PDF(Pubmed)
Abstract：
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. 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 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 Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs 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 insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.
摘要：
TALK-1K通道中的功能增益突变（p。L114P）与年轻人的成熟型糖尿病（MODY）有关。TALK-1是β细胞电活动和葡萄糖刺激的胰岛素分泌的关键调节剂。编码TALK-1的KCNK16基因是最丰富和β细胞限制性的K+通道转录物。为了研究KCNK16L114P对葡萄糖稳态的影响，并确认其与MODY的关联，产生含有Kcnk16L114P突变的小鼠模型.杂合和纯合Kcnk16L114P小鼠在C57BL/6J和CD-1（ICR）遗传背景下表现出增加的新生儿致死率，分别。死亡率可能是由于缺乏葡萄糖刺激的胰岛素分泌而在纯合Kcnk16L114P新生儿中观察到的严重高血糖的结果，并且可以通过胰岛素治疗来降低。Kcnk16L114P增加了全细胞β细胞K电流，导致葡萄糖刺激的Ca2进入减弱，并失去了葡萄糖诱导的Ca2振荡。因此，成年Kcnk16L114P小鼠的葡萄糖刺激胰岛素分泌和血浆胰岛素水平降低，显著损害葡萄糖稳态。一起来看,这项研究表明,MODY相关的Kcnk16L114P突变破坏了类似MODY表型的成年小鼠的葡萄糖稳态,并通过抑制发育过程中的胰岛胰岛素分泌而导致新生儿死亡.这些数据表明TALK-1是治疗糖尿病的胰岛限制性靶标。
