Nathaniel W. York, Zihan Yan, Anna B. Osipovich, Abbie Tate, Sumit Patel, David W. Piston, Mark A. Magnuson, Maria S. Remedi, Colin G. Nichols
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引用次数: 0
摘要
KATP 通道的功能缺失(LOF)突变会引起过度兴奋和胰岛素分泌过多,导致先天性高胰岛素血症(CHI)。矛盾的是,尽管最初胰岛素分泌过多,但许多先天性高胰岛素血症病例和 KATP 基因敲除(KO)动物最终都会 "跨入 "胰岛素分泌不足甚至糖尿病的行列。在这里,我们证实 Sur1 KO 小鼠在所有[葡萄糖]条件下都表现出较高的细胞内[Ca2+]([Ca2+]i),但葡萄糖刺激的胰岛素分泌却减少了。然而,当通过增加细胞外[Ca2+]来人为提高[Ca2+]i 时,Sur1 KO 小鼠的胰岛素分泌会增加到与 WT 小鼠相同的水平。这表明,胰岛素分泌的[Ca2+]i依赖性右移,而不是胰岛素含量或内在分泌能力的丧失,是造成交叉的主要原因。通过缓慢释放格列本脲来长期药物抑制颗粒植入小鼠的 KATP 通道活性,会导致与 Sur1 KO 动物非常相似的葡萄糖不耐受和胰岛素分泌受损的 "交叉"。整个胰岛和单细胞转录组分析表明,在这两种情况下,Trpm5 都明显减少。植入格列本脲颗粒的 Trpm5 KO 小鼠也表现出明显的葡萄糖不耐受。这表明,Trpm5 表达的减少可能在 KATP 缺失导致的胰岛素分泌紊乱中起了很小的作用。
Loss of β-cell KATP reduces Ca2+ sensitivity of insulin secretion and Trpm5 expression
Loss-of-function (LOF) mutations in KATP channels cause hyperexcitability and insulin hypersecretion, resulting in congenital hyperinsulinism (CHI). Paradoxically, despite the initial insulin hypersecretion, many CHI cases, as well as KATP knockout (KO) animals, eventually ‘crossover’ to undersecretion and even diabetes. Here we confirm that Sur1 KO islets exhibit higher intracellular [Ca2+] ([Ca2+]i) at all [glucose], but show decreased glucose-stimulated insulin secretion. However, when [Ca2+]i is artificially elevated by increasing extracellular [Ca2+], insulin secretion from Sur1 KO islets increases to the same levels as WT islets. This indicates that a right-shift in [Ca2+]i-dependence of insulin secretion, rather than loss of insulin content or intrinsic secretability, is the primary cause for the crossover. Chronic pharmacological inhibition of KATP channel activity by slow release of glibenclamide in pellet-implanted mice causes a very similar ‘crossover’ to glucose intolerance and impaired insulin secretion to that seen in Sur1 KO animals. Whole islet and single cell transcriptomic analysis reveal markedly reduced Trpm5 in both conditions. Glibenclamide pellet-implanted Trpm5 KO mice also exhibited significant glucose intolerance. However, this was not as severe as in WT animals, which suggests that decreased expression of Trpm5 may play a small role in the disruption of insulin secretion with KATP loss.
期刊介绍:
Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes.
However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.