The consumption of a diet high in fat and fructose induces sex-specific alterations in the expression of key genes related to insulin synthesis, inflammation and apoptosis in the pancreatic β-cells of rodents.

High-energy, sugar-rich diets are associated with obesity and pancreatic disorders. We investigated the effects of consumption of a high-fat and high-fructose diet (HFFrD) on gene expression related to insulin synthesis, inflammation, and apoptosis in pancreatic β-cells. Weaned Wistar rats were fed either a control diet (CD; 11% kcal from fat and 0% from fructose) or an HFFrD (48% kcal from fat and 33% from fructose) for 22 weeks; after a 6-hour fast, animals were euthanized. Body weight and total fat were recorded. Serum analyses included: glucose, insulin, triglycerides, malondialdehyde (MDA), TNFα, IL-6, IL-10, and advanced glycation end-products (AGEs). Pancreatic islets were analyzed for gene expression linked to insulin synthesis, inflammation, and apoptosis. Pancreatic assessments included TUNEL assay and immunohistochemistry. HFFrD increased body weight, total fat, MDA, insulin, HOMA-IR, AGEs, triglycerides, and IL-6 concentrations in both sexes. Gene expression revealed sex-dependent differences: Glut2, Gck, Khk, Ins2 and the transcription factor Mafa were downregulated in males but upregulated in females. Pdx1 expression increased in females, whereas NeuroD1 increased in males. Pro-inflammatory markers (Il-1β, Il-6) increased in both sexes, whereas Il-10 decreased in males and increased in females. Bax/Bcl2 ratio decreased in males but increased in females; antioxidant and apoptotic markers Nrf2 and Casp3 increased in females. Endocannabinoid receptors (Cnr1, Cnr2) increased in both sexes. HFFrD altered the expression of genes involved in insulin synthesis, inflammation, and apoptosis in a sex-specific manner. Compared with males, females showed lower vulnerability, possibly because of adaptive responses in insulin synthesis signaling influenced by sex hormones.