The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance
Open Access
- 24 September 2013
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (10), 4513-4524
- https://doi.org/10.1172/jci68807
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.Keywords
This publication has 82 references indexed in Scilit:
- Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn 2+ over Cd 2+ selectivityProceedings of the National Academy of Sciences of the United States of America, 2012
- Noninvasive MRI of β-cell function using a Zn 2+ -responsive contrast agentProceedings of the National Academy of Sciences of the United States of America, 2011
- Caveolin-1 Assembles Type 1 Inositol 1,4,5-Trisphosphate Receptors and Canonical Transient Receptor Potential 3 Channels into a Functional Signaling Complex in Arterial Smooth Muscle CellsPublished by Elsevier BV ,2011
- Local clustering of transferrin receptors promotes clathrin-coated pit initiationThe Journal of cell biology, 2010
- Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretionDiabetologia, 2010
- Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in miceProceedings of the National Academy of Sciences of the United States of America, 2009
- Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretionBiochemical Journal, 2009
- Insulin Signaling in α Cells Modulates Glucagon Secretion In VivoCell Metabolism, 2009
- A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility VariantsScience, 2007
- A genome-wide association study identifies novel risk loci for type 2 diabetesNature, 2007