Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. RAGE also functions as a signal transduction receptor for amyloid beta peptide, known to accumulate in Alzheimer disease in both affected brain parenchyma and cerebral vasculature. Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop whereby receptor occupancy triggers increased RAGE expression, thereby perpetuating another wave of cellular activation. Sustained expression of RAGE by critical target cells, including endothelium, smooth muscle cells, mononuclear phagocytes, and neurons, in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage. In a model of accelerated atherosclerosis associated with diabetes in genetically manipulated mice, blockade of cell surface RAGE by infusion of a soluble, truncated form of the receptor completely suppressed enhanced formation of vascular lesions. Amelioration of atherosclerosis in these diabetic/atherosclerotic animals by soluble RAGE occurred in the absence of changes in plasma lipids or glycemia, emphasizing the contribution of a lipid- and glycemia-independent mechanism(s) to atherogenesis, which we postulate to be interaction of RAGE with its ligands. Future studies using mice in which RAGE expression has been genetically manipulated and with selective low molecular weight RAGE inhibitors will be required to definitively assign a critical role for RAGE activation in diabetic vasculopathy. However, sustained receptor expression in a microenvironment with a plethora of ligand makes possible prolonged receptor stimulation, suggesting that interaction of cellular RAGE with its ligands could be a factor contributing to a range of important chronic disorders.

Activation of Receptor for Advanced Glycation End Products: A Mechanism for Chronic Vascular Dysfunction in Diabetic Vasculopathy and Atherosclerosis

Background— The aim of this study was to assess the level of urinary albumin excretion (microalbuminuria), which is associated with increased risk of coronary heart disease and death, in the population. Microalbuminuria has been suggested as an atherosclerotic risk factor. However, the lower cutoff level of urinary albumin excretion is unknown. It is also unknown whether impaired renal function confounds the association. Methods and Results— In the Third Copenhagen City Heart Study in 1992 to 1994, 2762 men and women 30 to 70 years of age underwent a detailed cardiovascular investigation program, including a timed overnight urine sample. The participants were then followed up prospectively by registers until 1999 with respect to coronary heart disease and until 2001 with respect to death. During follow-up, 109 incident cases of coronary heart disease and 276 deaths were traced. A urinary albumin excretion above the upper quartile, ie, 4.8 μg/min, was associated with increased risk of coronary heart diseas...

Very Low Levels of Microalbuminuria Are Associated With Increased Risk of Coronary Heart Disease and Death Independently of Renal Function, Hypertension, and Diabetes

https://www.kidney-international.org/article/S0085-2538(15)53157-8/pdf

Proteinuria in diabetic kidney disease : A mechanistic viewpoint

Disease management is an approach to patient care that emphasizes coordinated, comprehensive care along the continuum of disease and across health care delivery systems. Evidence-based medicine is an approach to practice and teaching that integrates pathophysiological rationale, caregiver experience, and patient preferences with valid and current clinical research evidence. Using diabetes mellitus as an example, we describe the importance of evidence-based medicine to the development of disease management programs. We present a method for developing and implementing evidence-based clinical guidelines, clinical pathways, and algorithms and describe the creation of systems to measure and report processes and outcomes that could drive quality improvement in diabetes care. Multidisciplinary teams are ideally suited to develop, lead, and implement evidence-based disease management programs, since they play an essential role in the preventive, diagnostic, and therapeutic decisions for patients with diabetes throughout the course of their disease.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=419018&pdfFileName=jama_278_20_033.pdf

Evidence-Based Disease Management

Objective: To evaluate mechanisms underlying diabetic neuropathy (DN) progression using indices of sural nerve morphometry obtained from two identical randomized placebo-controlled clinical trials. Research Design and Methods: Sural nerve myelinated fiber density (MFD), nerve conduction velocities, vibration perception thresholds, clinical symptom scores and a visual analogue scale for pain were analyzed in participants with DN. A loss of ≥ 500 fibers/mm 2 in sural nerve MFD over 52 weeks was defined as progressing DN and a MFD loss of ≤ 100 fibers/mm 2 during the same time interval as non-progressing DN. The progressing and non-progressing cohorts were matched for baseline characteristics using an O9Brien rank sum and baseline MFD. Results: At 52 weeks, the progressing cohort demonstrated a 25% decrease (p Conclusions: In this cohort of participants with mild/moderate DN, elevated triglycerides correlated with MFD loss independent of disease duration, age, diabetes control or other variables. These data support the evolving concept that hyperlipidemia is instrumental in the progression of DN.

https://diabetes.diabetesjournals.org/content/diabetes/58/7/1634.full.pdf

Elevated triglycerides correlate with progression of diabetic neuropathy

OBJECTIVE To evaluate microvascular permeability by the transcapillary escape rate of albumin (TERalb) in type II diabetic patients with normo- and microalbuminuria. RESEARCH DESIGN AND METHODS The TERalb has been measured following intravenous injection of 125 I-labeled human serum albumin in 32 normotensive type II diabetic patients and 9 healthy control subjects matched for sex and age. Type II diabetic subjects were grouped in normoalbuminuric, albumin excretion rate (AER) n = 18), and microalbuminuric, AER 20-200 μg/min ( n = 14) categories. RESULTS In type II diabetic patients, no differences were noted between normo- and microalbuminuric groups for known diabetes duration (8.3 ± 5.9 vs. 11.7 ± 8.0 years), blood pressure (BP) (129/76 ± 16/8 vs. 131/76 ± 14/5 mmHg), current metabolic control (HbA 1c : 8.0 ± 1.4 vs. 8.5 ± 1.6%), and serum lipids. However, previous 2-year mean HbA 1c levels were significantly higher in microalbuminuric patients (8.7 ± 1.45 vs. 7.6 ± 1.29%; P P r = 0.63, percent explained variance ∼40) and mean “historical” HbA 1c (multiple r = 0.705; total explained variance ∼50%). CONCLUSIONS Type II diabetic patients with microalbuminuria show an increased TERalb, i.e., a widespread microvascular damage that may be important in the pathogenesis of long-term complications. Our findings may contribute to the explanation of why albuminuria seems to be an independent cardiovascular risk factor in type II diabetes.

Increased Transcapillary Escape Rate of Albumin in Microalbuminuric Type II Diabetic Patients

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Increased Transcapillary Escape Rate of Albumin in Microalbuminuric Type II Diabetic Patients