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
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..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 28. Feb. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nakhe, Arya Y [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.06.20.545631 |
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| PPN (Katalog-ID): |
XBI039981754 |
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| 245 | 1 | 0 | |a 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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| 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). 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. | ||
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| 700 | 1 | |a Jacobson, David A |0 (orcid)0000-0003-1816-5375 |4 aut | |
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