The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

Elife. 2024 May 3:12:RP89967. doi: 10.7554/eLife.89967.


The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.

Keywords: TALK-1; calcium; computational biology; developmental biology; glucagon; insulin; islet; monogenic diabetes; mouse; systems biology.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Disease Models, Animal
  • Glucagon* / metabolism
  • Glucose* / metabolism
  • Homeostasis
  • Insulin / metabolism
  • Insulin Secretion* / drug effects
  • Insulin Secretion* / genetics
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Mutation
  • Potassium Channels / genetics
  • Potassium Channels / metabolism


  • Glucagon
  • Glucose
  • Insulin
  • Potassium Channels
  • Kcnk16 protein, mouse

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 2

Associated data

  • GEO/GSE239566