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The MODY-associated TALK-1 L114P mutation causes islet α-cell overactivity and β-cell inactivity resulting in transient neonatal diabetes and glucose dyshomeostasis in adults.

ABSTRACT: A gain-of-function mutation in the TALK-1 K⁺ channel (p.L114P) associated with maturity-onset diabetes of the young (MODY) was recently reported in two distinct families. TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion (GSIS). KCNK16, the gene that encodes TALK-1, is the most abundant and β-cell-restricted K⁺ channel transcript; polymorphisms in the KCNK16 locus are also associated with an increased risk of type-2 diabetes. To investigate the impact of TALK-1-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 GSIS and can be reduced with insulin treatment. TALK-1-L114P drastically increased whole-cell β-cell K⁺ currents resulting in blunted glucose-stimulated Ca²⁺ entry and loss of glucose-induced Ca²⁺ oscillations. Thus, adult Kcnk16 L114P mice have reduced GSIS and plasma insulin levels, which significantly impaired glucose homeostasis. Taken together, this study determined that the MODY-associated TALK-1-L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by altering islet hormone secretion during development. These data strongly suggest that TALK-1 is an islet-restricted target for the treatment of diabetes.

SUBMITTER: Nakhe AY

PROVIDER: S-EPMC10401960 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Nakhe Arya Y AY Dadi Prasanna K PK Kim Jinsun J Dickerson Matthew T MT Behera Soma S Dobson Jordyn R JR Shrestha Shristi S Cartailler Jean-Philippe JP Sampson Leesa L Magnuson Mark A MA Jacobson David A DA

bioRxiv : the preprint server for biology 20240227

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 ...[more]

PMID: 37546831

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Project description:BackgroundThere is evidence that calcium (Ca(2+)) increases the proliferation of human advanced prostate cancer (PCa) cells but the ion channels involved are not fully understood. Here, we investigated the correlation between alpha(1D)-adrenergic receptor (alpha(1D)-AR) and the transient receptor potential vanilloid type 1 (TRPV1) expression levels in human PCa tissues and evaluated the ability of alpha(1D)-AR to cross-talk with TRPV1 in PCa cell lines.MethodsThe expression of alpha1D-AR and TRPV1 was examined in human PCa tissues by quantitative RT-PCR and in PCa cell lines (DU145, PC3 and LNCaP) by cytofluorimetry. Moreover, alpha(1D)-AR and TRPV1 colocalization was investigated by confocal microscopy in PCa cell lines and by fluorescence microscopy in benign prostate hyperplasia (BPH) and PCa tissues. Cell proliferation was assessed by BrdU incorporation. Alpha(1D)-AR/TRPV1 knockdown was obtained using siRNA transfection. Signalling pathways were evaluated by measurement of extracellular acidification rate, Ca(2+) flux, IP3 production, western blot and MTT assay.ResultsThe levels of the alpha(1D)-AR and TRPV1 mRNAs are increased in PCa compared to BPH specimens and a high correlation between alpha(1D)-AR and TRPV1 expression levels was found. Moreover, alpha(1D)-AR and TRPV1 are co-expressed in prostate cancer cell lines and specimens. Noradrenaline (NA) induced an alpha(1D)-AR- and TRPV1-dependent protons release and Ca(2+) flux in PC3 cell lines; NA by triggering the activation of phospholipase C (PLC), protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways stimulated PC3 cell proliferation, that was completely inhibited by clopenphendioxan (WS433) and capsazepine (CPZ) combination or by alpha(1D)-AR/TRPV1 double knockdown.ConclusionsWe demonstrate a cross-talk between alpha1D-AR and TRPV1, that is involved in the control of PC3 cell proliferation. These data strongly support for a putative novel pharmacological approach in the treatment of PCa by targeting both alpha1D-AR and TRPV1 channels.

Dataset Information

The MODY-associated TALK-1 L114P mutation causes islet α-cell overactivity and β-cell inactivity resulting in transient neonatal diabetes and glucose dyshomeostasis in adults.

Publications

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.

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Dataset Information

The MODY-associated TALK-1 L114P mutation causes islet α-cell overactivity and β-cell inactivity resulting in transient neonatal diabetes and glucose dyshomeostasis in adults.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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.