Pancreatic Beta Cell-Selective Zinc Transporter 8 Insufficiency Accelerates Diabetes Associated With Islet Amyloidosis

GWAS have shown that the common R325W variant of SLC30A8 (ZnT8) increases the risk of type 2 diabetes (T2D). However, ZnT8 haploinsufficiency is protective against T2D in humans, counterintuitive to earlier work in humans and mouse models. Therefore, whether decreasing ZnT8 activity is beneficial or detrimental to beta cell function, especially under conditions of metabolic stress, remains unknown. In order to examine whether the existence of human islet amyloid polypeptide (hIAPP), a coresident of the insulin granule, affects the role of ZnT8 in regulating beta cell function, hIAPP-expressing transgenics were generated with reduced ZnT8 (ZnT8B(+/-) hIAPP) or null ZnT8 (ZnT8B(-/-) hIAPP) expression specifically in beta cells. We showed that ZnT8B(-/-) hIAPP mice on a high-fat diet had intensified amyloid deposition and further impaired glucose tolerance and insulin secretion compared with control, ZnT8B(-/-), and hIAPP mice. This can in part be attributed to impaired glucose sensing and islet cell synchronicity. Importantly, ZnT8B(+/-) hIAPP mice were also glucose intolerant and had reduced insulin secretion and increased amyloid aggregation compared with controls. These data suggest that loss of or reduced ZnT8 activity in beta cells heightened the toxicity induced by hIAPP, leading to impaired beta cell function and glucose homeostasis associated with metabolic stress.