Maternal Diabetes and a High-Fat Diet Program Transgenerational Dysfunction of the Endocrine Pancreas in Offspring

Background Maternal diabetes and exposure to a high‑fat diet (HFD) disrupt pancreatic development and glucose homeostasis, potentially inducing transgenerational metabolic changes. Objective Investigate how maternal diabetes and HFD exposure impact the endocrine pancreas across generations. Elucidate their effects on oxidative stress, cellular senescence, proliferation, cell death, and islet architecture in a transgenerational manner. Methods Female Sprague‑Dawley rats (F1) were allocated into four groups ( n =10/group): i) Offspring from non‑diabetic dams fed a standard diet (OC/SD); ii) Offspring from non‑diabetic dams fed an HFD (OC/HFD); iii) Offspring from diabetic dams fed a standard diet (OD/SD); and iv) Offspring from diabetic dams fed an HFD (OD/HFD). At postnatal day 90 (adulthood), the F1 females were mated and euthanized on gestational day 21 for pancreas harvesting for immunochemistry and morphological analysis. Their offspring (F2) were also obtained for pancreatic evaluation. Statistical significance was set at p <0.05. Results OD/HFD rats showed a 14.5% reduction in glucagon‑positive cells compared to the other groups. OC/HFD, OD/SD, and OD/HFD rats exhibited increased proportions of somatostatin‑positive (43.8%), cleaved caspase‑3‑positive (30.2%), and 4‑HNE‑positive (>100%) cells, along with reduced Ki‑67‑positive cells, relative to OC/SD rats. Newborns from OC/HFD dams had higher proportions of insulin‑, glucagon‑, and somatostatin‑positive cells than those from other dams. Conclusion Our findings suggest that maternal diabetes, regardless of HFD exposure, predisposes female offspring to future pancreatic dysfunction and an increased risk of metabolic disease, highlighting sex‑specific vulnerability of females to transgenerational programming.