A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young

JCI Insight. 2021 Jul 8;6(13):e138057. doi: 10.1172/jci.insight.138057.


Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β cell function. The mechanisms underlying MODY include β cell KATP channel dysfunction (e.g., KCNJ11 [MODY13] or ABCC8 [MODY12] mutations); however, no other β cell channelopathies have been associated with MODY to date. Here, we have identified a nonsynonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and β cell-restricted K+ channel transcript, encoding the two-pore-domain K+ channel TALK-1. Whole-cell K+ currents demonstrated a large gain of function with TALK-1 Leu114Pro compared with TALK-1 WT, due to greater single-channel activity. Glucose-stimulated membrane potential depolarization and Ca2+ influx were inhibited in mouse islets expressing TALK-1 Leu114Pro with less endoplasmic reticulum Ca2+ storage. TALK-1 Leu114Pro significantly blunted glucose-stimulated insulin secretion compared with TALK-1 WT in mouse and human islets. These data suggest that KCNK16 is a previously unreported gene for MODY.

Keywords: Calcium signaling; Diabetes; Endocrinology; Genetics; Ion channels.

Publication types

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

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Calcium Signaling*
  • Channelopathies / metabolism
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Gain of Function Mutation
  • Humans
  • Insulin Secretion / physiology*
  • Insulin-Secreting Cells / metabolism*
  • Membrane Potentials / physiology
  • Mice
  • Potassium Channels, Tandem Pore Domain / genetics*
  • Potassium Channels, Tandem Pore Domain / metabolism*


  • Blood Glucose
  • KCNK16 protein, human
  • Kcnk16 protein, mouse
  • Potassium Channels, Tandem Pore Domain

Supplementary concepts

  • Mason-Type Diabetes