Increased MAPK Activation and Impaired Insulin Signaling in Subcutaneous Microvascular Endothelial Cells in Type 2 Diabetes: The Role of Endothelin-1

Gogg, Silvia; Smith, Ulf; Jansson, Per Anders

doi:10.2337/db08-0961

Cited by 94 publications

(81 citation statements)

References 40 publications

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“…FOXO hyperphosphorylation would then be accompanied by the impaired expression of FOXO target genes, which we found in gene expression analysis. The elevated insulin response of FOXO compared with other Akt substrates suggests that there is selective insulin resistance, even within the Akt pathway itself, as previously reported in other pathways [4,47,50]. Selective insulin resistance in the face of persistent hyperinsulinemia is likely to result in previously unappreciated demands on metabolic control as well as having implications for the treatment of type 2 diabetes.…”

Section: Discussionmentioning

confidence: 62%

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

Tonks

Miller

et al. 2013

Diabetologia

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Aims/hypothesis Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood. Methods We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic individuals before and during a hyperinsulinaemic-euglycaemic clamp. Results Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160; also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant individuals. Conclusions/interpretation These results highlight nonlinearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex; and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2811-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionmentioning

confidence: 62%

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

Tonks

Miller

et al. 2013

Diabetologia

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“…Importantly, a selective insulin resistance has been observed in endothelial cells from volunteers with type 2 diabetes, whereby the insulin-stimulated PI3K/Akt pathway is impaired, yet insulin-stimulated ERK1/2 is unaffected or increased in the endothelium [7,74]. Given the different and opposing effects of these insulin signaling pathways on endothelial function, insulin resistance would be predicted to cause endothelial dysfunction, through reduced bioavailability of NO and unaffected or increased ET-1 synthesis.…”

Section: Does Vascular Insulin Resistance Contribute To the Cardiovasmentioning

confidence: 99%

Examining the Role of Insulin in the Regulation of Cardiovascular Health

Salt

2012

Future Cardiol.

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Examining the role of insulin in the regulation of cardiovascular health SUMMARYA substantial body of evidence has reported insulin has direct actions on the cardiovascular system independent of its systemic effects on plasma glucose or lipids. In particular, insulin regulates endothelial synthesis of the vasoactive mediators nitric oxide and endothelin-1, yet the importance of this in the maintenance of cardiovascular health remains poorly understood.Recent studies using animals with targeted downregulation of insulin signaling in vascular tissues are improving our understanding of the role of insulin in vascular health. This article focuses on the direct actions of insulin in cardiovascular tissues, with particular emphasis on the molecular mechanisms of insulin action on endothelial function. The potential contribution of impaired vascular insulin action to the cardiovascular complications of diabetes will also be discussed.

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“…Evidence is now strong for a role of the endothelin system in diabetes. Plasma ET-1 levels have been shown to be elevated in animal models of diabetes mellitus (31) and in diabetic patients (32). Furthermore, it has been reported that ET-receptor antagonist reduced the production of ECM proteins in experimental diabetes (33).…”

Section: Discussionmentioning

confidence: 99%

Bosentan ameliorates the expression of fibrotic related growth factors and collagen-1 in diabetic mice

Yang¹,

Li²,

Shi³

et al. 2012

Anadolu Kardiyol Derg

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Objective: To investigate the potential beneficial effect of bosentan in ameliorating fibrotic agents in diabetic mice. Methods: Male 6-week old C57BL/6 mice were divided into 3 groups (N=20): Control group, diabetes mellitus (DM) group and DM-B group (diabetes with bosentan group). Streptozotocin (STZ) was injected as 200 mg/Kg for single dose, i.p. (intraperitoneal injection). Fasting blood glucose (FBG) was measured at 0-, 1-, 2-week after STZ injection to confirm that diabetes was induced in the mice. Bosentan (100mg/Kg) and placebo was given i.g. (intragastric administration) once a day immediately after STZ injection for 18 weeks. The mRNA expression of tissue growth factor beta (TGF-b), connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF) and collagen-1 were evaluated by RT-PCR and real-time PCR. Differences in the data between the groups were compared by Student t-test for independent samples. Results: After 18 weeks of diabetic situation, FBG of DM-B mice was significantly higher than that of control mice and was similar with that of DM mice (DM mice vs. control mice, p<0.001; DM-B vs. control mice, p<0.001; DM mice vs. DM-B mice, p>0.05). The cardiac VEGF mRNA (a potent angiogenic factor) level in DM-B mice was significantly higher than DM mice (p<0.01). The heart of DM-B mice also showed lower expression of fibrotic genes (TGF-b, CTGF and collagen-1) than DM mice (p<0.01). Conclusion: These findings indicate the potential usefulness of an ET receptor antagonist bosentan in the amelioration of fibrotic agents, which may promote tissue fibrosis. This may provide a promising therapeutical strategy for diabetic cardiac fibrosis.

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Increased MAPK Activation and Impaired Insulin Signaling in Subcutaneous Microvascular Endothelial Cells in Type 2 Diabetes: The Role of Endothelin-1

Cited by 94 publications

References 40 publications

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

Impaired Akt phosphorylation in insulin-resistant human muscle is accompanied by selective and heterogeneous downstream defects

Examining the Role of Insulin in the Regulation of Cardiovascular Health

Bosentan ameliorates the expression of fibrotic related growth factors and collagen-1 in diabetic mice

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