Marked improvement of insulin resistance by reduced age intake; a non-pharmacologic, non-nutrient based intervention for type 2 diabetes
The clinical efficacy of strict glucose control against risk of diabetic macrovascular complications, despite effective treatment, has been disappointing, pointing to non-glucose related etiologic factors. Elevated inflammatory advanced glycation end products (AGEs), or Glycotoxins, known to increase the incidence and severity of diabetic complications, are recently shown to impair insulin production and insulin actions, hence are involved in the etiology of diabetes and insulin resistance. Further evidence indicates that high levels of AGEs in western diet may help precipitate diabetes, as well as diabetic complications, by a process which involves increased oxidant stress (OS) and depletion of anti-inflammatory reserves, including anti-AGE receptor, AGE-receptor-1 (AGER1). Attention has been drawn recently to the suppression of the longevity associated mammalian de-acetylase, Sirt-1 in type 2 diabetes (T2D). We found that both, AGER1 as well as Sirt-1 are down-regulated by AGEs in vitro and by high AGE feeding in vivo, leading to insulin resistance, T2D and vascular disease in mice. We now report strong correlations in diabetic patients between fasting insulin (r=0.526, P=0.001), BMI (r=0.4, P=0.0001) and sAGEs, factors which were profoundly influenced by dietary AGE intake, independent of glycaemia, nutritional or caloric intake. Isocaloric restriction of dietary AGEs (by ~50%) over 4 months markedly improved fasting insulin (P=0.001) and HOMA levels (P=0.023), reduced plasma leptin (P=0.05) and increased serum adiponectin (by 100%, P=0.002). Importantly, under reduced AGE intake, mononuclear (PMNC) AGER1 (P=0.018), and Sirt-1 levels (P=0.040) were restored to normal, IRS-1 Tyr-phosphorylation was enhanced, while Nf-kB p65 acetylation was ameliorated, indicating that the intervention improved both, the inflammatory and the metabolic states in these patients.
Thus, AGE-rich foods promote insulin resistance in T2D, possibly by interfering with key mechanisms, regulated by Sirt-1 and adiponectin. Reduced AGE intake may be required for the optimal treatment of T2D patients.