High-Protein Diet Exacerbates Insulin Resistance via the JNK/IKKβ-IRS-1 Pathway

To investigate the effects of a high-protein (HP) diet on insulin resistance in a type 2 diabetes (T2D) mouse model.

A high-fat diet combined with streptozotocin (STZ, 25 mg/kg) was used to induce a T2D model. Fasting blood glucose levels > 7 mmol/L were considered successful modelling. The models were further divided into three groups: the Normal-Protein-T2D (TN, n = 8), High-Protein-T2D (TH, n = 8), and High-Fat-T2D (TF, n = 8) groups. These groups were fed diets containing 20% protein, 60% protein, and 60% fat, respectively. Additionally, 24 Kunming (KM) mice, serving as non-T2D controls, were divided into a Normal-Protein-Control (N, n = 8), a High-Protein-Control (H, n = 8), and a Low-Protein-Control (L, n = 8), fed 20% protein, 60% protein, and 5% protein diets, respectively. After 6 weeks of dietary intervention, FBG, serum biochemical markers, hepatic inflammatory factors and pathological changes, and pancreatic immunohistochemistry were assessed. Expression of IRS-1, JNK, IKKβ, and their phosphorylated proteins were analysed.

Mice in the H group exhibited significantly impaired glucose tolerance, exacerbated insulin resistance, and reduced liver function. In the T2D model, TH mice exhibited more severe hyperglycemia, insulin resistance, and β-cell dysfunction than TN mice, accompanied by increased hepatic TNF-α and IL-6 expression, enhanced lipid accumulation, suppressed IRS-1 phosphorylation, and enhanced JNK and IKKβ phosphorylation.

A HP diet induces insulin resistance in normal mice and further exacerbates glucose metabolism disorders in T2D models, suggesting that restricting HP intake may serve as a strategy for preventing T2D.