Obesity is highly prevalent in Western populations and is considered a risk factor for the development of renal impairment. Interventions that reduce the tissue burden of advanced glycation end-products (AGEs) have shown promise in stemming the progression of chronic disease. Here we tested if treatments that lower tissue AGE burden in patients and mice would improve obesity-related renal dysfunction. Overweight and obese individuals (body mass index (BMI) 26-39 kg/m(2)) were recruited to a randomized, crossover clinical trial involving 2 weeks each on a low- and a high-AGE-containing diet. Renal function and an inflammatory profile (monocyte chemoattractant protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF)) were improved following the low-AGE diet. Mechanisms of advanced glycation-related renal damage were investigated in a mouse model of obesity using the AGE-lowering pharmaceutical, alagebrium, and mice in which the receptor for AGE (RAGE) was deleted. Obesity, resulting from a diet high in both fat and AGE, caused renal impairment; however, treatment of the RAGE knockout mice with alagebrium improved urinary albumin excretion, creatinine clearance, the inflammatory profile, and renal oxidative stress. Alagebrium treatment, however, resulted in decreased weight gain and improved glycemic control compared with wild-type mice on a high-fat Western diet. Thus, targeted reduction of the advanced glycation pathway improved renal function in obesity.

Background: The consumption of advanced glycation end products (AGEs) has increased because of modern food processing and has been linked to the development of type 2 diabetes in rodents. Objective: We determined whether changing dietary AGE intake could modulate insulin sensitivity and secretion in healthy, overweight individuals. Design: We performed a double-blind, randomized, crossover trial of diets in 20 participants [6 women and 14 men; mean 6 SD body mass index (in kg/m 2 ): 29.8 6 3.7]. Isoenergetic-and macronutrientmatched diets that were high or low in AGE content were alternately consumed for 2 wk and separated by a 4-wk washout period. At the beginning and end of each dietary period, a hyperinsulinemiceuglycemic clamp and an intravenous glucose tolerance test were performed. Dietary, plasma and urinary AGEs N V -(carboxymethyl) lysine (CML), N V -(carboxyethyl)lysin (CEL), and methylglyoxalderived hydroimadazolidine (MG-H1) were measured with the use of mass spectrometry. Results: Participants consumed less CML, CEL, and MG-H1 during the low-AGE dietary period than during the high-AGE period (all P , 0.05), which was confirmed by changes in urinary AGE excretion. There was an overall difference in insulin sensitivity of 22.1 mg $ kg 21 $ min 21 between diets (P = 0.001). Insulin sensitivity increased by 1.3 mg $ kg 21 $ min 21 after the low-AGE diet (P = 0.004), whereas it showed a tendency to decrease by 0.8 mg $ kg 21 $ min 21 after the high-AGE diet (P = 0.086). There was no difference in body weight or insulin secretion between diets (P = NS). Conclusions: A diet that is low in AGEs may reduce the risk of type 2 diabetes by increasing insulin sensitivity. Hence, a restriction in dietary AGE content may be an effective strategy to decrease diabetes and cardiovascular disease risks in overweight individuals. This trial was registered at clinicaltrials.gov as NCT00422253.

OBJECTIVE-Chronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes via a decrease in insulin sensitivity. Our study investigated potential relationships between nuclear factor-B (NF-B) and c-Jun NH 2 -terminal kinase (JNK) pathways-two pathways proposed as the link between CLAIS and insulin resistance.RESEARCH DESIGN AND METHODS-Adiposity (dualenergy X-ray absorptiometry), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinemic-euglycemic clamp) were measured in 22 healthy nondiabetic volunteers (aged 29 Ϯ 11 years, body fat 28 Ϯ 11%). NF-B activity (DNA-binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies of the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates. RESULTS-NF-B activities inPBMCs and muscle were positively associated with WHR after adjustment for age, sex, and percent body fat (both P Ͻ 0.05). NF-B activity in PBMCs was inversely associated with M after adjustment for age, sex, percent body fat, and WHR (P ϭ 0.02) and explained 16% of the variance of M. There were no significant relationships between NF-B activity and M in muscle or adipose tissue (both NS). Adipose-derived JNK1/2 activity was not associated with obesity (all P Ͼ 0.1), although it was inversely related to M (r ϭ Ϫ0.54, P Ͻ 0.05) and explained 29% of its variance. When both NF-B and JNK1/2 were examined statistically, only JNK1/2 activity in adipose tissue was a significant determinant of insulin resistance (P ϭ 0.02).

It has been postulated that chronic exposure to high levels of advanced glycation end products (AGEs), in particular from dietary sources, can impair insulin secretion. In the present study, we investigated the cross-sectional relationship between AGEs and acute insulin secretion during an intravenous glucose tolerance test (IVGTT) and following a 75 g oral glucose tolerance test (OGTT) in healthy humans. We report the cross-sectional association between circulating AGE concentrations and insulin secretory function in healthy humans (17 F: 27 M, aged 30 ± 10 years) with a wide range of BMI (24.6-31.0 kg/m(2)). Higher circulating concentrations of AGEs were related to increased first phase insulin secretion during IVGTT (r = 0.43; p < 0.05) and lower 2-h glucose concentrations during OGTT (r = -0.31; p < 0.05). In addition, fasting (r = -0.36; p < 0.05) and 2-h glucose concentrations were negatively related to circulating levels of soluble receptor for AGE (RAGE) isoforms (r = -0.39; p < 0.01). In conclusion, in healthy humans, we show a cross-sectional association between advanced glycation end products and acute insulin secretion during glucose tolerance testing.

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