The MODY-associatedKCNK16L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

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 (GSIS). TheKCNK16gene encoding TALK–1, is the most abundant and β-cell–restricted K⁺channel transcript. To investigate the impact ofKCNK16L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing theKcnk16L114P mutation was generated. Heterozygous and homozygousKcnk16L114P mice exhibit increased neonatal lethality in the C57BL/6J and the mixed C57BL/6J:CD–1(ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygousKcnk16L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment.Kcnk16L114P increased whole–cell β-cell K⁺currents resulting in blunted glucose-stimulated Ca²⁺entry and loss of glucose-induced Ca²⁺oscillations. Thus, adultKcnk16L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impaired glucose homeostasis. Taken together, this study shows that the MODY–associatedKcnk16L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet hormone secretion during development. These data strongly suggest that TALK–1 is an islet–restricted target for the treatment of diabetes.