Maternal Low-Protein Diet During Nursing Leads to Glucose–Insulin Dyshomeostasis and Pancreatic-Islet Dysfunction by Disrupting Glucocorticoid Responsiveness in Male Rats

Both perinatal malnutrition and elevated glucocorticoids are pivotal triggers of the growing global pandemic of metabolic diseases. Here, we studied the effects of metabolic stress responsiveness on glucose-insulin homeostasis and pancreatic-islet function in male Wistar offspring whose mothers underwent protein restriction during lactation. During the first two weeks after delivery, lactating dams were fed a low-protein (4% protein, LP group) or normal-protein diet (22.5% protein, NP group). At 90 days of age, male rat offspring were challenged with food deprivation (72 h of fasting), intracerebroventricular (icv) injection of dexamethasone (2 µL, 2.115 mmol/L) or chronic intraperitoneal injection of dexamethasone (1 mg/kg body weight/5 days). Body weight, food intake, intravenous glucose tolerance test (ivGTT) results, insulin secretion and biochemical parameters were assessed. LP rats did not display significant metabolic changes after long-term starvation (<i>p</i> > 0.05) or under the central effect of dexamethasone (<i>p</i> = 0.999). Chronic dexamethasone induced rapid hyperglycemia (~1.2-fold, <i>p</i> < 0.001) and hyperinsulinemia (NP: 65%; LP: 216%; <i>p</i> < 0.001), decreased insulin sensitivity (NP: ~2-fold; LP: ~4-fold; <i>p</i> < 0.001), reduced insulinemia (20%) and increased glycemia (35%) only in NP rats under ivGTT conditions (<i>p</i> < 0.001). Glucose and acetylcholine insulinotropic effects, as well as the muscarinic receptor antagonist response, were reduced by chronic dexamethasone only in pancreatic islets from NP rats (<i>p</i> < 0.05). The direct effect of dexamethasone on pancreatic islets reduced insulin secretion (NP: 60.2%, <i>p</i> < 0.001; LP: 33.8%, <i>p</i> < 0.001). Peripheral glucose-insulin dyshomeostasis and functional failure of pancreatic islets in LP rats, as evidenced by an impaired acute and chronic response to metabolic stress, may be due to excessive corticosterone action as a long-term consequence.