Review
Role of Sex Steroids in β Cell Function, Growth, and Survival

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Trends

The steroid receptors for estrogen (ER), androgen (AR), and progesterone (PR) are expressed in islet β cells and are involved in survival, insulin secretion, and mass expansion.

ERs are targets to improve functional β cell mass in type 1 diabetes by protection from proapoptotic stimuli and enhancing the immunomodulatory function of invariant natural killer T (iNKT) lymphocytes.

ARs enhance GLP-1-stimulated insulin secretion in males and represent a novel target to prevent diabetes in aging and androgen-deficient men.

Excess AR activation in female fetal and adult β cells causes β cell dysfunction in the adult by producing insulin hypersecretion leading to secondary failure.

PRs are important in β cell adaptation to pregnancy by increasing insulin secretion and opposing the late effect of prolactin on proliferation.

The gonads have long been considered endocrine glands, producing sex steroids such as estrogens, androgens, and progesterone (P4) for the sole purpose of sexual differentiation, puberty, and reproduction. Reproduction and energy metabolism are tightly linked, however, and gonadal steroids play an important role in sex-specific aspects of energy metabolism in various physiological conditions. In that respect, gonadal steroids also influence the secretion of insulin in a sex-specific manner. This review presents a perspective on the physiological roles of estrogens, androgens, and P4 via their receptors in pancreatic β cells in the gender-specific tuning of insulin secretion. I also discuss potential gender-specific therapeutic avenues that this knowledge may open in the future.

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)

  • F. Labrie

    All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause

    J. Steroid Biochem. Mol. Biol.

    (2015)
  • P.B. Beeson

    Age and sex associations of 40 autoimmune diseases

    Am. J. Med.

    (1994)
  • M.S. Christianson

    Multiple sclerosis at menopause: potential neuroprotective effects of estrogen

    Maturitas

    (2015)
  • A. Lateef et al.

    Hormone replacement and contraceptive therapy in autoimmune diseases

    J. Autoimmun.

    (2012)
  • U. Islander

    Estrogens in rheumatoid arthritis; the immune system and bone

    Mol. Cell. Endocrinol.

    (2011)
  • H.J. Hwang

    Improved islet transplantation outcome by the co-delivery of siRNAs for iNOS and 17β-estradiol using an R3V6 peptide carrier

    Biomaterials

    (2015)
  • J.H. Kim

    Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice

    Mol. Metab.

    (2014)
  • F. Mauvais-Jarvis

    Androgen-deprivation therapy and pancreatic beta-cell dysfunction in men

    J. Diabetes Complications

    (2016)
  • G. Navarro

    Extranuclear actions of the androgen receptor enhance glucose-stimulated insulin secretion in the male

    Cell Metab.

    (2016)
  • E.P. Smith

    The role of beta cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs

    Cell Metab.

    (2014)
  • F. Mauvais-Jarvis

    Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity

    Trends Endocrinol. Metab.

    (2011)
  • K. Veras

    DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet

    FEBS Open Bio

    (2014)
  • M. Zhang

    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

    (2014)
  • I.S. Ahmed

    Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity

    J. Biol. Chem.

    (2010)
  • J.L. Halaas

    Weight-reducing effects of the plasma protein encoded by the obese gene

    Science

    (1995)
  • P. Bostrom

    A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

    Nature

    (2012)
  • F. Mauvais-Jarvis

    The role of estrogens in control of energy balance and glucose homeostasis

    Endocr. Rev.

    (2013)
  • G. Navarro

    The role of androgens in metabolism, obesity, and diabetes in males and females

    Obesity (Silver Spring)

    (2015)
  • W.L. Miller et al.

    The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders

    Endocr. Rev.

    (2011)
  • A. Morales

    Synthesis of steroids in pancreas: evidence of cytochrome P-450scc activity

    Pancreas

    (1999)
  • M.M. Miettinen

    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.

    (1996)
  • M.J. Iqbal

    Sex-steroid enzymes, aromatase and 5α-reductase in the pancreas: a comparison of normal adult, foetal and malignant tissue

    Clin. Sci. (Lond.)

    (1983)
  • J.P. Tiano et al.

    Importance of oestrogen receptors to preserve functional beta-cell mass in diabetes

    Nat. Rev. Endocrinol.

    (2012)
  • E.A. Gale et al.

    Diabetes and gender

    Diabetologia

    (2001)
  • G. Blohme

    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

    (1992)
  • L. Nystrom

    Risk of developing insulin-dependent diabetes mellitus (IDDM) before 35 years of age: indications of climatological determinants for age at onset

    Int. J. Epidemiol.

    (1992)
  • I. Weets

    Sex- and season-dependent differences in C-peptide levels at diagnosis of immune-mediated type 1 diabetes

    Diabetologia

    (2006)
  • U. Samuelsson

    Residual beta cell function at diagnosis of type 1 diabetes in children and adolescents varies with gender and season

    Diabetes Metab. Res. Rev.

    (2013)
  • K.C. Herold

    Type 1 diabetes: translating mechanistic observations into effective clinical outcomes

    Nat. Rev. Immunol.

    (2013)
  • P. Gourdy

    Estrogen therapy delays autoimmune diabetes and promotes the protective efficiency of natural killer T-cell activation in female nonobese diabetic mice

    Endocrinology

    (2016)
  • A.M. Shapiro

    Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen

    N. Engl. J. Med.

    (2000)
  • B.J. Hering

    Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes

    JAMA

    (2005)
  • A.M. Shapiro

    International trial of the Edmonton protocol for islet transplantation

    N. Engl. J. Med.

    (2006)
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