Abstract
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 β 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 β cell function, hIAPP-expressing transgenics were generated with reduced ZnT8 (ZnT8B+/– hIAPP) or null ZnT8 (ZnT8B–/– hIAPP) expression specifically in β 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 β cells heightened the toxicity induced by hIAPP, leading to impaired β cell function and glucose homeostasis associated with metabolic stress.
Highlights
Zinc ions are highly concentrated in insulin secretory granules where they complex with insulin to form insulin crystals [1, 2]
We showed that during metabolic stress induced by a high-fat diet (HFD), global ZnT8-KO mice developed severe insulin resistance and obesity, whereas mice with specific deletion of ZnT8 in β cells did not [19]
Regarding loss of ZnT8 activity, some studies show the deterioration of β cell function, whereas others suggest no net effect and others suggest improvement [15, 18, 19, 22, 23]
Summary
Zinc ions are highly concentrated in insulin secretory granules where they complex with insulin to form insulin crystals [1, 2]. The major allele Arg325Trp variant, which is a risk allele, was associated with increased fasting plasma glucose, reduced insulin secretion, and impaired conversion of proinsulin to insulin [12,13,14]. Global ZnT8-KO mice show reduced islet zinc content, abnormal insulin secretory granule morphology with less insulin crystallization, and impaired glucose tolerance [15,16,17]. Β cell–specific ZnT8 knock out (ZnT8B-KO) mice show reduced insulin crystallization and impaired glucose tolerance [18, 19]. Tamaki et al reported decreased plasma insulin in ZnT8B-KO mice resulting from enhanced hepatic clearance of insulin [20]. We showed that during metabolic stress induced by a high-fat diet (HFD), global ZnT8-KO mice developed severe insulin resistance and obesity, whereas mice with specific deletion of ZnT8 in β cells did not [19]
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