Glycotoxins: A Missing Link in the “Relationship of Dietary Fat and Meat Intake in Relation to Risk of Type 2 Diabetes in Men”

We have read with great interest the article entitled “Dietary Fat and Meat Intake in Relation to Risk of Type 2 Diabetes in Men,” by Van Dam et al. (1), which suggests a relationship between increased consumption of animal fat and red and processed meats and higher risk of type 2 diabetes in men.

We propose that the recently recognized toxic derivatives of advanced glycation and lipoxidation abundant in diets may explain the associations observed. Advanced glycation end products (AGEs) and lipoxidation end products (ALEs) are well-known glucose-derived factors contributing to diabetes-related complications (2). In addition to endogenous glucose, diet constitutes an important exogenous source of reactive precursor and terminal AGE and ALE, including a-β-dicarbonyl–containing derivatives. Common methods of food processing include heating, sterilizing, or ionizing, all of which tend to accelerate the nonenzymatic addition of nonreducing sugars to free NH₂-groups of proteins and lipids, a chemical process known as the Maillard reaction (3). This process, also known as “browning” of foods, is largely responsible for the color and flavor of cooked foods that most people are drawn to.

Recent estimates of AGE levels in ∼200 commonly consumed foods, based on immunoreactivity assays for specific AGEs (4G9; Alteon, Northvale, NJ) (4), found AGE and ALE content of these foods to be relative not only to food composition, but also to mode of cooking, temperature, and duration of exposure to heat. In particular, the presence of fats, which are major generators of free radicals that can enhance oxidative processes, including butter and margarine, attributes to high AGE and ALE levels. Thus, the highest AGE levels were observed in animal products high in protein and fat, such as meats and cheeses. Furthermore, high AGE levels were observed in (industrially) preprocessed foods from animal products like frankfurters, bacon, and powdered egg whites, compared with the unprocessed forms. Across all categories, exposure to higher temperature raised the AGE and ALE content (for equal food weights). The temperature level appeared to be more critical than the duration. Also, microwaving increased AGE content more rapidly compared with conventional cooking methods (5).

Studies in humans and animals have confirmed the significant intestinal absorption of consumed meal AGEs and their subsequent tissue retention (6,7). Restriction of food AGE intake in animals offered a marked protection against significant pathology observed in animal models of diabetic atherosclerosis, nephropathy, wound healing, and postinjury restenosis (femoral artery) (8–11). Recently, a marked improvement of various features of insulin resistance was demonstrated in db/db mice fed a diet low in AGEs (lower glucose and insulin responses to glucose challenge and improved lipid profiles) (12). Preliminary data from a 6-week study in patients with type 1 or type 2 diabetes, randomized to a high- or low-AGE diet, showed a significant reduction in the low-AGE diet group of circulating markers of inflammation, typical of diabetes vascular disease (13).

Based on the above data, we propose that dietary glycoxidation products may constitute an important link between the increased consumption of animal fat and meats and the subsequent development of type 2 diabetes.