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

Abstract

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 <i>KCNK16</i> gene encoding TALK-1 is the most abundant and β-cell-restricted K⁺ channel transcript. To investigate the impact of <i>KCNK16</i> L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the <i>Kcnk16</i> L114P mutation was generated. Heterozygous and homozygous <i>Kcnk16</i> 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 <i>Kcnk16</i> L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. <i>Kcnk16</i> L114P increased whole-cell β-cell K⁺ currents resulting in blunted glucose-stimulated Ca²⁺ entry and loss of glucose-induced Ca²⁺ oscillations. Thus, adult <i>Kcnk16</i> 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 <i>Kcnk16</i> 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.