoya
T
Mita
Akio
A
Kanazawa
Mica O
MO
Imaizumi
Takaya
T
Abe
Hiroshi
H
Kiyonari
Shintaro
S
Hojyo
Toshiyuki
T
Fukada
Takeshi
T
Kawauchi
Shinya
S
Nagamatsu
Toshio
T
Hirano
Ryuzo
R
Kawamori
Hirotaka
H
Watada
D000328:Adult; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004705:Endocytosis; D005838:Genotype; D005934:Glucagon / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D021381:Protein Transport; D011972:Receptor, Insulin / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015032:Zinc / Q000378:metabolism; D000075703:Zinc Transporter 8
D027682:Cation Transport Proteins; D007328:Insulin; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D005934:Glucagon; D011972:Receptor, Insulin; D015032:Zinc