Early weaning induces short‐ and long‐term effects on pancreatic islets in Wistar rats of both sexes

Abstract

Key points The World Health Organization recommends exclusive breastfeeding until 6 months of age as an important strategy to reduce child morbidity and mortality. Studies have associated early weaning with the development of obesity and type 2 diabetes in adulthood. In our model, we demonstrated that early weaning leads to increased insulin secretion in adolescent males and reduced insulin secretion in adult offspring. Early weaned males exhibit insulin resistance in skeletal muscle. Early weaning did not change insulin signalling in the muscle of female offspring. Taking into account that insulin resistance is one of the primary factors for the development of type 2 diabetes mellitus, this work demonstrates the importance of breastfeeding in the fight against this disease. Abstract Early weaning (EW) leads to short‐ and long‐term obesity and diabetes. This phenotype is also observed in experimental models, in which early‐weaned males exhibit abnormal insulinaemia in adulthood. However, studies regarding the effect of EW on pancreatic islets are rare. We investigated the mechanisms by which glycaemic homeostasis is altered in EW models through evaluations of insulin secretion and its signalling pathway in offspring. Lactating Wistar rats and their pups were divided into the following groups: non‐pharmacological EW (NPEW): mothers were wrapped with an adhesive bandage on the last 3 days of lactation; pharmacological EW (PEW): mothers received bromocriptine to inhibit prolactin (1 mg/kg body mass/day) on the last 3 days of lactation; and control (C): pups underwent standard weaning at PN21. Offspring of both sexes were euthanized at PN45 and PN180. At PN45, EW males showed higher insulin secretion (vs. C). At PN170, PEW males exhibited hyperglycaemia in an oral glucose tolerance test (vs. C and NPEW). At PN180, EW male offspring were heavier; however, both sexes showed higher visceral fat. Insulin secretion was lower in EW offspring of both sexes. Males from both EW groups had lower glucokinase in islets, but unexpectedly, PEW males showed higher GLUT2, than did C. EW males exhibited lower insulin signalling in muscle. EW females exhibited no changes in these parameters compared with C. We demonstrated distinct alterations in the insulin secretion of EW rats at different ages. Despite the sex dimorphism in insulin secretion in adolescence, both sexes showed impaired insulin secretion in adulthood due to EW.

Early life stress determines insulin signalling in adulthood

“…They also demonstrate marked sex differences with respect to insulin secretion in early life and adulthood, as well as with regard to the susceptibility to weaning-induced pancreatic islet cell dysfunction, indicating some of the potential molecular mechanisms involved. The studies by Pietrobon et al (2020) further support the importance of endogenous sex hormones in the regulation of glucose metabolism and insulin function. Given that all three oestrogen receptors (ERα, ERβ and GPER) modulate insulin secretion and sensitivity (Alonso-Magdalena et al 2008;Ropero et al 2012;Sharma & Prossnitz, 2011), future studies should also investigate the effect of ovariectomy or oestrogen supplementation and include the use of animal models in which these receptors have been deleted from the genome (Meyer et al 2011) to further decipher the underlying mechanisms.…”

“…When the investigators repeated the studies in animals at 6 months of age, the sex differences in insulin secretion in normally weaned animals not only disappeared, but were actually reversed, with much greater insulin secretion in males. However, compared to both adult controls and early weaned adolescent animals, insulin secretion was greatly attenuated in both males and females (Pietrobon et al 2020). These novel and important findings indicate that significant early life sex differences exist with regard to pancreatic insulin secretion, and also that, in adulthood, previous early life stress caused by maternal separation is associated with long-term attenuation of insulin secretion in both males and females.…”

“…Interestingly, no regulation of pancreatic proteins involved in insulin secretion was observed, nor was ERα protein expression changed. Finally, circulating adiponectin levels were also determined, which, when compared with visceral fat mass, were reduced after early weaning in both male and female animals (Pietrobon et al 2020). The studies by Pietrobon et al (2020) demonstrate for the first time that early life stress induced by maternal separation and terminating breast-feeding early negatively affects insulin signalling in adulthood, which might contribute to the risk of developing diabetes with age.…”

“…Finally, circulating adiponectin levels were also determined, which, when compared with visceral fat mass, were reduced after early weaning in both male and female animals (Pietrobon et al 2020). The studies by Pietrobon et al (2020) demonstrate for the first time that early life stress induced by maternal separation and terminating breast-feeding early negatively affects insulin signalling in adulthood, which might contribute to the risk of developing diabetes with age. They also demonstrate marked sex differences with respect to insulin secretion in early life and adulthood, as well as with regard to the susceptibility to weaning-induced pancreatic islet cell dysfunction, indicating some of the potential molecular mechanisms involved.…”

“…Unexpectedly, early life stress from natural early weaning had no effect in males but, if weaning was chemically induced by bromocriptine, insulin secretion almost tripled. Only these animals showed an abnormal oral glucose tolerance test, whereas, in females, early weaning or pharmacological early weaning was without effect (Pietrobon et al 2020). When the investigators repeated the studies in animals at 6 months of age, the sex differences in insulin secretion in normally weaned animals not only disappeared, but were actually reversed, with much greater insulin secretion in males.…”