Potential positive and negative consequences of ZnT8 inhibition

Abstract

<jats:p><jats:italic>SLC30A8</jats:italic> encodes the zinc transporter ZnT8. <jats:italic>SLC30A8</jats:italic> haploinsufficiency protects against type 2 diabetes (T2D), suggesting that ZnT8 inhibitors may prevent T2D. We show here that, while adult chow fed <jats:italic>Slc30a8</jats:italic> haploinsufficient and knockout (KO) mice have normal glucose tolerance, they are protected against diet-induced obesity (DIO), resulting in improved glucose tolerance. We hypothesize that this protection against DIO may represent one mechanism whereby <jats:italic>SLC30A8</jats:italic> haploinsufficiency protects against T2D in humans and that, while <jats:italic>SLC30A8</jats:italic> is predominantly expressed in pancreatic islet beta cells, this may involve a role for ZnT8 in extra-pancreatic tissues. Consistent with this latter concept we show in humans, using electronic health record-derived phenotype analyses, that the ‘C’ allele of the non-synonymous rs13266634 SNP, which confers a gain of ZnT8 function, is associated not only with increased T2D risk and blood glucose, but also with increased risk for hemolytic anemia and decreased mean corpuscular hemoglobin (MCH). In <jats:italic>Slc30a8</jats:italic> KO mice, MCH was unchanged but reticulocytes, platelets and lymphocytes were elevated. Both young and adult <jats:italic>Slc30a8</jats:italic> KO mice exhibit a delayed rise in insulin after glucose injection, but only the former exhibit increased basal insulin clearance and impaired glucose tolerance. Young <jats:italic>Slc30a8</jats:italic> KO mice also exhibit elevated pancreatic <jats:italic>G6pc2</jats:italic> gene expression, potentially mediated by decreased islet zinc levels. These data indicate that the absence of ZnT8 results in a transient impairment in some aspects of metabolism during development. These observations in humans and mice suggest the potential for negative effects associated with T2D prevention using ZnT8 inhibitors.</jats:p>

Pancreatic β cell–selective zinc transporter 8 insufficiency accelerates diabetes associated with islet amyloidosis

“…In contrast, a recent study showed that heterozygous deletion of ZnT8 in young mice and partial knockdown of ZnT8 in adult mice had no effect on glucose tolerance, suggesting that haploinsufficiencies are likely tolerated because of compensatory adaptations during development ( 43 ). The study also suggested that ZnT8 haploinsufficiency protects against diet-induced obesity depending on the genetic background ( 43 ).…”

“…This is in agreement with a study that showed ZnT8 haploinsufficiency in MIN6 cells led to reduced cellular zinc, cellular insulin, cell proliferation, and survival (41) and a study that showed ZnT8 overexpression and supplementation in human islets protect against palmitate-induced reductions in glucose-stimulated insulin secretion and cell death, respectively (42). In contrast, a recent study showed that heterozygous deletion of ZnT8 in young mice and partial knockdown of ZnT8 in adult mice had no effect on glucose tolerance, suggesting that haploinsufficiencies are likely tolerated because of compensatory adaptations during development (43). The study also suggested that ZnT8 haploinsufficiency protects against diet-induced obesity depending on the genetic background (43).…”

“…Therefore, the discrepancy observed between the current study and in human carriers of the ZnT8 loss-of-function alleles may be due in part to the contribution from extra–β cell tissue/cells. In addition, a recent study suggested that mice with complete deletion of ZnT8 may have an early impairment of glucose tolerance at a young age that is transient due to adaptation during development, leading to restoration of glucose tolerance at an older age ( 43 ). In the current study, we observed that ZnT8B –/– mice on a chow diet showed similar glucose tolerance compared with controls at 14 weeks of age.…”

Inside the Insulin Secretory Granule

“…Recognition of variable factors such as the mode of deletion, and mouse age, sex, and genetic background are hoped to assist in study design to clear up the matter [ 261 ]. Indeed, a study published in 2020 revealed both positive and negative age-dependent consequences of ZnT8 deletion in mice [ 266 ]. Moreover, assessing the importance of Zn 2+ for SG biogenesis is complicated by the presence of multiple ZnTs.…”

Nutrient Sensor mTOR and OGT: Orchestrators of Organelle Homeostasis in Pancreatic β-Cells

“…In terms of secretory granule cation concentrations, Znt8 acts as the major transporter for zinc into β -cell secretory granules. Znt8 genetic polymorphisms have been associated with variations in the risk of T2D [ 104 ]. This may be due to defects in β -cell function, as deletion of Znt8 from β -cells reduces the number of insulin granules, the amount of mature granules, and proinsulin-to-insulin processing [ 105 ].…”