Impact of Low-Molecular-Weight (<3 kDa) Camel Milk Casein and Whey Protein Hydrolysates on Hyperglycemia and Associated Hyperlipidemia, Oxidative Stress, and Reproductive Health in Type 2 Diabetic Male Rats

Abstract

This study investigated the antidiabetic potential of ultrafiltered, low-molecular-weight (<3 kDa) camel milk protein hydrolysates (CMPHs) derived from casein and whey proteins. Hydrolysates were generated using gastrointestinal enzymes─pepsin (P), trypsin (T), and chymotrypsin (C)─both individually and in combinations (P, T, C, PT, PC, TC, and PTC) and screened for dipeptidyl peptidase-IV (DPP-IV) inhibitory activity and glucagon-like peptide-1 (GLP-1) secretion. Casein hydrolysates produced with PC and whey hydrolysates with PTC showed the highest bioactivity. These were further fractionated into >10 kDa, 3–10 kDa, and <3 kDa, with the <3 kDa fractions of D-CN-PC and D-WP-PTC showing the highest DPP-IV inhibition (55.38% and 80.67 ± 2.18%) and GLP-1 secretion (2.67 and 2.68 ng/mL), surpassing intact proteins. The most effective fractions were evaluated in streptozotocin (STZ) and nicotinamide-induced type-2 diabetic male Wistar rats. Six-week oral administration of the hydrolysates significantly improved hyperglycemia, oxidative stress, lipid profile, and reproductive function, with D-WP-PTC < 3 kDa being most effective─reducing blood glucose by 66.03% and OGTT to 148.44 mg/dL. Histology confirmed restoration of disturbed pancreatic and testicular architecture, while gene expression studies revealed favorable modulation of hepatic glucose metabolism genes, i.e., Phosphoenolpyruvate Carboxykinase (PEPCK), Glucose-6-Phosphatase (G6 Pase), Glucose Transporter Type 2 (GLUT2), and Gluco Kinase (GK). These findings suggest that both CMPHs, particularly D-WP-PTC < 3 kDa, possess strong therapeutic potential for managing diabetes and its complications by enhancing insulin secretion, improving antioxidant defense, regulating metabolism, and restoring reproductive health in diabetic rats.