Bioactive compounds produced during food processing can have strong pro-inflammatory properties with potential health implications. Modulation of chronic inflammation may be the mechanism linking diet to risk of chronic diseases such as diabetes and CVD. Advanced glycation endproducts (AGEs) are a heterogeneous group of pro-inflammatory bioactive compounds produced via Maillard reactions during cooking and processing. It is now well established that AGEs are mainly formed from several dicarbonyl compounds, including methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG). The glycation activity of these biologically reactive dicarbonyl compounds is much higher as compared to that of sugars, with MGO as the most reactive precursor in the formation of AGEs. We have recently found high levels of MGO in many different foods. There is increasing evidence that elevated levels of MGO are involved in weight gain and the development of diabetes and other chronic inflammatory diseases including cardiovascular disease. However, bioavailability and physiological consequences of dietary MGO are largely unknown. Our aim is to explore the consequences of dietary MGO on the intestinal microbiota and on the development of metabolic diseases.

We will determine the effect of dietary MGO on the gastrointestinal tract and microbiota (WP1) and on the onset of diabetes, vascular diseases and cognitive function in mice (WP2). We will develop a detailed database of dietary MGO exposures and assess the association of dietary MGO with overweight, weight gain, obesity and risk of associated metabolic diseases (type 2 diabetes, CVD), as well as cognitive function using existing data from 3 large and deep-phenotyping prospective cohort studies (WP3). For WP3, the main objectives are to develop a food composition database of dietary dicarbonyl consumption in major European foods and to utilize that information to investigate associations between these compounds and the risk of development of diabetes, cardiovascular diseases, cognitive function, and obesity in major European prospective cohort studies.

This comprehensive project will elucidate the role of food-derived MGO as a possible risk factor for overweight and overweight-related metabolic diseases.

For WP1 the main part of dietary methylglyoxal is scavenged during simulated digestion. As shown in a study with human volunteers, the Maillard reaction takes most likely place during digestion to form the glycation compound MG-HCr if Manuka honey with Methylglyoxal and creatine was ingested simultaneously. The concentrations of methylglyoxal that reach the gut seem to be not harmful to gut bacteria.

For WP2 on the dietary MGO and physiological consequences in mice. In both healthy and diabetic mice subjected to 1 mM MGO via drinking water, we found improved insulin sensitivity in both healthy and diabetic mice compared to the control. Interestingly, after 13 weeks, both systolic and diastolic blood pressure were significantly increased in diabetic mice compared to the control, which was prevented by MGO. In addition, in both control and diabetic mice, MGO improved NO-mediated vasorelaxation in small and large arteries, NO sensitivity, and arterial nerve functioning. Thus, results indicate that supplementation of 1 mM MGO favors vascular relaxation in both small and large arteries and vascular nerve-ending functioning. In healthy mice, 1 mM MGO supplementation resulted in lower intracellular MGO levels in organs including the heart, kidney, brain, and muscle, except for the liver compared to the control group with no effect on the glyoxalase MGO detoxification system, except for a decreased in muscles compared to the control. Similar analyses of organs of diabetic mice supplemented with 1 mM MGO are currently ongoing. Interestingly, with respect to the microbiome, findings on the first mice study showed that mice fed with a high concentration of methylglyoxal (50 mM) have less Ligilactobacillus and Lactobacillus in their gut microbiota. Measures of 1 mM MGO supplementation in healthy and diabetic mice will follow soon. Also, a large panel of biomarkers, reflecting endothelial dysfunction and low-grade inflammation were analyzed in the plasma of all groups. In diabetic mice supplemented with MGO, increased levels of the pro-inflammatory marker CRP were prevented as well as the endothelial function markers ICAM-1 and E-Selectin, indicative of the protective potential of MGO against inflammation and vascular dysfunction in diabetes.

For WP3 on the impact of dietary MGO and its consequences in humans using existing data and resources from large-scale international prospective cohort studies.  We established the (a) first highly detailed and complete database of dietary dicarbonyl content of major European foods and food products, (b) descriptive analysis of the consumption levels of dicarbonyls in Europe, and (c) detailed epidemiological analyses of the association of dietary dicarbonyl consumption levels with risk of diabetes, cardiovascular diseases and obesity in the EPIC and Maastricht prospective cohort studies. The analyses showed surprising inverse associations between the consumption of MGO and 3-DG with the risk of diabetes, as well as with the risk of fatal and non-fatal CVD. Findings on associations of these compounds with cognitive function, overweight/obesity and description of European consumption levels are pending.