The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance

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Abstract

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.

Authors

Motoyuki Tamaki, Yoshio Fujitani, Akemi Hara, Toyoyoshi Uchida, Yoshifumi Tamura, Kageumi Takeno, Minako Kawaguchi, Takahiro Watanabe, Takeshi Ogihara, Ayako Fukunaka, Tomoaki Shimizu, Tomoya Mita, Akio Kanazawa, Mica O. Imaizumi, Takaya Abe, Hiroshi Kiyonari, Shintaro Hojyo, Toshiyuki Fukada, Takeshi Kawauchi, Shinya Nagamatsu, Toshio Hirano, Ryuzo Kawamori, Hirotaka Watada