O desmame precoce e a exposição à nicotina na lactação programa para esteatose pancreática que compromete a função das células beta e a homeostase glicêmica em ratos de ambos os sexos

Abstract

Studies showed that early weaning (EW) and icotine exposure during breastfeeding lead to endocrine-metabolic changes, such as obesity and type 2 diabetes mellitus (T2DM) in adult offspring. We demonstrated that adult male rats submitted to these two programming models present similar phenotypes in relation to glycemic homeostasis, suggesting insulin resistance. Thus, we investigate the mechanisms by which male glycemic homeostasis is altered in both models and propose to study females for the first time. Early weaning programming model: Lactating Wistar rats were separated into 3 groups: Non- pharmacological EW (NPEW): mothers were wrapped with an adhesive bandage at 3 last days of lactation; Pharmacological EW (PEW): mothers received bromocriptine (1mg / kg BW / day) in the last 3 days of lactation; and Control (C): whose pups were weaned in PN21. One pup of each litter/sex/group was euthanized in PN45 and the rest of the animals were euthanized in PN180. At PN45 only EW males showed increased insulin secretion (vs C). At PN180: PEW males showed glucose intolerance (OGTT), as well reduced in insulin secretion, glucokinase, and increased GLUT2, while NPEW males showed only reduced in insulin secretion and glucokinase. Early weaned females had lower insulin secretion (vs C). Adult offspring had a lower adiponectin/visceral fat as well pancreatic steatosis. In skeletal muscle, NPEW males showed reduction in insulin receptor, pAKT and GLUT4 expression, while PEW males showed reduction only GLUT4 expression. In contrast, females showed no alteration. Programming model for maternal nicotine exposure during breastfeeding: At PN2, minipumps were implanted in lactating Wistar rats, which were separated into 2 groups: Nicotine (NIC, 6 mg/kg/day for 14 days) and Control (CON, saline solution for 14 days). The animals were euthanized in PN180. Adult offspring of both sexes presented glucose intolerance (OGTT), increased IRI, reduced adiponectin/visceral fat ratio and greater accumulation of ectopic fat in the pancreas. Males of NIC group had hyperinsulinemia, while females were hyperglycemic with no changes in insulin. In pancreatic islets, NIC males exhibited PDX-1 reduction and NIC females increased PDX-1 and GLUT2 with reduced α2 adrenergic receptor. In muscle, NIC males showed reduction in insulin receptor, pAKT and GLUT4 expression, while NIC females showed only reduction of GLUT4. Both programming models induce changes related to glycemic homeostasis. We observed that males from the EW or NIC group are negatively and similarly affected, whereas the female EW does not appear to have such a higher impairment in glycemic homeostasis, which is different in the model of nicotine exposure, where female offspring are as harmed as males. Despite the sexual dimorphism observed between the different insults, both contribute to the obesity and T2DM pandemic, since it predisposes the offspring to increased chances for the development of these diseases.