Dataset Information

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

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.

SUBMITTER: Bostrom P

PROVIDER: S-EPMC2911056 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Boström Pontus P Andersson Linda L Vind Birgitte B Håversen Liliana L Rutberg Mikael M Wickström Ylva Y Larsson Erik E Jansson Per-Anders PA Svensson Maria K MK Brånemark Richard R Ling Charlotte C Beck-Nielsen Henning H Borén Jan J Højlund Kurt K Olofsson Sven-Olof SO

Diabetes 20100511 8

<h4>Objective</h4>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.<h4>Research design and methods</h4>We ...[more]

PMID: 20460426

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Project description:Diabetic 'lipotoxicity' theory suggests that fat-induced skeletal muscle insulin resistance (FISMIR) in obesity induced by a high-fat diet (HFD), which leads to ectopic lipid accumulation in insulin-sensitive tissues, may play a pivotal role in the pathogenesis of type 2 diabetes. However, the changes in gene expression and the molecular mechanisms associated with the pathogenesis of FISMIR have not yet been fully elucidated. In the present study the changes in skeletal muscle gene expression were examined in FISMIR in obese insulin-resistant and diabetic hamster models induced by HFD with or without low-dose streptozotocin-treatment. Microarray technology and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to explore the potential underlying molecular mechanisms. The pathophysiological and metabolic features of obesity and type 2 diabetes in humans are closely resembled by these hamster models. The results of microarray analysis showed that the differentially expressed genes associated with metabolism were mostly related to the abnormal regulation and changes in the gene expression of liver X receptor (LXR), peroxisome proliferator-activated receptor (PPAR) and sterol regulatory element-binding protein (SREBP) transcriptional programs in the skeletal muscle from insulin-resistant and diabetic hamsters. The microarray findings confirmed by RT-qPCR indicated that the increased expression of SREBPs and LXRβ and the decreased expression of LXRα and PPARs were involved in the molecular mechanisms of FISMIR pathogenesis in insulin-resistant and diabetic hamsters. A significant difference in the abnormal expression of skeletal muscle LXRs, PPARs and SREBPs was found between insulin-resistant and diabetic hamsters. It may be concluded that the combined abnormal expression of LXR, PPAR and SREBP transcriptional programs may contribute to the development of FISMIR mediated by skeletal muscle lipid accumulation resulting from abnormal skeletal muscle glucose and lipid metabolism in these HFD- and streptozotocin injection-induced insulin-resistant and diabetic hamsters.

Dataset Information

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

Objective

Research design and methods

Results

Conclusions

Publications

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

Similar Datasets

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