Oral administration of spa-derived green alga improves insulin resistance in overweight subjects: Mechanistic insights from fructose-fed rats.

Advanced glycation end products (AGEs) and their receptor (RAGE) system evoke inflammatory reactions and insulin resistance in adipocytes. Spa-derived green alga Mucidosphaerium sp. (MS) had anti-inflammatory properties in vitro. We examined here whether and how MS could ameliorate insulin resistance in fructose-rich diet-fed rats, and conducted a randomized, double blind, placebo-controlled trial to investigate the effects of MS on insulin resistance in overweight subjects. Oral administration of MS for 8 weeks significantly decreased random blood glucose, and fasting insulin, oxidative stress levels, and improved homeostasis model assessment of insulin resistance (HOMA-IR) values in fructose-fed rats, which were associated with the reduction of AGEs, RAGE, 8-hydroxy-2'-deoxy-guanosine, NADPH oxidase activity, macrophage and lymphocyte infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, and adipocyte size in the adipose tissues as well as restoration of adiponectin levels. MS decreased the AGE-induced NADPH oxidase activity, ROS generation, MCP-1 and RAGE gene expression, and lipid accumulation in differentiated adipocytes, while it restored the decrease in adiponectin mRNA levels. An anti-oxidant, N-acetylcysteine mimicked the effects of MS on ROS generation, RAGE gene expression, and lipid accumulation. Oral intake of MS for 12 weeks significantly decreased systolic and diastolic blood pressure, fasting plasma glucose, fasting insulin, HOMA-IR, HDL-cholesterol and creatinine in overweight subjects. Baseline-adjusted diastolic blood pressure, fasting plasma glucose, fasting insulin, and HOMA-IR values were significantly lower in MS treatment group than in placebo. Our present findings suggest that MS may improve insulin resistance by blocking the AGE-RAGE-oxidative stress axis in the adipose tissues.

Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes.

A nonenzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules and subsequently alters their structural integrity and function. This process has been known to progress at an accelerated rate under hyperglycemic and/or oxidative stress conditions. Over a course of days to weeks, early glycation products undergo further reactions such as rearrangements and dehydration to become irreversibly cross-linked, fluorescent and senescent macroprotein derivatives termed advanced glycation end products (AGEs). There is a growing body of evidence indicating that interaction of AGEs with their receptor (RAGE) elicits oxidative stress generation and as a result evokes proliferative, inflammatory, thrombotic and fibrotic reactions in a variety of cells. This evidence supports AGEs' involvement in diabetes- and aging-associated disorders such as diabetic vascular complications, cancer, Alzheimer's disease and osteoporosis. Therefore, inhibition of AGE formation could be a novel molecular target for organ protection in diabetes. This report summarizes the pathophysiological role of AGEs in vascular complications in diabetes and discusses the potential clinical utility of measurement of serum levels of AGEs for evaluating organ damage in diabetes.

DNA Aptamer Raised against Advanced Glycation End Products Prevents Abnormalities in Electroretinograms of Experimental Diabetic Retinopathy.

PURPOSE: Abnormalities in electroretinograms (ERG), such as reduced amplitudes and delayed implicit times of a- and b-wave and oscillatory potentials (OPs), are one of the earliest features of diabetic retinopathy prior to obvious vascular changes in diabetic retinas. We have previously shown that serum levels of advanced glycation end products (AGEs) are correlated with a delayed latency of OPs in type 2 diabetic rats. However, the pathological role of AGEs in ERG abnormalities remains unclear. We examined here whether high-affinity DNA aptamer directed against AGEs (AGE-aptamer) prevents ERG abnormalities in experimental type 1 diabetic retinopathy. METHODS: Streptozotocin-induced diabetic rats or control rats received continuous intraperitoneal infusion of either AGE-aptamer or control aptamer via an osmotic mini pump for 16 weeks. Anthropometric, metabolic, and hemodynamic variables were measured, and an ERG was performed. RESULTS: Although AGE-aptamer did not affect body weight, fasting and random blood glucose, HbA1c, blood pressure, or lipid parameters, it completely prevented the increase in serum AGE levels as well as the reduction of a- and b-wave and OP amplitudes in diabetic rats. CONCLUSION: The present study demonstrated for the first time that AGE-aptamer prevents abnormalities in ERG in experimental diabetic retinopathy probably by blocking the harmful effects of AGEs.