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
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ABSTRACT:
PROVIDER: PRJNA999711 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25451109_1.fastq.gz | Fastqsanger.gz | |||
| SRR25451109_2.fastq.gz | Fastqsanger.gz | |||
| SRR25451110_1.fastq.gz | Fastqsanger.gz | |||
| SRR25451110_2.fastq.gz | Fastqsanger.gz | |||
| SRR25451111_1.fastq.gz | Fastqsanger.gz |
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Project description: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
2023-09-26 | GSE239566 | GEO
Project description: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.
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Project description:Global gene expression of the rat soleus muscle was assessed with microarrays after 11 days of intermittent physical inactivity (10 hr/day) and compared to normally caged rats with voluntary standing and intermittent cage movements. Keywords: between group design
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Project description:Global gene expression of the rat soleus muscle was assessed with microarrays after 12 hrs of physical inactivity and also after 12 hours of physical inactivity immediately followed by 2 hrs treadmill walking and compared to normally caged rats with voluntary standing and intermittent cage movements. Experiment Overall Design: Rats were either prevented from standing on the their hindlimbs for 12 hrs or were prevented from standing on the their hindlimbs for 12 hrs and then immediately engaged in 2 hours treadmill walking and compared to caged rats with normal standing/ambulatory activity. RNA was extracted from soleus muscles and each array represents the pooling of the RNA from the soleus of 8-10 different rats.
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Project description:We demonstrate whole body inflammation (miR146a-/-) exacerbated inactivity-induced fat gain and glucose dysregulation, while muscle specific MyD88 KO mitigated these outcomes in female mice. Higher gene expression of Igf1 and decreased expression of Ip6k3 in muscle of MyD88 KO female mice may explain enhancement of glucose uptake in the soleus. Whereas protection from fat accumulation may be related to visceral fat gene changes in adipose tissue expansion (Prc1↓, Gulp1↑, Anxa2↓, Cav2↓, EHD1↓), adipose beiging (Fgf10↑), metainflammation (Hmox1↓), and genes involved in perfusion. Of noteworthy to mention, two genes decreased in common between muscle and fat with the ablation of muscle MyD88. These were expression of the negative regulator for GLUT4 translocation, Ralgapa2, and uncharacterized 993011J21Rik2, a potential interferon interacting gene. We conclude that future therapeutic strategies for prevention or treatment of obesity and metabolic disturbances in populations unable to be physically active should focus on further understanding how skeletal muscle inflammation communicates with fat storage depots, and how this cross-talk is influenced by sex hormones.
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Project description:Skeletal muscle plasticity is imperative for functional adaptation to changing demands. Although a great deal is known about the structural and functional plasticity of healthy skeletal muscle, far less is known about plasticity in diseased muscle. Here, we created an experimental design to better understand how dystrophin-deficient zebrafish muscle responds to inactivity versus activity. We tested two inactivity paradigms, intermittent versus extended inactivity, and found that extended inactivity, defined as 72 hours in low-dose tricaine, worsens muscle structure and decreases survival. Strikingly, extended inactivity followed by a single session of neuromuscular electrical stimulation (NMES) further worsens muscle structure and obliterates its ability to regenerate. Next, we tested four unique NMES paradigms that varied in their frequency and voltage, and found that each NMES paradigm differentially affected muscle structure, function, and survival. However, one NMES paradigm, which we refer to as endurance NMES, improved all three components of muscle health. Accompanying these improvements, we observed increased sarcomere lengths as well as larger surface areas, volumes, and filament indices of muscle nuclei. Additionally, time-lapse imaging reveals less degeneration and improved regeneration of the fast-twitch muscle fibers. RNAseq analysis highlights two potential mechanisms, one in which gene expression levels are returned to wild-type levels as well as remodeling of the extracellular matrix. Collectively, these data provide a new methodology with which to study neuromuscular plasticity in healthy versus diseased muscle. In addition, our data clearly indicate that, at least in the zebrafish model, NMES is beneficial whereas inactivity is deleterious for dystrophic muscle.
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