Cardiovascular risk continuum: implications of insulin resistance and diabetes

Hsueh, Willa A.; Law, Ronald E.

doi:10.1016/s0002-9343(98)00205-8

Cited by 152 publications

(103 citation statements)

References 109 publications

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“…This pathway is thought to be vasculo-protective, leading to a rise in nitric oxide as well as facilitating insulin-mediated glucose transport in adipocytes and skeletal muscle [81]. Liver endothelial cells expressing macrophage scavenger receptors (MSR) showed an insulin-mediated increase in endocytic uptake of labelled AGE.…”

Section: Age Metabolismmentioning

confidence: 99%

Advanced glycation end-products: a review

et al. 2001

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Diabetes is a common condition with multiple complications. There has been much work done to elaborate on the aetiology, prevention and treatment of diabetes related complications. The DCCT [1] and UKPDS [2] studies have emphasised the role of tight glucose control as being important in reducing diabetic microvascular disease in Type I (insulin-dependent) diabetes mellitus (DCCT) and Type II (non-insulin-dependent) diabetes mellitus (UKPDS). The relation between tight glucose control and macrovascular complications is, however, not clear [3]. Recently the importance of blood pressure control in reducing diabetic microvascular complications has been shown [4]. Apart from these factors, damage induced by hyperglycaemia involves a complex interaction between many influences including genetic predisposition, smoking, BMI, dyslipidaemia and alterations in coagulation factors [3]. The presence of advanced glycation end-products (AGE) is closely related to Diabetologia (2001) AbstractAdvanced glycation end-products are a complex and heterogeneous group of compounds that have been implicated in diabetes related complications. At present it is not known if they are the cause or the consequence of the complications observed. We discuss the chemistry of advanced glycated end-product formation and their patho-biochemistry particularly in relation to the diabetic microvascular complications of retinopathy, neuropathy and nephropathy as well as their role in the accelerated vasculopathy observed in diabetes. The concept of carbonyl stress as a cause for advanced glycated end-product toxicity is mentioned. We discuss alterations in the concentrations of advanced glycated end-products in the body, particularly in relation to changes occuring with age, diabetes and its complications such as nephropathy. Problems relating to current methods of advanced glycated end-product detection and measurement are highlighted including the lack of a universally established method of detection or unit of measurement. Agents used for the treatment of advanced glycated end-product accumulation are reviewed, with an emphasis on the results of the recent phase III trials using aminoguanidine and diabetes related complications. [Diabetologia (2001) 44: 129±146]Keywords Advanced glycated end-products, diabetes mellitus, microvascular disease, carbonyl stress, aminoguanidine.Corresponding author: Dr R. Singh MRCP (UK), FRACP, University Dept of Medicine, Royal Perth Hospital, PO Box X2213, Perth 6847, Western Australia Abbreviations: ESRD, End-stage renal disease; 3-DG, 3-deoxyglucosone; MGO, methylglyoxal; DOLD, deoxyglucosone-lysine dimer; MOLD, methyl glyoxal-lysine dimer; CML, N e -[carboxymethyl]-lysine; FFI, furoyl-furanyl imidazole; PTB, phenacyl thiozolium bromide; RAGE, receptor for AGE; NF-kB, nuclear factor-kB; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intracellular adhesion molecule-1; PECAM-1, platelet endothelial cell adhesion molecule-1; ELAM-1, endothelial leucocyte adhesion molecule-1; MSR, macrophage scavenger recepto...

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Section: Age Metabolismmentioning

confidence: 99%

Advanced glycation end-products: a review

et al. 2001

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“…MBCD alone induces PAI-1 mRNA to a certain extent (Fig. 2), but this level of induction can be explained by a slight activation of Erk, because Erk has been reported to up-regulate the PAI-1 gene by activating the AP-1 transcription factor (43). However, the MBCD-mediated synergistic increase in insulininduced PAI-1 gene expression cannot be explained by Erk activation, because the extent of insulin-induced Erk phosphorylation (Fig.…”

Section: Discussionmentioning

confidence: 98%

Identification and modulation of a caveolae-dependent signal pathway that regulates plasminogen activator inhibitor-1 in insulin-resistant adipocytes

Venugopal

Hanashiro

Yang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathogenesis of obesity-driven type 2 diabetes mellitus and associated cardiovascular complications. Here, we show that perturbation of caveolar microdomains leads to insulin resistance and concomitant up-regulation of PAI-1 in 3T3L1 adipocytes. We present several lines of evidence showing that the phosphatidylinositol 3-kinase (PI3K) pathway negatively regulates PAI-1 gene expression. Insulin-induced PAI-1 gene expression is up-regulated by a specific inhibitor of PI3K. In addition, serum PAI-1 level is elevated in protein kinase B␣-deficient mice, whereas it is reduced in p70 ribosomal S6 kinase 1-deficient mice. The PI3K pathway phosphorylates retinoblastoma protein (pRB), known to release free E2 (adenoviral protein) factor (E2F), which we have previously demonstrated to be a transcriptional repressor of PAI-1 gene expression. Accordingly, cell-penetrating peptides that disrupt pRB-E2F interaction, and thereby release free E2F, are able to suppress PAI-1 levels that are elevated during insulin-resistant conditions. This study identifies a caveolar-dependent signal pathway that up-regulates PAI-1 in insulin-resistant adipocytes and proposes a previously undescribed pharmacological paradigm of disrupting pRB-E2F interaction to suppress PAI-1 levels. diabetes T ype 2 diabetes mellitus (T2DM) is characterized by insulin resistance, where the insulin receptor (IR) fails to elicit the metabolic signaling that is required for glucose metabolism and energy homeostasis. In insulin-sensitive tissues, the IR transduces two main signaling cascades: a metabolic signaling that is responsible for glucose uptake and glycogen synthesis and a mitogenic signaling that is responsible for cell proliferation and growth. The IR substrate (IRS)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) and Cbl-CAP-Flotillin pathways represents the major metabolic signaling, whereas the Shc-Rasextracellular regulated kinase (Erk) pathway represents the major mitogenic signaling (1). Both in animal models and clinical T2DM subjects, a selective impairment of metabolic signaling has been observed, whereas mitogenic signaling is more or less unaffected (2-4).Obesity is prominent among the plethora of factors that leads to the development of T2DM, although the molecular mechanism underlying the pathogenesis of obesity-driven T2DM is not well understood. Comparative analysis of large and small fat cells within the same fat pad reveals a 2-fold reduction in the levels of plasma membrane cholesterol in large fat cells, suggesting that a decrease in membrane cholesterol is characteristic of adipocyte hypertrophy per se (5). Recently, it has been proposed that the protein levels of caveolin-1 and -3 are inversely correlated to the body-mass index. § Plasma membrane cholesterol (6) and caveolins (7) are indispensable for the structural and functional integrity of caveolar microdomains. We therefore reasoned that obesity might lead to caveolar dysfunction. Because the IR...

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“…However, we found a strong, inverse correlation of plasma insulin concentration with EDV in the fasting and the postprandial state. Chronic hyperinsulinaemia is believed to affect endothelial function adversely through activation of the mitogen-activated protein kinase pathway [47] and by disturbing the balance between vasoconstricting and vasodilating endothelial mediators [48]. Endothelial dysfunction has been shown to be associated with insulin resistance and the evidence for a causal relationship is mounting [48,49].…”

Section: Discussionmentioning

confidence: 99%

The postprandial state does not impair endothelial function in women with Type 2 diabetes irrespective of glycaemic control

et al. 2004

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Aims/hypothesis. The postprandial state has been shown to be associated with endothelial dysfunction, a predictor of cardiovascular morbidity. In Type 2 diabetes, postprandial metabolic excursions are prolonged and exaggerated, but less pronounced if glycaemic control is optimised. We investigated the impact of improved glycaemic control on endothelial function in the postprandial state. Methods. We studied 19 postmenopausal women with Type 2 diabetes and ten non-diabetic subjects. Participants with diabetes were re-studied 3 months after intensive glucose regulation. We measured forearm blood flow by strain gauge plethysmography during rest, during acetylcholine infusion and post ischaemia in the fasting state, and again 3 hours after a mixed meal (660 kcal, 55% fat). Results. Endothelium-dependent vasodilation was impaired in the diabetic group (p<0.005) and improved following an HbA 1 c reduction of 0.96% (p<0.05 for high-dose acetylcholine infusion). Postprandial metabolic excursions were higher in the diabetic group (p<0.001, p<0.01 and p<0.05 for glucose, insulin and triglycerides respectively). Resting forearm blood flow increased in all groups after the meal (p<0.005). There was no difference in fasting and postprandial endothelium-dependent vasodilation before and after improved glucose regulation in either group. Conclusions/interpretation. The postprandial state does not impair endothelial function in non-diabetic women and does not make pre-existing endothelial dysfunction worse in women with Type 2 diabetes, irrespective of glycaemic control.

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Cardiovascular risk continuum: implications of insulin resistance and diabetes

Cited by 152 publications

References 109 publications

Advanced glycation end-products: a review

Advanced glycation end-products: a review

Identification and modulation of a caveolae-dependent signal pathway that regulates plasminogen activator inhibitor-1 in insulin-resistant adipocytes

The postprandial state does not impair endothelial function in women with Type 2 diabetes irrespective of glycaemic control

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