The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance

Abstract

Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.

Zinc and diabetes

“…Increased ZnT8 expression was associated with improved glucose tolerance. Interestingly, we were able to ascribe the improvement not to increased insulin secretion but rather to enhanced Zn 2+ secretion, possibly via an autocrine/paracrine on neighbouring cells (see below) and via an inhibition of insulin clearance as described by Tamaki and colleagues [82]. …”

“…As demonstrated in β cell-specific ZnT8 KO mice, zinc secreted from islets also regulates hepatic insulin clearance mediated by clathrin-dependent internalisation of the insulin receptor [82].…”

“…A recent study by Tamaki et al [82] showed that mice with β cell ZnT8 specific deletion had lower peripheral insulin concentrations whereas insulin secretion from the isolated perfused pancreas was increased. In an elegant set of experiments this group also showed that the apparently contradictory results could be explained by a role for secreted zinc in inhibiting insulin internalization and degradation by the liver.…”

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

“…To further elucidate the role of ZnT8 in glucose homeostasis, several groups including our own have produced animal models harbouring either global ZnT8 deletion (72,(75)(76)(77) or deletion restricted to the β-cell (78,79) , with some recombination in the hypothalamus (80) . Each mouse model shows variations in certain phenotypic traits (see Table 3) (81) , which are attributed to differences in genetic background, deletion strategy and housing conditions.…”

“…Although circulating insulin levels were significantly lowered in ZnT8 null mice compared with controls, glucose-stimulated insulin release was unchanged or slightly increased in islets isolated from ZnT8 null mice. Providing an elegant explanation for these apparently contradictory results, Tamaki et al (79) recently demonstrated a role for Zn 2+ co-secreted with insulin from granules in regulating the rate of hepatic insulin clearance mediated by clathrin-dependent internalisation of the insulin receptor. As Zn 2+ does not affect the uptake of C-peptide or proinsulin, this mechanism could potentially explain the impairments in both circulating insulin and the increased proinsulin:insulin ratio seen in risk allele carriers (82) .…”