Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats

Abstract

Background Insulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largely unknown in both sexes. Sexual dimorphism in insulin sensitivity is observed since early stages of development. We propose that during periods of accelerated growth, such as around weaning, at postnatal day 20 (p20) in rats, the kinase S6K1 is overactivated and induces impairment of insulin signaling in its target organs. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage. Methods We determined systemic insulin sensitivity through insulin tolerance tests, glucose tolerance tests, and blood glucose and insulin levels under fasting and fed conditions at p20 and adult male and female Wistar rats. Furthermore, we quantified levels of S6K1 phosphorylated at threonine 389 (T389) (active form) and its target IRS1 phosphorylated at serine 1101 (S1101) (inhibited form). In addition, we assessed insulin signal transduction by measuring levels of Akt phosphorylated at serine 473 (S473) (active form) in white adipose tissue and skeletal muscle through western blot. Finally, we determined the presence and function of GLUT4 in the plasma membrane by measuring the glucose uptake of adipocytes. Results were compared using two-way ANOVA (With age and sex as factors) and one-way ANOVA with post hoc Tukey’s tests or t-student test in each corresponding case. Statistical significance was considered for P values < 0.05. Results We found that both male and female p20 rats have elevated levels of glucose and insulin, low systemic insulin sensitivity, and glucose intolerance. We identified sex- and tissue-related differences in the activation of insulin signaling proteins in p20 rats compared to adult rats. Conclusions Male and female p20 rats present physiological insulin resistance with differences in the protein activation of insulin signaling. This suggests that S6K1 overactivation and the resulting IRS1 inhibition by phosphorylation at S1101 may modulate to insulin sensitivity in a sex- and tissue-specific manner.

Intrauterine and early-life malnutrition in rats disrupts the circadian rhythm programming of energy metabolites through adulthood

“…Research has highlighted sexual dimorphism in various metabolic parameters, particularly in glucose regulation. For instance, insulin signaling (IRS1), which is higher in males, and glucose-induced expression of GLUT4 in early stages affect glucose regulation differently between males and females [ 49 ]. This sexual dimorphism extends to metabolic impacts, with males showing increased insulin resistance.…”

Cannabidiol treatment improves metabolic profile and decreases hypothalamic inflammation caused by maternal obesity

“…It is worth noting that the sexual dimorphisms observed in this study regarding glucose metabolism and IR corroborate with what has been demonstrated in different models of obesity and maternal obesity ( 71 ). Female sex hormones play a fundamental role in dimorphic insulin signaling since estrogens increase insulin sensitivity in metabolic tissues and upregulate insulin transcription in pancreatic beta cells as well as GLUT4 synthesis in adipose tissue and muscle ( 72 ). Female mice fed an HFD showed reduced susceptibility to developing obesity-induced IR and WAT inflammation when compared to HFD-fed males.…”

NGF effects promote the maturation of rat pancreatic beta cells by regulating GLUT2 levels and distribution, and glucokinase activity

“…Before each experiment, adult rats were fasted for 12 h while P20 rats were fasted for 4 h. These fasting times were used because glucose reached basal levels and remained stable after this fasting period for each age [27]. Fasted animals were anesthetized with sodium Pentobarbital (40 mg/kg of weight) intraperitoneally; after the dissection, cervical dislocation was…”

“…Therefore, NGF may promote beta-cell functional maturation. However, to our knowledge, no studies have assessed the NGF effects on GSIS in beta cells obtained from P20 rats, characterized by physiological insulin resistance due to high fasting plasma glucose and insulin levels [19,27].…”