Soluble RAGE and atherosclerosis in youth with type 1 diabetes: a 5-year follow-up study

Abstract

BackgroundAdvanced glycation end products (AGEs) play a role in the development of late complications and atherosclerosis in diabetes by engaging the receptor for advanced glycation end products, RAGE. Receptor binding leads to activation of the vascular endothelium and increased inflammation in the vessel wall. The soluble variants of the receptor, endogenous secretory RAGE (esRAGE) and the cleaved cell-surface part of RAGE, which together comprise soluble RAGE (sRAGE), are suggested to have a protective effect acting as decoys for RAGE. We aimed to test whether high levels of soluble variants of RAGE could be protective against atherosclerosis development.MethodsParticipants in the prospective atherosclerosis and childhood diabetes study were examined at baseline (aged 8–18) and at follow-up after 5 years. Both sRAGE and esRAGE were measured by immunoassay in 299 patients with type 1 diabetes and 112 healthy controls at baseline and 241 patients and 128 controls at follow-up. The AGEs methylglyoxal-derived hydroimidazolone-1 (MG-H1) and carboxymethyllysine (CML) were measured by immunoassay. The surrogate markers of atherosclerosis assessed were carotid intima-media thickness (cIMT), C-reactive protein (CRP) and Young’s modulus, measures of arterial wall thickness, inflammation and arterial stiffness, respectively.ResultsLevels of sRAGE and esRAGE correlated strongly both at baseline and at follow-up in both diabetes patients and controls. With increasing age, mean values of both variants declined, independent of gender, diabetes or pubertal stage. In the diabetes group, multiple regression analysis showed a positive association between both variants of soluble RAGE and cIMT. There was no significant relationship with Young’s modulus, but a negative association between sRAGE at baseline and CRP at follow-up. The ratios between the AGEs and the variants of soluble RAGE were increased in diabetes patients compared to controls.ConclusionsThe results show a possible protective effect of high levels of sRAGE at baseline against inflammation 5 years later, but not on arterial stiffness or wall thickness, in this cohort of adolescents and young adults with T1D.

Procoagulant activity in children and adolescents on intensive insulin therapy

“…However, whether daily glucose fluctuations influence procoagulant activity we cannot answer. It has previously been published from this cohort that the degree of atherosclerosis (carotid intima media thickness, cIMT) was only slightly increased in the diabetes group, which may explain the current results. Ten years of disease duration is relatively short, and at this low age children and adolescents are free from longstanding exposure from other vascular risk factors, demonstrated in our cohort by the absence of microvascular complications.…”

Cellular mechanisms and consequences of glycation in atherosclerosis and obesity

“…Examples of recently published work demonstrate that in type 1 diabetic children, with increasing age, levels of total sRAGE and esRAGE declined, and were associated with carotid intima-media thickness [80]. Others showed that levels of sRAGE were inversely correlated with vascular calcification in hemodialysis subjects, in a manner independent of levels of S100A12 RAGE ligand [81].…”

Is insulin pro-atherogenic at the cellular level?

“…Several hypotheses exist, which try to describe the molecular, cellular and biochemical mechanisms of premature atherogenesis in diabetic patients, but all have failed to sufficiently explain this phenomenon. Proposed mechanisms include the harmful effects of advanced glycosylation end products, modification of low density lipoproteins by non-enzymatic glycosylation, lipoprotein retention in the arterial wall, enhanced oxidative stress, inflammation, endothelial dysfunction, and alterations in metabolism of vitamins and minerals [1][2][3][4][5] . In addition to these potential factors, it is necessary to consider the possible role of insulin in the process of atherosclerosis development.…”