Fetal androgen signaling defects affect pancreatic β-cell mass and function, leading to glucose intolerance in high-fat diet-fed male rats

Abstract

We previously demonstrated that androgen signaling expands pancreatic β-cell mass in the sexual maturation period ( Am J Physiol Endocrinol Metab 314: E274–E286, 2018). The aim of this study was to elucidate whether fetal androgen signaling plays important roles in β-cell mass development and β-cell function in adulthood, defects of which are associated with type 2 diabetes mellitus. In the pancreas of male fetuses, androgen receptor (AR) was strongly expressed in the cytoplasm and at the cell membrane of Nkx6.1-positive β-cell precursor cells but was markedly reduced in insulin-positive β-cells. Administration of the anti-androgen flutamide to pregnant dams during late gestation reduced β-cell mass and Ki67-positive proliferating β-cells at birth in a male-specific manner without affecting body weight. The decrease of β-cell mass in flutamide-exposed male rats was not recovered when rats were fed a standard diet, whereas it was fully recovered when rats were fed a high-fat diet (HFD), at 6 and 12 wk of age. Flutamide exposure in utero led to the development of glucose intolerance in male rats due to a decrease in insulin secretion when fed HFD but not standard diet. Insulin sensitivity did not differ between the two groups irrespective of diet. These results indicated that the action of fetal androgen contributed to β-cell mass expansion in a sex-specific manner at birth and to the development of glucose intolerance by decreasing the secretion of insulin in HFD-fed male rats. Our data demonstrated the involvement of fetal androgen signaling in hypothesized sex differences in the developmental origins of health and disease by affecting pancreatic β-cell function.

Relationship between gut environment, feces-to-food ratio, and androgen deficiency-induced metabolic disorders

“…Fetal androgen not only acts to promote the development of reproductive organs such as internal and external genitalia but also acts on the development of non-reproductive organs such as pancreatic βcells in males. 2,3 A transient testosterone surge in neonates is responsible for brain masculinization. 1 Additionally, an increase in testosterone during puberty contributes to the development of secondary sexual characteristics in males.…”

Insulin and glucose responses to hypoxia in male and female neonatal rats: Effects of the androgen receptor antagonist flutamide

“…Previous studies have shown that the activity of the androgen receptor can regulate insulin secretion from islet beta‐cells in rats and mice (Harada et al., 2018, 2019; Kooptiwut et al., 2015; Li et al., 2008; Xu et al., 2017). There seems to be an overall protective effect in rat islet cells exposed to testosterone via attenuation of superoxide production and decreased Caspase 3 cleavage under a high‐glucose environment (Kooptiwut et al., 2015).…”

“…If so and based on previous findings by others showing that testosterone increases insulin secretion (More, Mishra, Hankins, et al., 2016; Morimoto et al., 2001, 2005; Ramaswamy et al., 2016), we thought it possible that flutamide, an AR antagonist, would attenuate the plasma insulin in response to separation and hypoxia and possibly improve insulin sensitivity. Furthermore, we might expect reciprocal changes in plasma glucose due to the flutamide‐mediated modulation of pancreatic islet cell activity (Harada et al., 2019; Kupreeva et al., 2019). Or, it could be possible that corticosterone‐driven insulin resistance (Dallman et al., 1995; Jimeno et al., 2018; Morakinyo et al., 2019; Strack et al., 1995; Tadaishi et al., 2018) could increase plasma glucose which would then stimulate the release in insulin, and that this could be modulated by AR blockade.…”

“…We have previously shown the short‐term effects of androgen regulation on the HPA axis in the neonatal rat (Rolon et al., 2019). It seems that androgen secretion may also play a key role directly in the control of rat pancreatic beta‐cell function as well as the overall regulation of plasma insulin and glucose via effects on insulin sensitivity (Harada et al., 2018, 2019; Li et al., 2008; More, Mishra, Gopalakrishnan, et al., 2016; Pignatelli et al., 2006; Zhou et al., 2017). This is a follow‐up study of a cohort of neonatal rats treated with flutamide (Eulexin®), an androgen receptor (AR) antagonist, and subsequently exposed to acute normoxic or hypoxic separation (with acute fasting).…”

“…However, subsequent metabolic effects of neonatal androgens in female rats could result from the production of adrenal androgen precursors (Pignatelli et al., 2006; Zhou et al., 2015). While the adult rat adrenal does not express CYP17 and cannot synthesize appreciable androgens (Gallo‐Payet & Battista, 2014), the neonatal rat adrenal may have the capacity to synthesize androgens that function as critical regulators of normal development and could possibly account for non‐sexually dimorphic effects of androgen receptor actions (Harada et al., 2018, 2019; Li et al., 2008; More, Mishra, Gopalakrishnan, et al., 2016; More, Mishra, Hankins, et al., 2016; Pignatelli et al., 2006; Zhou et al., 2015).…”