Changes in Matrix Proteoglycans Induced by Insulin and Fatty Acids in Hepatic Cells May Contribute to Dyslipidemia of Insulin Resistance

Olsson, Urban; Egnell, Ann-Charlotte; Lee, Mariam Rodríguez; Lundén, Gunnel Östergren; Lorentzon, Mattias; Salmivirta, Markku; Bondjers, Göran; Camejo, Germán

doi:10.2337/diabetes.50.9.2126

Cited by 47 publications

(30 citation statements)

References 33 publications

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“…Besides glucose, insulin has also been considered to underlie alteration of HSPG. The 35 S labelled HSPG from liver were lower in obese and insulin-resistant Zucker rats than in their unaffected littermates [39]. Our results suggest that besides glucose, insulin might independently induce a pattern change in HSPG in cultured adipocytes.…”

Section: Discussionmentioning

confidence: 54%

Insulin modulates the secretion of proteins from mature 3T3-L1 adipocytes: a role for transcriptional regulation of processing

Wang

Keijer²,

Bunschoten³

et al. 2006

Diabetologia

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Aims/hypothesis Under conditions of insulin resistance and type 2 diabetes, fat cells are subjected to increased levels of insulin, which may have a major impact on the secretion of adipokines. Materials and methods Using transcriptomics and proteomics, we investigated how insulin affects the transcription and protein secretion profile of mature 3T3-L1 adipocytes. Results We found that insulin has a significant impact on protein secretion of 3T3-L1 adipocytes. However, transcription is not the major regulation point for these secreted proteins. For extracellular matrix components, our data suggest that the mRNA level of processing enzymes, but not of target proteins, is the regulating point at which insulin stimulates secretion and function of the relevant proteins. Among these enzymes, we report a novel finding, namely that sulfatase 2 gene is regulated by insulin, which may induce a functional change in cultured adipocytes. Conclusions/interpretation We propose that enhancement of protein processing and secretion rather than transcription of the secreted protein genes is part of the strategic role of insulin in the induction of cellular responses.

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Section: Discussionmentioning

confidence: 54%

Insulin modulates the secretion of proteins from mature 3T3-L1 adipocytes: a role for transcriptional regulation of processing

Wang

Keijer²,

Bunschoten³

et al. 2006

Diabetologia

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“…From this position, OPG can be competitively washed into the circulation by heparin (6). Since insulin may alter proteoglycan composition (14,15,40) it is possible that the observed effects of insulin could be explained by altered binding to surface proteoglycans. In addition to alterations in synthesis and releasability from vascular surfaces, it is also theoretically possible that the degradation of plasma OPG may partly explain the observed effects of insulin.…”

Section: Discussionmentioning

confidence: 99%

Acute hyperinsulinemia decreases plasma osteoprotegerin with diminished effect in type 2 diabetes and obesity

Jörgensen

Vind²,

Nybo³

et al. 2009

European Journal of Endocrinology

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Objective: Osteoprotegerin (OPG) is a soluble tumour necrosis factor-receptor-like molecule present in connective tissues, especially bone and vasculature. It is known to accumulate in the arterial wall in diabetes. As its synthesis in vascular cells is decreased by insulin, we wanted to elucidate the acute effects of insulin on plasma OPG concentrations in individuals with type 2 diabetes and obese individuals compared with lean controls. Design: The study population consisted of ten type 2 diabetic, ten obese subjects, and ten lean subjects with no family history of diabetes. Methods: All subjects underwent a 4-h euglycemic-hyperinsulinemic clamp. Plasma OPG, insulin, lactate, HbA1c, cholesterol, triglycerides, free fatty acids (FFA), and glucose disposal rate were measured before and at the end of the clamp. Results: Baseline OPG concentrations did not differ significantly between groups. Insulin infusion decreased plasma OPG concentrations in all groups (P!0.01); however, the fall in OPG was 50% less in obese and type 2 diabetic individuals (PZ0.007). Baseline OPG correlated with fasting insulin, baseline lactate, and low density lipoprotein cholesterol in the diabetic group, and with baseline FFA in the lean group. The relative change of OPG in response to insulin correlated inversely with HbA1c and baseline FFA in the lean group. Conclusions: Acute hyperinsulinemia decreases plasma OPG, but with diminished effect in individuals with type 2 diabetes and obesity. Increased levels of OPG in arteries and plasma in diabetes together with the capability of plasma OPG as a cardiovascular risk predictor may be related to the described effects of insulin.European Journal of Endocrinology 161 95-101

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“…Dried gels were exposed to a phosphorimaging plate (3 days) and scanned on a BAS-1000 MacBas phosphorimager (Fuji Photo Film, Tokyo, Japan). Computer analysis (MacBas Version 1.0) was used to quantify the bound and free proteoglycans [18]. Experiments were repeated with LDL from different plasma donors.…”

Section: Methodsmentioning

confidence: 99%

Fenofibrate modifies human vascular smooth muscle proteoglycans and reduces lipoprotein binding

et al. 2004

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Aims/hypothesis. Vascular disease in type 2 diabetes is associated with an up-regulation of atherogenic growth factors, which stimulate matrix synthesis including proteoglycans. We have examined the direct actions of fenofibrate on human vascular smooth muscle cells (VSMCs) and have specifically investigated proteoglycan synthesis and binding to LDL. Methods. Proteoglycans synthesised by human VSMCs treated with fenofibrate (30 µmol/l) were assessed for binding to human LDL using a gel mobility shift assay, metabolically labelled with [ 35 S]-sulphate and quantitated by cetylpyridinium chloride. They were then assessed for electrophoretic mobility by SDS-PAGE, for size by gel filtration, for sulphation pattern by fluorophore-assisted carbohydrate electrophoresis, and for glycosaminoglycan (GAG) composition by enzyme digestion. Results. Proteoglycans synthesised in the presence of fenofibrate showed an increase in the half-maximum saturation concentration of LDL from 36.8±12.4 µg/ml to 77.7±17 µg/ml under basal conditions, from 24.9±4.6 µg/ml to 39.1±6.1 µg/ml in the presence of TGF-β1, and from 9.5±4.4 µg/ml to 31.1±3.4 µg/ml in the presence of platelet-derived growth factor/insulin. Fenofibrate treatment in the presence of TGF-β1 inhibited the incorporation of [ 35 S]-sulphate into secreted and cell-associated proteoglycans synthesised by human VSMCs by 59.2% (p<0.01) and 39.8% (p<0.01) respectively. The changes in sulphate incorporation following treatment with fenofibrate were associated with a concentration-related increase in the electrophoretic mobility due to a reduction in GAG length. There was no change in the sulphation pattern; however, there was an alteration in the disaccharide composition of the GAGs. Conclusions/interpretation. Fenofibrate modifies the structure of vascular proteoglycans by reducing the length of the GAG chains and GAG composition, resulting in reduced binding to human LDL, a mechanism which may lead to a reduction of atherosclerosis and cardiovascular disease in people with diabetes treated with fenofibrate.

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Changes in Matrix Proteoglycans Induced by Insulin and Fatty Acids in Hepatic Cells May Contribute to Dyslipidemia of Insulin Resistance

Cited by 47 publications

References 33 publications

Insulin modulates the secretion of proteins from mature 3T3-L1 adipocytes: a role for transcriptional regulation of processing

Insulin modulates the secretion of proteins from mature 3T3-L1 adipocytes: a role for transcriptional regulation of processing

Acute hyperinsulinemia decreases plasma osteoprotegerin with diminished effect in type 2 diabetes and obesity

Fenofibrate modifies human vascular smooth muscle proteoglycans and reduces lipoprotein binding

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