CAP defines a second signalling pathway required for insulin-stimulated glucose transport

Baumann, Christian A.; Ribon, Vered; Kanzaki, Makoto; Thurmond, Debbie C.; Mora, Sílvia; Shigematsu, Satoshi; Bickel, Perry E.; Pessin, Jeffrey E.; Saltiel, Alan R.

doi:10.1038/35025089

Cited by 597 publications

(641 citation statements)

References 30 publications

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“…The data suggest that, at least under these conditions, the observed insulin resistance in the diabetic subjects and FDR was caused by alterations at nonstudied locations, eg. downstream signalling elements, alternative pathways [17,39], or the final glucose transport effector system itself. It must also be considered that, in the intact cell, the compartmentalisation of the investigated signalling molecules may be very important.…”

Section: Discussionmentioning

confidence: 99%

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

et al. 2002

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Aims/hypothesis. Alterations in insulin signalling could contribute to insulin resistance in Type II (non-insulindependent) diabetes mellitus. Some of these alterations could be secondary to the diabetic state, ie. the hyperglycaemia or increased NEFA concentrations. We sought to exclude such secondary factors and to investigate whether Type II diabetes in itself is associated with altered insulin signalling in skeletal muscle. Methods. Hyperinsulinaemic-euglycaemic clamps were performed in 10 obese Type II diabetic patients whose glucose concentrations had been normalised for 8 h by plasma glucose-adapted insulin infusion, 10 BMImatched first-degree relatives of Type II diabetic patients, and 10 BMI-matched non-diabetic subjects. Muscle biopsies were obtained before and at the end of the clamps, and insulin receptor kinase activity, phosphatidylinositol-3′-kinase activity, Akt-Thr 308 -phosphorylation, and glycogen synthase activity determined. Results. At similar steady-state clamp insulin concentrations (~400 pmol/l) similar receptor kinase activities, phosphatidylinositol-3′-kinase activities, AktThr 308 -phosphorylation, and glycogen synthase activities were found in all subject groups although glucose disposal was reduced in the diabetic subjects and relatives. Pre-clamp signalling levels were different between subject groups, most likely due to different preclamp insulin concentrations. Conclusion/interpretation. Our results in subjects at risk for the development of diabetes and Type II diabetic patients with normalized glucose concentrations suggest that Type II diabetes in itself is not associated with reduced signalling intensity at the studied signalling molecules, at least not at the chosen clamp insulin concentration and under the chosen conditions. Alterations responsible for the reduced glucose disposal could be located downstream of the investigated steps or in alternative insulin signalling pathways. A different spatial organisation of the investigated signalling molecules can also not be excluded. [Diabetologia (2002) Type II (non-insulin-dependent) diabetes mellitus is associated with a reduced insulin-stimulated glucose disposal in skeletal muscle and other tissues [1]. Because insulin resistance is also observed in non-diabetic first-degree relatives of diabetic subjects [2,3,4,5], and because it seems to precede the development of frank diabetes [6], an inherited basis of at least a part of the diabetes-associated insulin resistance has been proposed [7]. On the other hand metabolic abnormalities in the diabetic state itself such as hyper-

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Section: Discussionmentioning

confidence: 99%

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

et al. 2002

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“…Recent findings have shown that Cbl-associated protein (CAP), known as a positive regulator of glucose transport into cells, plays a role in obesity-related inflammation due to its function in maintaining normal macrophage activity [13]. Cap knockout mice (Sorbs1 À/À ) are protected from high fat diet-induced insulin resistance because of decreased adipose tissue macrophage content and reduced inflammation.…”

Section: Cbl-associated Proteinmentioning

confidence: 99%

Inflammation and insulin resistance

2007

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Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Proinflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but to a larger extent the activated tissue resident macrophages. While the initiating factors of this inflammatory response remain to be fully determined, chronic inflammation in these tissues could cause localized insulin resistance via autocrine/paracrine cytokine signaling and systemic insulin resistance via endocrine cytokine signaling all of which contribute to the abnormal metabolic state.

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“…137 Sorbin and SH3-domain-containing-1 (SORBS1) is the human homologue of c-Cbl associated protein, which is highly expressed in adipocytes and through interaction with the INSR regulates glucose uptake. 138 A non-synonymous SORBS1 SNP, Thr228Ala in exon 7, has been associated with obesity and T2DM. 139 Mice deficient in the alpha(2)-Heremans-Schmid glycoprotein (AHSG) gene, which inhibits insulin-induced INSR autophosphorylation and tyrosine kinase activity in vitro, display improved insulin sensitivity and resistance to weight gain.…”

Section: Pathways Controlling Lipid Storage In Adipocytesmentioning

confidence: 99%

Obesity and polymorphisms in genes regulating human adipose tissue

Dahlman

Arner

2007

Int J Obes

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Obesity is the result of an imbalance between food intake and energy expenditure resulting in the storing of energy as fat. Adipose tissue contains the largest store of energy in the body and plays important roles in regulating energy partitioning. Developments in genomics, in particular microarray-based expression profiling, have provided scientists with a number of new candidate genes whose expression in adipose tissue is regulated by obesity. Integrating expression profiles with genome-wide linkage and/or association analyses is a promising strategy to identify new genes underlying susceptibility to obesity. This article provides a comprehensive review of adipose-tissue-expressed genes implicated in predisposition to human obesity. The authors consider the following genes of particular interest: peroxisome proliferator-activated receptor gamma and, potentially, INSIG2 acting in adipogenesis; the adrenoreceptors beta 2 and 3, as well as hormone-sensitive lipase acting on lipolysis; uncoupling protein 2 acting in mitochondria energy expenditure; and among secreted molecules the cytokine tumor necrosis factor alpha and the hormone leptin. With the rapid development in genome research, we predict that additional alleles in genes regulating adipose tissue function will be established as risk factors for common obesity in the coming years. This has important implications for the prevention of obesity and may also offer new therapeutic targets.

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CAP defines a second signalling pathway required for insulin-stimulated glucose transport

Cited by 597 publications

References 30 publications

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

Inflammation and insulin resistance

Obesity and polymorphisms in genes regulating human adipose tissue

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