The MODY-associated KCNK16 L114P 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). 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
|---|---|
| Enthalten in: |
bioRxiv : the preprint server for biology - (2024) vom: 27. Feb. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Nakhe, Arya Y [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 13.03.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1101/2023.06.20.545631 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36046503X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36046503X | ||
| 003 | DE-627 | ||
| 005 | 20240313233544.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2023.06.20.545631 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1326.xml |
| 035 | |a (DE-627)NLM36046503X | ||
| 035 | |a (NLM)37546831 | ||
| 035 | |a (PII)2023.06.20.545631 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Nakhe, Arya Y |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Dadi, Prasanna K |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Jinsun |e verfasserin |4 aut | |
| 700 | 1 | |a Dickerson, Matthew T |e verfasserin |4 aut | |
| 700 | 1 | |a Behera, Soma |e verfasserin |4 aut | |
| 700 | 1 | |a Dobson, Jordyn R |e verfasserin |4 aut | |
| 700 | 1 | |a Shrestha, Shristi |e verfasserin |4 aut | |
| 700 | 1 | |a Cartailler, Jean-Philippe |e verfasserin |4 aut | |
| 700 | 1 | |a Sampson, Leesa |e verfasserin |4 aut | |
| 700 | 1 | |a Magnuson, Mark A |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobson, David A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv : the preprint server for biology |d 2020 |g (2024) vom: 27. Feb. |w (DE-627)NLM31090014X |7 nnns |
| 773 | 1 | 8 | |g year:2024 |g day:27 |g month:02 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.06.20.545631 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 27 |c 02 | ||