Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

Nat Genet. 2019 Nov;51(11):1596-1606. doi: 10.1038/s41588-019-0513-9. Epub 2019 Nov 1.

Abstract

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Female
  • Genotype
  • Glucose / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Insulin Secretion*
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Male
  • Middle Aged
  • Young Adult
  • Zinc Transporter 8 / genetics
  • Zinc Transporter 8 / metabolism*

Substances

  • SLC30A8 protein, human
  • Zinc Transporter 8
  • Glucose