Trends in Endocrinology & Metabolism
ReviewRole of Sex Steroids in β Cell Function, Growth, and Survival
Introduction
The pituitary, the thyroid, and the adrenal glands are endocrine organs with the sole known function of synthesizing and secreting hormones that act on distant tissues and organs. Other organs have emerged as endocrine peptide secretors that regulate energy homeostasis through secretion of the adipose-derived satiety hormone leptin [1], the incretin glucagon like peptide-1 (GLP-1) produced by intestinal L cells [2], and the bone-derived regulator of energy homeostasis osteocalcin [3]. The liver can also be considered an endocrine organ that stimulates energy metabolism via production of the fasting hormone fibroblast growth factor 21 and influences pancreatic β cell function and proliferation by producing kisspeptin [4] and serpin B1 [5]. The list can be extended to include the hunger hormone ghrelin produced by the stomach and the controversial myokine irisin produced by skeletal muscle during exercise [6]. Historically, the gonads have been viewed as endocrine organs secreting steroids for the sole purpose of sexual differentiation, puberty, and reproduction. However, because energy stores need to reach a minimum threshold to allow reproduction to occur, reproduction is tightly linked to energy metabolism. Thus, under physiological conditions gonadal hormones play an important role in sex-specific aspects of energy metabolism 7, 8. For example, secretion of insulin, an anabolic hormone produced by the β cells of the pancreatic islets of Langerhans that promotes energy storage, is influenced by gonadal steroids in a sex-specific manner. This review discusses the physiological roles of the ovarian– and testicular–islet axes in the biology of insulin-producing β cells in females and males. I discuss the roles of estrogens, androgens, and progestogens via their receptors (ER, AR, and PR, respectively) in the gender-specific tuning of insulin secretion and outline potential gender-specific therapeutic avenues that these signaling pathways open.
Section snippets
Sex Steroid Biosynthesis in Males and Females
Pregnenolone, a steroid hormone synthesized from the enzymatic cleavage of cholesterol, is the precursor for the synthesis of gonadal steroids via a reaction catalyzed by cytochrome P450 side-chain cleavage (P450scc) in the mitochondria (Figure 1) (for a review see [9]). In the adult male, the testicular Leydig cells are the sites of testosterone biosynthesis in response to luteinizing hormone (LH) secreted from the pituitary (Figure 1). In the female ovary, both granulosa and theca cells
Evidence of Local Islet Steroidogenesis
The brain also synthesizes steroids de novo from cholesterol that are referred to as neurosteroids [10]. Evidence suggests that the pancreas also has the machinery to synthesize steroids. Cytochrome P450scc, responsible for the first limiting step in steroid biosynthesis (Figure 1), was detected in dog pancreas mitochondria [11]. The enzymatic activities of 17β-hydroxysteroid dehydrogenase (17β-HSD), which produces testosterone from androstenedione and E2 from estrone (E1) (Figure 1), have been
Role of Estrogens
The role of female hormone E2 and related estrogens via ERα, ERβ, and the G protein-coupled ER (GPER) in islet biology has been recently reviewed [20] and can be summarized as follows (Figure 2). ERα is involved in survival, insulin biosynthesis, and nutrient homeostasis, while ERβ enhances glucose-stimulated insulin secretion (GSIS). GPER is implicated in GSIS and islet survival. Unlike the classical nuclear ERs, which act as a ligand-activated transcription factors in breast and uterine
Males
The AR has long been considered a classical ligand-activated nuclear receptor that regulates the expression of target genes in reproductive tissues through binding to cognate response elements on the DNA 53, 54, 55. Although the function of testosterone and the AR in adiposity and insulin sensitivity in males is known, the role of the AR in islet function has been poorly explored 8, 56. This is surprising, because large observational studies have reported that, among prostate cancer patients,
Progestogens
Progestogens are named for their function in maintaining pregnancy (i.e., progestational) and activate PRs. The most important progestogen is P4. Historically, P4 was shown to enhance the insulin response to glucose, suggesting that P4 promotes islet adaptation to gestational insulin resistance [71]. The discovery of PRs in the primate and human endocrine pancreas suggested a direct role of P4 in islet function 72, 73. Treatment of female rats with a combination of E2 and P4 increased GSIS and
Concluding Remarks and Future Perspectives
Receptors for estrogens, androgens, and progestogens are expressed in male and female β cells. Although male and female mammals exhibit the same overall mechanism of nutrient-induced insulin secretion, evidence presented here demonstrates that the fine-tuning of insulin secretion can be regulated in a sex-specific manner by gonadal steroids. Thus, ERs are targets to improve functional β cell mass and modulate immune function in T1D. However, ARs enhance GLP-1-stimulated insulin secretion in
Acknowledgments
This work was supported by grants from the National Institutes of Health (DK074970 and DK107444) and the American Diabetes Association (7-13-BS-101).
References (87)
The biology of incretin hormones
Cell Metab.
(2006)Endocrine regulation of energy metabolism by the skeleton
Cell
(2007)Glucagon regulates hepatic kisspeptin to impair insulin secretion
Cell Metab.
(2014)SerpinB1 promotes pancreatic beta cell proliferation
Cell Metab.
(2016)- et al.
Neurosteroids: a new brain function?
J. Steroid Biochem. Mol. Biol.
(1990) Distribution of 17β-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues
J. Steroid Biochem. Mol. Biol.
(1992)17β-Hydroxysteroid dehydrogenase activity in canine pancreas
Biochem. Biophys. Res. Commun.
(1988)Systemic distribution and tissue localizations of human 17β-hydroxysteroid dehydrogenase type 12
J. Steroid Biochem Mol. Biol.
(2006)Cytochrome P-45017α in beta-cells of rat pancreas and its local steroidogenesis
J. Steroid Biochem. Mol. Biol.
(2008)Δ5-3β-Hydroxysteroid dehydrogenase–isomerase activity in canine pancreas
Life Sci.
(1990)
All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause
J. Steroid Biochem. Mol. Biol.
Age and sex associations of 40 autoimmune diseases
Am. J. Med.
Multiple sclerosis at menopause: potential neuroprotective effects of estrogen
Maturitas
Hormone replacement and contraceptive therapy in autoimmune diseases
J. Autoimmun.
Estrogens in rheumatoid arthritis; the immune system and bone
Mol. Cell. Endocrinol.
Improved islet transplantation outcome by the co-delivery of siRNAs for iNOS and 17β-estradiol using an R3V6 peptide carrier
Biomaterials
Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice
Mol. Metab.
Androgen-deprivation therapy and pancreatic beta-cell dysfunction in men
J. Diabetes Complications
Extranuclear actions of the androgen receptor enhance glucose-stimulated insulin secretion in the male
Cell Metab.
The role of beta cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs
Cell Metab.
Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity
Trends Endocrinol. Metab.
DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet
FEBS Open Bio
Progesterone receptor membrane component 1 is a functional part of the glucagon-like peptide-1 (GLP-1) receptor complex in pancreatic beta cells
Mol. Cell. Proteomics
Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity
J. Biol. Chem.
Weight-reducing effects of the plasma protein encoded by the obese gene
Science
A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
Nature
The role of estrogens in control of energy balance and glucose homeostasis
Endocr. Rev.
The role of androgens in metabolism, obesity, and diabetes in males and females
Obesity (Silver Spring)
The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders
Endocr. Rev.
Synthesis of steroids in pancreas: evidence of cytochrome P-450scc activity
Pancreas
Human 17β-hydroxysteroid dehydrogenase type 1 and type 2 isoenzymes have opposite activities in cultured cells and characteristic cell- and tissue-specific expression
Biochem. J.
Sex-steroid enzymes, aromatase and 5α-reductase in the pancreas: a comparison of normal adult, foetal and malignant tissue
Clin. Sci. (Lond.)
Importance of oestrogen receptors to preserve functional beta-cell mass in diabetes
Nat. Rev. Endocrinol.
Diabetes and gender
Diabetologia
Male predominance of type 1 (insulin-dependent) diabetes mellitus in young adults: results from a 5-year prospective nationwide study of the 15-34-year age group in Sweden
Diabetologia
Risk of developing insulin-dependent diabetes mellitus (IDDM) before 35 years of age: indications of climatological determinants for age at onset
Int. J. Epidemiol.
Sex- and season-dependent differences in C-peptide levels at diagnosis of immune-mediated type 1 diabetes
Diabetologia
Residual beta cell function at diagnosis of type 1 diabetes in children and adolescents varies with gender and season
Diabetes Metab. Res. Rev.
Type 1 diabetes: translating mechanistic observations into effective clinical outcomes
Nat. Rev. Immunol.
Estrogen therapy delays autoimmune diabetes and promotes the protective efficiency of natural killer T-cell activation in female nonobese diabetic mice
Endocrinology
Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen
N. Engl. J. Med.
Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes
JAMA
International trial of the Edmonton protocol for islet transplantation
N. Engl. J. Med.
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