Endocrine Reviews

Diabetes has been known since antiquity. We present here a historical perspective on the concepts and ideas regarding the physiopathology of the disease, on the progressive focus on the pancreas, in particular on the islets discovered by Langerhans in 1869, leading to the iconic experiment of Minkowski and von Mering in 1889 showing that pancreatectomy in a dog induced polyuria and diabetes mellitus. Subsequently, multiple investigators searched for the active substance of the pancreas and some managed to produce extracts that lowered blood glucose and decreased polyuria in pancreatectomized dogs, but were too toxic to be administered to patients...

The pathogenesis of hyperglycemia observed in most forms of diabetes is intimately tied to the islet β cell. Impairments in propeptide processing and secretory function along with the loss of these vital cells is demonstrable not only in those in whom the diagnosis is established, but typically also in individuals who are at increased risk of developing the disease. Biomarkers are used to inform on the state of a biological process, pathological condition or response to an intervention and are increasingly being used for predicting, diagnosing and prognosticating disease...

Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters depending on underlying genetic alterations. With around 30-35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35-40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver-mutations...

The obesity pandemic increasingly causes morbidity and mortality from type 2 diabetes, cardiovascular diseases and many other chronic diseases. Fat cell size (FCS) predicts numerous obesity-related complications such as lipid dysmetabolism, ectopic fat accumulation, insulin resistance, and cardiovascular disorders. Nevertheless, the scarcity of systematic literature reviews on this subject is compounded by the use of different methods by which FCS measurements are determined and reported. In this paper, we provide a systematic review of the current literature on the relationship between adipocyte hypertrophy and obesity-related glucose and lipid dysmetabolism, ectopic fat accumulation, and cardiovascular disorders...

Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous skeletal dysplasia characterized by bone fragility, growth deficiency and skeletal deformity. Previously known to be caused by defects in type I collagen, the major protein of extracellular matrix, it is now also understood to be a collagen-related disorder caused by defects in collagen folding, post-translational modification and processing, bone mineralization and osteoblast differentiation, with inheritance of OI types spanning autosomal dominant and recessive as well as X-linked recessive...

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments...

Steroid receptors (SRs) are members of the nuclear hormonal receptor family, many of which are transcription factors regulated by ligand binding. SRs regulate various human physiological functions essential for maintenance of vital biological pathways, including development, reproduction and metabolic homeostasis. In addition, aberrant expression of SRs or dysregulation of their signaling has been observed in a wide variety of pathologies. SR activity is tightly and finely controlled by posttranslational modifications targeting the receptors and/or their coregulators...

Work over the last 40 years has described macrophages as a heterogeneous population that serve as the frontline surveyors of tissue immunity. As a class, macrophages are found in almost every tissue in the body and as distinct populations within discrete microenvironments in any given tissue. During homeostasis, macrophages protect these tissues by clearing invading foreign bodies and/or mounting immune responses. In addition to varying identities regulated by transcriptional programs shaped by their respective environments, macrophage metabolism serves as an additional regulator to temper responses to extracellular stimuli...

In May 2014, the National Institutes of Health (NIH) stated its intent to "require applicants to consider sex as a biological variable (SABV) in the design and analysis of NIH-funded research involving animals and cells." Since then, proposed research plans that include animals routinely state that both sexes/genders will be used; however, in many instances, researchers and reviewers are at a loss about the issue of sex differences. Moreover, the terms sex and gender are used interchangeably by many researchers, further complicating the issue...

The burden of adverse pregnancy outcomes such as preterm birth and low birth weight is considerable across the world. Several risk factors for adverse pregnancy outcomes have been identified. One risk factor for adverse pregnancy outcomes receiving considerable attention in recent years is gestational exposure to endocrine-disrupting chemicals (EDCs). Humans are exposed to a multitude of environmental chemicals with known endocrine-disrupting properties, and evidence suggests exposure to these EDCs have the potential to disrupt the maternal-fetal environment culminating in adverse pregnancy and birth outcomes...

Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as Primary Ovarian Insufficiency, Hypothalamic Amenorrhea, Congenital Hypogonadotropic Hypogonadism and Early Menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system...

Islet autoantibodies are key markers for the diagnosis of type 1 diabetes. Since their discovery, they have also been recognized for their potential to identify at-risk individuals prior to symptoms. To date, risk prediction using autoantibodies has been based on autoantibody number; it has been robustly shown that nearly all multiple-autoantibody-positive individuals will progress to clinical disease. However, longitudinal studies have demonstrated that the rate of progression amongst multiple-autoantibody-positive individuals is highly heterogenous...

Hormone therapy (HT) is an effective treatment for menopausal symptoms, including vasomotor symptoms and genitourinary syndrome of menopause. Randomized trials also demonstrate positive effects on bone health, and age-stratified analyses indicate more favorable effects on coronary heart disease and all-cause mortality in younger women (close proximity to menopause) than in women more than a decade past menopause. In the absence of contraindications or other major comorbidities, recently menopausal women with moderate or severe symptoms are appropriate candidates for HT...

Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance, was shown to be synthesized by the ovary in the eighties. This article reviews the main findings of the past 20 years on the regulation of the expression of AMH and its specific receptor AMHR2 by granulosa cells, the mechanism of action of AMH, the different roles it plays in the reproductive organs, its clinical utility and its involvement in the principal pathological conditions affecting women. The findings in respect of regulation tell us that AMH and AMHR2 expression is mainly regulated by Bone Morphogenetic Proteins, gonadotropins and estrogens...

This review focuses on the human pancreatic islet - including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms...

Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory response to ACTH that are best indexed by dehydroepiandrosterone sulfate (DHEAS) rise. These changes are related to the development of the zona reticularis (ZR) and its unique gene/enzyme expression pattern of low 3ß-hydroxysteroid dehydrogenase type 2 with high cytochrome b5A, sulfotransferase 2A1, and 17ß-hydroxysteroid dehydrogenase type 5. Recently 11-ketotestosterone was identified as an important bioactive adrenarchal androgen...

Plasma triglyceride-rich lipoproteins (TRL), particularly atherogenic remnant lipoproteins, contribute to atherosclerotic cardiovascular disease (ASCVD). Hypertriglyceridemia may arise in part from hypersecretion of TRLs by the liver and intestine. Here we focus on the complex network of hormonal, nutritional, and neuronal interorgan communication that regulates secretion of TRLs, and provide our perspective on the relative importance of these factors. Hormones and peptides originating from the pancreas (insulin, glucagon), gut (GLP-1, GLP-2, ghrelin, CCK, peptide YY), adipose tissue (leptin, adiponectin) and brain (GLP-1) modulate TRL secretion by receptor-mediated responses and indirectly via neural networks...

Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity...

Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review...

Regulatory T cells (Tregs) have become highly relevant in the pathophysiology and treatment of autoimmune diseases, such as type 1 diabetes (T1D). As these cells are known to be defective in T1D, recent efforts have explored ex vivo and in vivo Treg expansion and enhancement as a means for restoring self-tolerance in this disease. Given their capacity to also modulate alloimmune responses, studies using Treg-based therapies have recently been undertaken in transplantation. Islet transplantation provides a unique opportunity to study the critical immunological crossroads between auto- and alloimmunity...