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

## TL;DR

Replacing carbs with casein protein in obese diabetic mice worsened insulin resistance and increased harmful AGEs in fat tissue, while soy protein had no such effects.

## Contribution

The study reveals that high-protein diets based on casein, but not soy, worsen insulin resistance and AGE accumulation in diabetic mice.

## Key findings

- Casein-based high-protein diets increased insulin resistance and glycer-AGE accumulation in adipose tissue.
- Soy-based high-protein diets had no significant effects on insulin resistance or AGE levels compared to standard diets.
- Casein-HPD also caused mild kidney damage and oxidative stress without structural changes.

## Abstract

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.

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.

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.

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.

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.