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人骨骼肌中的 SNARE 蛋白 SNAP23 和 SNARE 相互作用蛋白 Munc18c 与胰岛素抵抗/2 型糖尿病有关。

The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes.

机构信息

Sahlgrenska Center for Cardiovascular and Metabolic Research, Wallenberg Laboratory, Sahlgrenska University Hospital, Göteborg, Sweden.

出版信息

Diabetes. 2010 Aug;59(8):1870-8. doi: 10.2337/db09-1503. Epub 2010 May 11.

DOI:10.2337/db09-1503
PMID:20460426
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2911056/
Abstract

OBJECTIVE

Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23.

RESEARCH DESIGN AND METHODS

We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp. Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6.

RESULTS

We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects. Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes. Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes. Studies in L6 cells showed that Munc18c promoted the expression of SNAP23.

CONCLUSIONS

We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23.

摘要

目的

我们之前的研究表明，突触相关蛋白 23kDa（SNAP23）与心肌细胞中脂质水平升高和胰岛素抵抗之间的联系有关。本研究旨在确定 SNAP23 是否也与骨骼肌中脂质积累与人类胰岛素抵抗/2 型糖尿病之间的已知关联有关，并鉴定 SNAP23 的潜在调节剂。

研究设计和方法

我们分析了 2 型糖尿病患者和健康、胰岛素敏感的对照者的骨骼肌活检组织，检测 SNAP23 的表达（mRNA 和蛋白质）和细胞内定位（亚细胞分级分离和免疫组织化学），以及与 SNARE 蛋白相互作用的蛋白质的表达。通过正葡萄糖高胰岛素钳夹试验测定胰岛素抵抗。还在骨骼肌细胞系 L6 中研究了 SNAP23 调节的潜在机制。

结果

与瘦对照者相比，我们发现 2 型糖尿病患者的骨骼肌中 SNAP23 水平升高。此外，SNAP23 在 2 型糖尿病患者中从质膜重新分布到微粒体/胞质区室。2 型糖尿病患者的骨骼肌中 SNARE 相互作用蛋白 Munc18c 的表达较高。L6 细胞研究表明，Munc18c 促进 SNAP23 的表达。

结论

我们通过显示 2 型糖尿病患者骨骼肌中 SNAP23 向细胞内分布的变化，将我们之前的体外结果转化为人类。我们还表明，Munc18c 是 SNAP23 的潜在调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/f7fc8a09376c/zdb0081062070006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/cfedad9278bf/zdb0081062070001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/a681997226ce/zdb0081062070002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/aa5ecd71e404/zdb0081062070003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/de3be77c40a1/zdb0081062070004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/e24b2e2cbc99/zdb0081062070005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/f7fc8a09376c/zdb0081062070006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/cfedad9278bf/zdb0081062070001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/a681997226ce/zdb0081062070002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/aa5ecd71e404/zdb0081062070003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/de3be77c40a1/zdb0081062070004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/e24b2e2cbc99/zdb0081062070005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/831b/2911056/f7fc8a09376c/zdb0081062070006.jpg

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