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| Status |
Public on Sep 26, 2023 |
| Title |
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 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
A strong association of the gain-of-function mutation in the TALK-1 K+ channel (p.L114P) 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 and KCNK16 locus is strongly associated to 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 TALK-1-L114P mutation was generated. Heterozygous and homozygous TALK-1-L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1(ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous TALK-1-L114P neonates due to lack of GSIS and can be reduced with insulin treatment. TALK-1-L114P drastically increases whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and a complete loss of glucose-induced Ca2+ oscillations. Thus, adult TALK-1-L114P mice have reduced GSIS and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows 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 for diabetes
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| Overall design |
Total of 8 samples were analyzed, 4 were wild type (WT) and 4 were Kcnk16 L114P (L/P) mutation samples. RNA was extracted from each of these samples for bulk RNA-Sequencing analysis
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| Web link |
https://elifesciences.org/reviewed-preprints/89967
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| Contributor(s) |
Nakhe AY, Dadi PK, Kim J, Shrestha S, Cartailler J, Sampson L, Magnuson MA, Jacobson DA |
| Citation(s) |
38700926 |
| |
| Submission date |
Jul 28, 2023 |
| Last update date |
May 24, 2024 |
| Contact name |
Shristi Shrestha |
| E-mail(s) |
shristi.shrestha.2@vanderbilt.edu
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| Organization name |
Vanderbilt University
|
| Street address |
2213 Garland Ave
|
| City |
Nashville |
| ZIP/Postal code |
37232 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA999711 |
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