Allelic insufficiency of Znt8 had improved glucose tolerance in male mice after high fat intake

Abstract

Zinc transporter 8 (ZNT8) is mainly expressed in the pancreatic β‐cell. ZNT8 transports zinc from the cytosol into the insulin‐containing secretory vesicle for insulin crystallization and secretion. Reduced ZNT8 expression affects glucose‐stimulated insulin secretion. Genome Wide‐Association Studies revealed that people with one null allele of ZNT8 are 65% less likely to develop type 2 diabetes (T2D) than those with two normal alleles. The molecular mechanism underling this protective function of ZNT8 allelic insufficiency is not clear. Our specific aim was to uncover this mechanism using Znt8+/− mice. We hypothesized that Znt8 allelic insufficiency caused a decrease in glucose‐stimulated insulin secretion which triggered a compensatory action that ensured normal blood glucose levels after a meal. In the current study, we fed Znt8+/− and control mice a high‐fat diet to induce insulin resistance. The results from this study suggest a gender‐dependent role of Znt8 allelic insufficiency in the protection of mice from T2D. We found that male mice were benefited from Znt8 heterozygosity for controlling glucose levels whereas Znt8 heterozygosity helped female mice for handling dietary lipids. Importantly, we found that glucagon may play a key role in controlling glucose levels in Znt8+/− mice. In conclusion, our data support the notion that allelic Znt8 insufficiency can provide a protective effect against diet‐induced glucose intolerance, possibly through regulation of glucagon secretion.Support or Funding InformationUSDA/ARS 2032‐51000‐005‐00D.