Casein- and Soy-Based High-Protein Diets Differentially Affect Insulin Resistance and Adipose Tissue Advanced Glycation End Product Accumulation in Obese Diabetic Mice

Background: Replacing dietary carbohydrates with protein has been proposed as a nutritional strategy to improve glycemic control and reduce obesity in individuals with type 2 diabetes. However, high-protein diets (HPDs) may also facilitate the formation of advanced glycation end products (AGEs), pathogenic molecules associated with insulin resistance and various diabetic complications. Objectives: This study investigated the effects of animal- and plant-based high-protein, low-carbohydrate diets on insulin resistance and tissue AGE accumulation in obese diabetic mice. Methods: Male KK-Ay mice were fed either a standard diet (STD; 64% carbohydrate and 20% casein of total energy) or casein- and soy-based HPDs (casein-HPD and soy-HPD; 43% carbohydrate and 41% casein or soy protein of total energy, respectively) for 12 wk. Blood, urine, epididymal adipose tissue, and kidneys were collected for biochemical, histological, and molecular analyses. Results: Compared with the STD, the casein-HPD reduced glycated hemoglobin concentrations (12.4% compared with 9.9%) without affecting body weight gain or energy intake, but it significantly exacerbated insulin resistance (467% increase compared with STD). In epididymal adipose tissue, the casein-HPD-induced marked accumulation of glyceraldehyde-derived AGEs (glycer-AGEs), a highly toxic subtype, accompanied by increased oxidative stress, macrophage infiltration, and reduced adiponectin expression. The casein-HPD also modestly impaired renal function and increased renal glycer-AGE and oxidative stress concentrations without affecting proteinuria or structural changes. In contrast, the soy-HPD did not alter glycated hemoglobin, insulin resistance, renal function, or tissue AGE accumulation. All diets contained negligible glycer-AGE concentrations, indicating that endogenous formation was selectively enhanced by the casein-HPD. Conclusions: A casein-HPD was associated with greater insulin resistance in this model, concurrent with increased glycer-AGE accumulation in visceral adipose tissue, whereas the soy-HPD did not result in substantial differences compared with the STD. These observations suggest that the metabolic effects of HPDs may differ depending on the protein source.