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http://purl.uniprot.org/citations/30707251http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
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Aims/hypothesis

Skeletal muscle accounts for >80% of insulin-stimulated glucose uptake; dysfunction of this process underlies insulin resistance and type 2 diabetes. Insulin sensitivity is impaired in mice deficient in the double C2 domain β (DOC2B) protein, while whole-body overexpression of DOC2B enhances insulin sensitivity. Whether insulin sensitivity in the skeletal muscle is affected directly by DOC2B or is secondary to an effect on other tissues is unknown; the underlying molecular mechanisms also remain unclear.

Methods

Human skeletal muscle samples from non-diabetic or type 2 diabetic donors were evaluated for loss of DOC2B during diabetes development. For in vivo analysis, new doxycycline-inducible skeletal-muscle-specific Doc2b-overexpressing mice fed standard or high-fat diets were evaluated for insulin and glucose tolerance, and insulin-stimulated GLUT4 accumulation at the plasma membrane (PM). For in vitro analyses, a DOC2B-overexpressing L6-GLUT4-myc myoblast/myotube culture system was coupled with an insulin resistance paradigm. Biochemical and molecular biology methods such as site-directed mutagenesis, co-immunoprecipitation and mass spectrometry were used to identify the molecular mechanisms linking insulin stimulation to DOC2B.

Results

We identified loss of DOC2B (55% reduction in RNA and 40% reduction in protein) in the skeletal muscle of human donors with type 2 diabetes. Furthermore, inducible enrichment of DOC2B in skeletal muscle of transgenic mice enhanced whole-body glucose tolerance (AUC decreased by 25% for female mice) and peripheral insulin sensitivity (area over the curve increased by 20% and 26% for female and male mice, respectively) in vivo, underpinned by enhanced insulin-stimulated GLUT4 accumulation at the PM. Moreover, DOC2B enrichment in skeletal muscle protected mice from high-fat-diet-induced peripheral insulin resistance, despite the persistence of obesity. In L6-GLUT4-myc myoblasts, DOC2B enrichment was sufficient to preserve normal insulin-stimulated GLUT4 accumulation at the PM in cells exposed to diabetogenic stimuli. We further identified that DOC2B is phosphorylated on insulin stimulation, enhancing its interaction with a microtubule motor protein, kinesin light chain 1 (KLC1). Mutation of Y301 in DOC2B blocked the insulin-stimulated phosphorylation of DOC2B and interaction with KLC1, and it blunted the ability of DOC2B to enhance insulin-stimulated GLUT4 accumulation at the PM.

Conclusions/interpretation

These results suggest that DOC2B collaborates with KLC1 to regulate insulin-stimulated GLUT4 accumulation at the PM and regulates insulin sensitivity. Our observation provides a basis for pursuing DOC2B as a novel drug target in the muscle to prevent/treat type 2 diabetes."xsd:string
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http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Zhang J."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Oh E."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Ahn M."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Thurmond D.C."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Veluthakal R."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Tunduguru R."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Salunkhe V.A."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Aslamy A."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/author"Merz K.E."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/date"2019"xsd:gYear
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/name"Diabetologia"xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/pages"845-859"xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/title"DOC2B promotes insulin sensitivity in mice via a novel KLC1-dependent mechanism in skeletal muscle."xsd:string
http://purl.uniprot.org/citations/30707251http://purl.uniprot.org/core/volume"62"xsd:string
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