人回肠细胞中Kir6.2/SUR1通道复合物与胰高血糖素样肽-1及葡萄糖依赖性促胰岛素多肽表达的共定位及其对新发1型糖尿病血糖控制的意义

Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes.

作者信息

Nielsen Lotte B, Ploug Kenneth B, Swift Peter, Ørskov Cathrine, Jansen-Olesen Inger, Chiarelli Francesco, Holst Jens J, Hougaard Philip, Pörksen Sven, Holl Reinhard, de Beaufort Carine, Gammeltoft Steen, Rorsman Patrik, Mortensen Henrik B, Hansen Lars

机构信息

Department of Paediatrics, Glostrup University Hospital, Ndr. Ringvej 57, DK-2600 Glostrup, Denmark.

出版信息

Eur J Endocrinol. 2007 Jun;156(6):663-71. doi: 10.1530/EJE-06-0756.

DOI:10.1530/EJE-06-0756

PMID:17535866

Abstract

OBJECTIVE

The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the K(ATP) channel subunits, Kir6.2 and SUR1, in human L- and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu23Lys, exerts a functional impact on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes.

DESIGN AND METHODS

Western blot and immunohistochemical analyses were performed for expression and co-localisation studies. Meal-stimulated C-peptide test was carried out in 257 children at 1, 6 and 12 months after diagnosis. Genotyping for the Glu23Lys variant was by PCR-restriction fragment length polymorphism.

RESULTS

Kir6.2 and SUR1 co-localise with GLP-1 in L-cells and with GIP in K-cells in human ileum tissue. Children with type 1 diabetes carrying the hyperactive Glu23Lys variant had higher HbA1C at diagnosis (coefficient = 0.61%, P = 0.02) and 1 month after initial insulin therapy (coefficient = 0.30%, P = 0.05), but later disappeared. However, when adjusting HbA1C for the given dose of exogenous insulin, the dose-adjusted HbA1C remained higher throughout the 12 month study period (coefficient = 0.42%, P = 0.03).

CONCLUSIONS

Kir6.2 and SUR1 co-localise in the gastrointestinal endocrine L- and K-cells. The hyperactive Glu23Lys variant of the K(ATP) channel subunit Kir6.2 may cause defective glucose sensing in several tissues and impaired glycaemic control in children with type 1 diabetes.

摘要

目的

ATP 依赖性钾通道（K(ATP)）对于胰腺内分泌α细胞和β细胞的葡萄糖感知以及正常胰高血糖素和胰岛素分泌至关重要。胃肠道内分泌 L 细胞和 K 细胞也是葡萄糖感知细胞，分别分泌胰高血糖素样肽 -1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）。本研究的目的是：1）研究 K(ATP)通道亚基 Kir6.2 和 SUR1 在人 L 细胞和 K 细胞中的表达及共定位；2）研究 Kir6.2 亚基的一种常见高活性变体 Glu23Lys 是否对体内葡萄糖感知组织产生功能影响，这可能会影响新诊断的 1 型糖尿病儿童的整体血糖控制。

设计与方法

进行蛋白质免疫印迹和免疫组织化学分析以进行表达及共定位研究。对 257 名儿童在诊断后 1、6 和 12 个月进行餐时刺激 C 肽试验。通过聚合酶链反应 - 限制性片段长度多态性对 Glu23Lys 变体进行基因分型。

结果

在人回肠组织中，Kir6.2 和 SUR1 与 GLP-1 在 L 细胞中共定位，与 GIP 在 K 细胞中共定位。携带高活性 Glu23Lys 变体的 1 型糖尿病儿童在诊断时（系数 = 0.61%，P = 0.02）和初始胰岛素治疗后 1 个月（系数 = 0.30%，P = 0.05）的糖化血红蛋白（HbA1C）较高，但随后消失。然而，在根据给定剂量的外源性胰岛素调整 HbA1C 后，在整个 12 个月的研究期间，剂量调整后的 HbA1C 仍然较高（系数 = 0.42%，P = 0.03）。