The MODY-associated KCNK16 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 (GSIS). 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 mixed C57BL/6J: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 Ca ²⁺ entry and loss of glucose-induced Ca ²⁺ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impaired 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 hormone secretion during development. These data strongly suggest that TALK–1 is an islet–restricted target for the treatment of diabetes.

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