Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion

Abstract

Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.

The Diabetes Susceptibility Gene SLC30A8 that Encodes the Zinc Transporter ZnT8 is a Pseudogene in Guinea Pigs Potentially Contributing to Low Guinea Pig Islet Zinc Content

“…In mice individual deletion of Slc30a8 or Slc30a7, which encodes ZnT7, markedly reduces islet zinc content but has little effect on glucose-stimulated insulin secretion (GSIS) (Syring et al 2016). However, deletion of Slc30a8 in combination with Slc30a7 abolishes GSIS (Syring et al 2016).…”

“…However, deletion of Slc30a8 in combination with Slc30a7 abolishes GSIS (Syring et al 2016). This further suggests that high islet zinc levels are not important for GSIS and that ZnT7 can compensate for the absence of ZnT8 in islets.…”

“…Because SLC30A8 is expressed most highly in islets it has been assumed that this protection against T2D is mediated through an effect on islet function. However, multiple groups have shown that deletion of Slc30a8 in mice has little or no effect on GSIS (Davidson et al 2014; Rutter and Chimienti 2015) leading to the hypothesis that ZnT8 is not essential for islet function and that SLC30A8 haploinsufficiency may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function (Syring et al 2016). The observation that SLC30A8 is a pseudogene in Guinea pigs (Table I; Fig.…”

Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway

“…The relationship between ZNT8 and type 2 diabetes therefore requires further investigation [ 115 ]. The transporters ZNT5 and ZNT7 are also relatively highly expressed in pancreatic β-cells, [ 61 , 116 , 117 ], and both may be associated with β-cell function: loss-of-function of Znt5 is associated with attenuation of the incidence of diabetes and mortality [ 103 ], whereas loss-of-function of Znt7 impairs glucose tolerance and reduces glucose-stimulated increases in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content [ 104 , 105 , 118 ]. Moreover, loss-of-function of Znt7 results in a markedly-reduced zinc content in β-cells, which is made more profound by the combined loss of function of Znt8 [ 118 ].…”

Implications of impaired zinc homeostasis in diabetic cardiomyopathy and nephropathy

“…ZnT7 overexpression in β‐islets increases total cellular insulin content and the basal insulin secretion, but not the intracellular Zn levels (Table ). A recent study shows that deletion of ZnT7 alone has no effect on glucose‐stimulated insulin secretion in isolated islets, whereas combined deletion of ZnT7 and ZnT8 affects insulin secretion (Table ). However, in vivo Znt7 knock‐down in male Znt7 KO mice fed with the high‐fat diet leads to severe glucose intolerance and insulin resistance providing evidence for a direct involvement of ZnT7 in the regulation of glucose metabolism.…”