Restriction of dietary AGEs to prevent diabetes in overweight individuals: a randomized controlled trial

It is generally accepted that a change in diet is a key determinant of type 2 diabetes (T2DM) epidemic. Among other factors, advanced glycation end products (AGEs) in food are potential risk factors for insulin resistance and T2DM. AGEs are a heterogeneous group of bioactive compounds that are formed in the body when reducing sugars reacts with amino acids in proteins and other macromolecules. Our previous research in vitro has demonstrated that AGEs are implicated in the pathogenesis of age-related diseases in particular insulin resistance, diabetes and vascular disease. In addition, AGEs are direct modulators of beta-cell function. Moreover, we recently demonstrated in an animal model of obesity-induced insulin resistance, that inhibition of AGEs improved insulin sensitivity. Thus, there is ample evidence for an association between AGEs and insulin resistance and beta-cell function. In addition to endogenous formation, AGEs are also formed during processing of food. We have recently developed a new dietary AGE database of 192 specific food items, based on a state-of-the art UPLC-MSMS technique for the detection of AGEs. In the first analysis we have found that higher levels of dietary AGEs are associated with free plasma and urinary AGE levels. In animals, dietary AGE restriction has been associated with reduction of serum AGEs in parallel with a reduction of markers of endothelial dysfunction, as well as improvement of insulin sensitivity. However, it is still unresolved whether dietary AGEs are directly involved in the aetiology of insulin resistance in human. Studies so far have yielded inconsistent results. We hypothesize that insulin sensitivity and beta-cell function are improved by reducing dietary AGEs. The aim of this project is to find out whether the consumption of meals with low levels of dietary AGEs in overweight subjects attenuates the development of insulin resistance and improves beta-cell function and vascular function. Work plan: We will conduct a randomized trial in overweight subjects (n=80) in two parallel groups in which the enrolled subjects will be allocated into either a low dietary AGE group or a high dietary AGE group, to determine whether low dietary AGEs can improve insulin sensitivity (primary outcome) and beta-cell function and vascular function. We will use state-of the art UPLC-MS/MS to measure AGEs and our recently developed dietary AGE database. We will prescribe diets which differ greatly in AGEs content, but which are carefully matched for energy and macronutrients. Before and after the intervention period of 4 weeks, all subjects will undergo a hyperinsulinemia euglycaemic clamp to determine insulin sensitivity and an oral glucose tolerance test (OGTT). We will measure the effect of dietary AGEs on beta-cell function as measured by state-of-the-art physiologically-based mathematical modeling of the OGTT data. In addition, we will combine these outcomes with microvascular function measurements in the muscle with ultrasound, macrovascular function measurements, biomarkers of AGEs and endothelial dysfunction. This project will lead to important novel insights into the role of dietary AGEs in insulin resistance and beta-cell function as well as vascular function. With this knowledge it may be of utmost importance to reduce dietary AGE intake by having food available with low AGE content in order to improve insulin sensitivity and halt the development of type 2 diabetes. The project is timely since the rapidly increasing epidemic of diabetes asks for better intervention. Aiming to reduce dietary AGE intake seems to be a sound target.