MODY-Associated TALK-1 L114P Mutation Causes Transient Neonatal Diabetes and Glucose Dysregulation in Adults

Core Concepts

The MODY-associated TALK-1 L114P mutation disrupts islet function, leading to transient neonatal hyperglycemia and glucose intolerance in adult mice.

Abstract

The study investigated the impact of the MODY-associated KCNK16 (TALK-1) L114P mutation on glucose homeostasis using a mouse model. Key findings: Heterozygous and homozygous Kcnk16 L114P mice exhibit neonatal lethality due to severe hyperglycemia and lack of glucose-stimulated insulin secretion. Insulin treatment extended the lifespan of homozygous neonates, suggesting lethality is caused by inadequate insulin secretion. In adult Kcnk16 L114P mice, the mutation blunts glucose-stimulated β-cell electrical activity, Ca2+ handling, and insulin secretion, leading to glucose intolerance. Male Kcnk16 L114P mice show more severe glucose dysregulation compared to females. The Kcnk16 L114P mutation increases α-cell area fraction and glucagon secretion under fasting conditions, contributing to fasting hyperglycemia. Transcriptomic analysis of Kcnk16 L114P islets reveals changes in genes involved in β-cell function, ion channel activity, inflammatory signaling, and extracellular matrix interactions, which may compensate for the loss of glucose-stimulated insulin secretion. Overall, the study confirms that the MODY-associated TALK-1 L114P mutation disrupts islet function, causing transient neonatal diabetes and glucose dysregulation in adults, highlighting TALK-1 as a potential therapeutic target for diabetes.

Stats

Heterozygous Kcnk16 L114P neonates exhibit severe hyperglycemia (blood glucose ~400 mg/dL) and reduced plasma insulin levels compared to controls on postnatal day 4. Homozygous Kcnk16 L114P neonates show complete loss of glucose-stimulated Ca2+ entry and insulin secretion in islets. Adult male Kcnk16 L114P mice develop fasting hyperglycemia and glucose intolerance, while female Kcnk16 L114P mice exhibit moderate glucose intolerance. Kcnk16 L114P islets show a 2.13-fold increase in Adcy5 expression, a gene involved in Ca2+-independent insulin secretion.

Quotes

"Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1(ICR) genetic background, respectively." "Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations." "Kcnk16 L114P islets also show reduced expression of Fxyd3, which encodes the auxiliary subunit of Na+/K+-ATPase and is a known negative regulator of glucose-stimulated insulin secretion."

Key Insights Distilled From

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

by Nakhe,A. Y.,... at www.biorxiv.org 06-21-2023

https://www.biorxiv.org/content/10.1101/2023.06.20.545631v3

Deeper Inquiries

How do the biophysical properties of TALK-1 channels differ from KATP channels, and how do these differences contribute to the more modest MODY phenotype observed in KCNK16-MODY patients compared to KATP-MODY?

The biophysical properties of TALK-1 channels differ from KATP channels in several ways. TALK-1 channels exhibit depolarization-dependent activation (outward rectification), which limits their activity at resting membrane potential. On the other hand, KATP channels have larger unitary conductance, less voltage dependence, and are nucleotide-gated. These differences contribute to the more modest MODY phenotype observed in KCNK16-MODY patients compared to KATP-MODY. The unique biophysical properties of TALK-1 channels, such as depolarization-dependent activation, may limit the impact of gain-of-function mutations like L114P on β-cell function. This limitation in activity at resting membrane potential could explain why TALK-1 L114P channels only result in a partial blunting of glucose-stimulated insulin secretion, unlike KATP gain-of-function mutations that completely inhibit insulin secretion. Therefore, the differences in biophysical properties between TALK-1 and KATP channels play a crucial role in the manifestation of the MODY phenotype in patients with KCNK16 mutations.

How do the potential mechanisms by which the Kcnk16 L114P mutation leads to increased α-cell area fraction and glucagon secretion, and how do these changes contribute to the fasting hyperglycemia observed in adult mice?

The Kcnk16 L114P mutation can lead to increased α-cell area fraction and glucagon secretion through several potential mechanisms. One possible mechanism is the loss of inhibitory paracrine signaling due to reduced somatostatin secretion from δ-cells. TALK-1 L114P channels may hyperpolarize β-cell membrane potential, inhibiting α-cell Ca2+ entry and somatostatin secretion, which would normally suppress glucagon secretion. This loss of inhibition could result in increased α-cell area fraction and elevated glucagon secretion, contributing to fasting hyperglycemia in adult mice. Additionally, the hyperglucagonemia observed in Kcnk16 L114P mice may be mediated by increased α-cell activity or secretion, potentially due to changes in the SLIT-ROBO signaling pathway. The increase in α-cell area fraction and glucagon secretion could disrupt the balance between insulin and glucagon levels, leading to fasting hyperglycemia in adult mice. These changes in α-cell function, coupled with alterations in β-cell insulin secretion, contribute to the dysregulation of glucose homeostasis observed in Kcnk16 L114P mice.

Given the sexual dimorphism in the glucose intolerance phenotype of Kcnk16 L114P mice, are there any sex-specific differences in the manifestation of KCNK16-MODY in human patients, and what are the underlying biological factors that may contribute to these differences?

Sex-specific differences in the manifestation of KCNK16-MODY in human patients may exist, similar to what is observed in Kcnk16 L114P mice. These differences could be influenced by biological factors such as hormonal regulation, genetic predisposition, and metabolic differences between males and females. Hormonal factors, particularly estrogen, play a significant role in glucose homeostasis and insulin sensitivity. Estrogen has been shown to protect against glucolipotoxicity and oxidative stress, which could impact the development and progression of MODY in female patients with KCNK16 mutations. Genetic predisposition may also contribute to sex-specific differences, as certain genetic variations or regulatory mechanisms could affect the expression or function of TALK-1 channels differently in males and females. Metabolic differences between males and females, such as differences in insulin sensitivity, adipose tissue distribution, and energy metabolism, could also influence the manifestation of KCNK16-MODY. These metabolic factors may interact with the genetic mutation in KCNK16 to produce varying phenotypes in male and female patients. Further research is needed to elucidate the specific sex-specific differences in KCNK16-MODY and the underlying biological mechanisms driving these differences.