Reviews in Endocrine and Metabolic Disorders

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is the major controlling hormone of intestinal calcium absorption. As the body's demand for calcium increases from a diet deficient in calcium, from growth, pregnancy or lactation, the synthesis of 1,25(OH)(2)D(3) is increased resulting in the stimulation of intestinal calcium absorption. However a complete description of the molecular mechanisms involved in the 1,25(OH)(2)D(3) regulated calcium absorptive process remains incomplete. Intestinal calcium absorption occurs by both an active saturable transcellular pathway and a passive nonsaturable paracellular pathway. Each step in the process of transcellular calcium transport (apical entry of calcium, translocation of calcium through the interior of the enterocyte and basolateral extrusion of calcium by the plasma membrane pump) has been reported to involve a vitamin D dependent component. This article will review recent studies, including those using knockout mice, that have suggested that 1,25(OH)(2)D(3) mediated calcium absorption is more complex than the traditional three step model of transcellular calcium transport. Current concepts are reviewed and questions that remain are addressed. Evidence for a role of 1,25(OH)(2)D(3) in the regulation of the paracellular pathway is also discussed.

Vitamin D has emerged as a pleiotropic regulator of human physiology, and recent work has revealed that it has several roles in control of human immune system function. Vitamin D was originally characterized for its role in calcium homeostasis, and the active form, 1,25-dihydroxyvitamin D (1,25D), can be produced in the kidney by 1α-hydroxylation of circulating 25-hydroxyvitamin D catalyzed by the enzyme CYP27B1. Renal CYP27B1 expression is regulated by calcium regulatory inputs, and 1,25D produced in the kidney was thought to function largely as an endocrine hormone. However, it is now clear that CYP27B1 is expressed in numerous tissues, and that 1,25D acts at several sites in the body in an intracrine or paracrine manner. In particular, both CYP27B1 and the vitamin D receptor (VDR) are expressed in several cell types in the immune system, where CYP27B1 production is controlled by a number of immune-specific inputs. Recent research has opened several windows on the molecular mechanisms by which 1,25D signaling regulates both innate and adaptive immune responses in humans. Moreover, intervention trials are beginning to provide evidence that vitamin D supplementation can bolster clinical responses to infection. This review will discuss recent developments in our understanding of how immune signaling controls local vitamin D metabolism and how, in turn, the 1,25D-bound VDR modulates immune system function. A particular emphasis will be placed on the interplay between vitamin D signaling and signaling through different classes of pattern recognition receptors in the production of antimicrobial peptides during innate immune responses to microbial infection.

The traditional view that gene and environment interactions control disease susceptibility can now be expanded to include epigenetic reprogramming as a key determinant of origins of human disease. Currently, epigenetics is defined as heritable changes in gene expression that do not alter DNA sequence but are mitotically and transgenerationally inheritable. Epigenetic reprogramming is the process by which an organism's genotype interacts with the environment to produce its phenotype and provides a framework for explaining individual variations and the uniqueness of cells, tissues, or organs despite identical genetic information. The main epigenetic mediators are histone modification, DNA methylation, and non-coding RNAs. They regulate crucial cellular functions such as genome stability, X-chromosome inactivation, gene imprinting, and reprogramming of non-imprinting genes, and work on developmental plasticity such that exposures to endogenous or exogenous factors during critical periods permanently alter the structure or function of specific organ systems. Developmental epigenetics is believed to establish "adaptive" phenotypes to meet the demands of the later-life environment. Resulting phenotypes that match predicted later-life demands will promote health, while a high degree of mismatch will impede adaptability to later-life challenges and elevate disease risk. The rapid introduction of synthetic chemicals, medical interventions, environmental pollutants, and lifestyle choices, may result in conflict with the programmed adaptive changes made during early development, and explain the alarming increases in some diseases. The recent identification of a significant number of epigenetically regulated genes in various model systems has prepared the field to take on the challenge of characterizing distinct epigenomes related to various diseases. Improvements in human health could then be redirected from curative care to personalized, preventive medicine based, in part, on epigenetic markings etched in the "margins" of one's genetic make-up.

Congenital hyperinsulinism is a leading cause of severe hypoglycaemia in the newborn period. There are two (diffuse and focal) histological subtypes of congenital hyperinsulinism. The diffuse form affects the entire pancreas and if medically unresponsive will require a near total (95%-98%) pancreatectomy. The focal form affects only a small region of the pancreas (with the rest of the pancreas being normal in endocrine and exocrine function) and only requires a limited pancreatectomy. This limited section of the focal lesion has the potential for curing the patient. Thus the pre-operative differentiation of these two subgroups is extremely important. Recent advances in Fluorine-18-L-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET/CT) have radically changed the clinical approach to patient with congenital hyperinsulinism. In most patients this novel imaging technique is able to offer precise pre-operative localisation of the focal lesion, thus guiding the extent of surgical resection.

Stroke is the leading cause of adult disability in Westernized societies with increased incidence along ageing and it represents a major health and economical threat. Inactive lifestyle, smoking, hypertension, atherosclerosis, obesity and diabetes all dramatically increase the risk of stroke. While preventive strategies based on lifestyle changes and risk factor management can delay or decrease the likelihood of having a stroke, post stroke pharmacological strategies aimed at minimizing stroke-induced brain damage are highly needed. Unfortunately, several candidate drugs that have shown significant preclinical neuroprotective efficacy, have failed in clinical trials and no treatment for stroke based on neuroprotection is available today. Glucagon-like peptide 1 (GLP-1) is a peptide originating in the enteroendocrine L-cells of the intestine and secreted upon nutrient ingestion. The activation of the GLP-1R by GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon secretion and exerts multifarious extrapancreatic effects. Stable GLP-1 analogues and inhibitors of the proteolytic enzyme dipeptidyl peptidase 4 (DPP-4) (which counteract endogenous GLP-1 degradation) have been developed clinically for the treatment of type 2 diabetes. Besides their antidiabetic properties, experimental evidence has shown neurotrophic and neuroprotective effects of GLP-1R agonists and DPP-4 inhibitors in animal models of neurological disorders. Herein, we review recent experimental data on the neuroprotective effects mediated by GLP-1R activation in stroke. Due to the good safety profile of the drugs targeting the GLP-1R, we also discuss the high potential of GLP-1R stimulation in view of developing a safe clinical treatment against stroke based on neuroprotection in both diabetic and non-diabetic patients.

The androgen-producing cells in the postnatal mammalian ovary are located in the interstitial compartment of the ovary. The most important types of androgen-producing interstitial cells are the cells in the theca interna and the cells of the secondary interstitial glands. There has been some confusion in recent years regarding the terminology used to describe the ovarian androgen-producing cells, namely that “theca-interstitial” cells are somehow different from “theca” cells. In fact, these are the same cells. The name “theca-interstitial” was used by Erickson et al. [1] to describe the theca cells as one of the four androgen-producing cell types in the interstitial compartment of the ovary along with primary interstitial cells which are present only during embryonic development, secondary interstitial gland cells, and steroidogenic cells located in the hilar region of the ovary. For the sake of clarity and according to current convention, the term theca cell will be used throughout this review to refer to cells in the theca interna of the ovarian follicle.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal-recessive disease causing cortisol deficiency, aldosterone deficiency and hyperandrogenism. Diagnosis of 21-OHD is confirmed by steroid analysis in newborn screening or later on. Standard medical treatment consists of oral glucocorticoid and mineralocorticoid administration in order to suppress adrenal androgens and to compensate for adrenal steroid deficiencies. However, available treatment is far from ideal, and not much is known about the long-term outcome in CAH as trials in patients in adulthood or old age are rare. Here we briefly describe the pathophysiology, clinical picture, genetics and epidemiology of 21-OHD. This is followed by a comprehensive review of the recent advances in diagnosis, treatment and outcome. Novel insights have been gained in the fields of newborn screening, specific steroid measurement utilizing mass spectrometry, genetics, glucocorticoid stress dosing, additive medical therapy, prenatal treatment, side-effects of medical treatment, adrenomedullary involvement, metabolic morbidity, fertility and gender identity. However, many issues are still unresolved, and novel questions, which will have to be answered in the future, arise with every new finding.

Progression of diabetic nephropathy (DN) is manifested by gradual scarring of both the renal glomerulus and tubulointerstitial region. Over the past several years, the general understanding of the pathogenic factors that lead to renal fibrosis in DN has expanded considerably. In this review, some of the important factors that appear to be involved in driving this fibrosing process are discussed, with special emphasis on newer findings and insights. It is now clear that multiple cell types in the kidney contribute to progressive fibrosis in DN. New concepts about bradykinin, TGF-beta and eNOS signaling as well as JAK/STAT activation and the central role of inflammation in both glomerular and tubulointerstitial fibrosis are discussed.

Many investigations of cancer development have pursued the mechanisms by which genetic mutations stimulate tumor development through activation of oncogenes or loss of tumor suppressor genes. However, there is an increasing awareness that signals provided by the stroma can induce the genetic alterations that underlie tumor formation, can stimulate tumor growth and progression, and can dictate both therapeutic response and ultimate clinical outcome. This principle is particularly clear in breast cancer, where recent investigations using sophisticated three-dimensional cell culture models and transgenic animals have been used to define how altered signals from the microenvironment contribute to breakdown of tissue structure, increased cellular proliferation, and transition to the malignant phenotype. We review here recent studies identifying new roles for cancer-associated fibroblasts in promoting tumor progression, through stimulation of inflammatory pathways and induction of extracellular matrix-remodelling proteases. These studies identify mechanisms by which development of a reactive tumor stroma causes mammary hyperproliferation, progression to fibrosis, development of neoplasia, increasing invasiveness, and eventual metastasis, and how intervention in these processes may provide new avenues for therapy.

Skeletal homeostasis is determined by systemic hormones and local factors. Bone morphogenetic proteins (BMPs) are unique because they induce the commitment of mesenchymal cells toward cells of the osteoblastic lineage and also enhance the differentiated function of the osteoblast. BMP activities in bone are mediated through binding to specific cell surface receptors and through interactions with other growth factors. BMPs are required for skeletal development and maintenance of adult bone homeostasis, and play a role in fracture healing. BMPs signal by activating the mothers against decapentaplegic (Smad) and mitogen activated protein kinase (MAPK) pathways, and their actions are tempered by intracellular and extracellular proteins. The BMP antagonists block BMP signal transduction at multiple levels including pseudoreceptor, inhibitory intracellular binding proteins, and factors that induce BMP ubiquitination. A large number of extracellular proteins that bind BMPs and prevent their binding to signaling receptors have emerged. The extracellular antagonists are differentially expressed in cartilage and bone tissue and exhibit BMP antagonistic as well as additional activities. Both intracellular and extracellular antagonists are regulated by BMPs, indicating the existence of local feedback mechanisms to modulate BMP cellular activities.

Transient Neonatal Diabetes (type 1) is the commonest cause of diabetes presenting in the first week of life. The majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes in later life. It is associated with low birth weight but rapid catch up by 1 year of life. The condition is usually due to genetic or epigenetic aberrations at an imprinted locus on chromosome 6q24 and can be sporadic or inherited. Early diagnosis alters medical treatment strategies and differentiates it from other types of early onset diabetes. In some individuals, diabetes may be the initial presentation of a more complex imprinting disorder due to recessive mutations in the gene ZFP57 and may be associated with other developmental problems.

The ATP-sensitive potassium (K(ATP)) channel is composed of two subunits SUR1 and Kir6.2. The channel is key for glucose stimulated insulin release from the pancreatic beta cell. Activating mutations have been identified in the genes encoding these subunits, ABCC8 and KCNJ11, and account for approximately 40% of permanent neonatal diabetes cases. The majority of patients with a K(ATP) mutation present with isolated diabetes however some have presented with the Developmental delay, Epilepsy and Neonatal Diabetes syndrome. This review focuses on mutations in the K(ATP) channel which result in permanent neonatal diabetes, we review the clinical and functional effects as well as the implications for treatment.

During the last two decades a large number of genetically modified mouse lines with altered gonadotropin action have been generated. These mouse lines fall into three categories: the lack-of-function mice, gain-of-function mice, and the mice generated by breeding the abovementioned lines with other disease model lines. The mouse strains lacking gonadotropin action have elucidated the necessity of the pituitary hormones in pubertal development and function of gonads, and revealed the processes from the original genetic defect to the pathological phenotype such as hypo- or hypergonadotropic hypogonadism. Conversely, the strains of the second group depict consequences of chronic gonadotropin action. The lines vary from those expressing constitutively active receptors and those secreting follicle-stimulating hormone (FSH) with slowly increasing amounts to those producing human choriogonadotropin (hCG), amount of which corresponds to 2000-fold luteinizing hormone (LH)/hCG biological activity. Accordingly, the phenotypes diverge from mild anomalies and enhanced fertility to disrupted gametogenesis, but eventually chronic, enhanced and non-pulsatile action of both FSH and LH leads to female and male infertility and/or hyper- and neoplasias in most of the gonadotropin gain-of-function mice. Elevated gonadotropin levels also alter the function of several extra-gonadal tissues either directly or indirectly via increased sex steroid production. These effects include promotion of tumorigenesis in tissues such as the pituitary, mammary and adrenal glands. Finally, the crossbreedings of the current mouse strains with other disease models are likely to uncover the contribution of gonadotropins in novel biological systems, as exemplified by the recent crossbreed of LHCG receptor deficient mice with Alzheimer disease mice.

Bone is a dynamic tissue that undergoes constant remodeling in response to local and environmental stimuli. Bone mass is maintained by this delicate equilibrium between bone formation and bone resorption. In growing children, the balance is tilted toward bone formation until peak bone mass is achieved in the second decade of life. Alterations in bone metabolism can result in decreased bone mass (osteopenia and osteoporosis) or impaired mineralization of the bone protein matrix (rickets and osteomalacia). Diseases of the alimentary tract such as celiac disease, inflammatory bowel diseases, gastrectomy, cholestatic liver diseases, liver transplantation, and hepatitis C can affect bone mineralization, remodeling, or bone mass. This article presents a summary of recent reports concerning bone disorders associated with disorders of the liver and gastrointestinal tract.

Abnormalities in mineral metabolism and changes in skeletal histology may contribute to growth impairment in children with chronic renal failure. Hyperphosphatemia, hypocalcemia, metabolic acidosis, alterations in vitamin D and IGF synthesis and parathyroid gland dysfunction play significant roles in the development of secondary hyperparathyroidism and subsequently, bone disease in renal failure. The recent KDIGO conference has made recommendations to consider this as a systemic disorder (chronic kidney disease-mineral bone disorder) and to standardize bone histomorphometry to include bone turnover, mineralization and volume (TMV). The use of DXA to assess bone mass is controversial in children with chronic renal failure. Questions arise regarding the accuracy of bone measurements and difficulty in data interpretation especially in children with renal failure who are not only growth retarded but often have pubertal delay and osteosclerosis. The validity and feasibility of new modalities of skeletal imaging which can detect changes in both trabecular and cortical bone are currently being investigated in children. The management of mineral abnormalities and bone disease in chronic renal failure is multifactorial. To manage hyperphosphatemia, dietary phosphate restriction accompanied by intake of calcium-free and metal-free phosphate binding agents are widely utilized. Vitamin D analogs remain the primary therapy for secondary hyperparathyroidism, although the use of the less hypercalcemic agents is preferred due to concerns of calciphylaxis and vascular calcification. Future clinical studies are needed to evaluate the long-term effects of calcimimetic agents and bisphosphonate therapy in children with chronic renal failure.

The vascular endothelium has been identified as an important component in diabetes-associated complications, which include many cardiovascular disorders such as atherosclerosis, hypertension and peripheral neuropathy. Additionally, insulin's actions on the endothelium are now seen as a major factor in the metabolic effects of the hormone by increasing access to insulin sensitive tissues. Endothelial function is impaired in diabetes, obesity, and the metabolic syndrome, which could reduce insulin access to the tissue, and thus reduce insulin sensitivity independently of direct effects at the muscle cell. As such, the endothelium is a valid target for treatment of both the impaired glucose metabolism in diabetes, as well as the vascular based complications of diabetes. Here we review the basics of the endothelium in insulin action, with a focus on the skeletal muscle as insulin's major metabolic organ, and how this is affected by diabetes. We will focus on the most recent developments in the field, including current treatment possibilities.

An alarming increase in the prevalence of obesity, type 2 diabetes mellitus, and associated diseases can be observed world-wide during the past 20 years. In obesity, profound alterations in the secretion profile of adipokines and inflammatory markers as well as increased lipolysis occur, leading besides other events to elevated levels of free fatty acids, which in turn are distributed to nonadipose tissue such as skeletal muscle. While the amount of intramyocellular lipids can be used as a marker of insulin resistance in physical inactive individuals, these neutral triglycerides themselves are not thought to be harmful. However, they provide a source for the generation of harmful lipid metabolites such as diacylglycerol and ceramide, which are implicated in insulin resistance by perturbing insulin signaling pathways. In this review, we will discuss the role of lipid metabolites in insulin resistance and potential mechanism involved in accumulation of intramyocellular lipids. Furthermore, we will highlight the key role of PGC-1α, which is a master regulator of mitochondrial biogenesis and coordinates the activation of genes involved in oxidative energy production as well as genes involved in fiber type transformation. Finally, the role of exercise in stimulating PGC-1α activity and expression as well as the release of contraction-induced myokines is discussed.

Abbreviations: ACH, achondroplasia; BMP, bone morphogenetic protein; ERK, extracellular signal-related protein kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; HYP, hypochondroplasia; MAPK, mitogen activated protein kinase; PI3K, phosphoinositol phosphate-3-kinase; PLCγ , phospholipase C gamma; SH2, src homology 2; Sox, sry-like high mobility group box transcription factor; STAT, signal transducer and activator of transcription; TD, thanatophoric dysplasia. The emergence of fibroblast growth factor receptor 3 (FGFR3) as an important local regulator of linear bone growth is historically linked to the search for the “achondroplasia gene” and its mutations. Achondroplasia is by far the most common human chondrodysplasia. It is the prototype of short-limbed dwarfism in humans and the archetype of a group of disorders that range from the much more severe thanatophoric dysplasia (TD) to the less severe hypochondroplasia [1]. These disorders share a common qualitative clinical phenotype dominated by short limbs, long trunk, large head with frontal bossing, and midfacial hypoplasia [2]. Infants with achondroplasia typically present with mild to moderate limb shortening, moderate craniofacial manifestations and a lumbar gibbis. These features typically become more noticable with time. The gibbis usually gives way to a lumbar lordosis, and infants and children with achondroplasia are at risk for spinal cord compression at the foramen magnum. Thanatophoric dysplasia is much more severe in general and usually lethal in the perinatal period. Craniofacial abormalities are much more dramatic

Pituitary tumors are among the most common neoplasms in man; they account for approximately 15% of all primary intracranial lesions (Jagannathan et al., Neurosurg Focus, 19:E4, 2005). Although almost never malignant and rarely clinically expressed, pituitary tumors may cause significant morbidity in affected patients. First, given the critical location of the gland, large tumors may lead to mass effects, and, second, proliferation of hormone-secreting pituitary cells leads to endocrine syndromes. Acromegaly results from oversecretion of growth hormone (GH) by the proliferating somatotrophs. Despite the significant efforts made over the last decade, still little is known about the genetic causes of common pituitary tumors and even less is applied from this knowledge therapeutically. In this review, we present an update on the genetic syndromes associated with pituitary adenomas and discuss the related genetic defects. We next review findings on sporadic, non-genetic, pituitary tumors with an emphasis on pathways and animal models of pituitary disease. In conclusion, we attempt to present an overall, integrative approach to the human molecular genetics of both familiar and sporadic pituitary tumors.

Acromegaly is a rare and chronic condition that is characterized by sustained unregulated hypersecretion of growth hormone (GH). More than 99% of the cases of acromegaly are due to a pathologic proliferation of pituitary somatotrophs presenting in the form of a pituitary adenoma. The excessive amounts of GH and its target hormone, insulin like growth factor-1 (IGF-1) cause metabolic changes and tissue enlargement that, collectively, lead to significant morbidity and a two to threefold increase in mortality. Thus, early diagnosis has proved to be crucial to improve survival and quality of life in this condition. The development of radioimmunoassay (RIA) in the 1960s provided clinicians with a biochemical tool to diagnose acromegaly. Many limitations were inherent to this methodology which necessitated the development of more sensitive tools, such as immunoradiometric (IRMA) or immunoluminometric (ILMA) assays for GH and IGF-1 measurements. These newer assays have not come without imperfections. The reference ranges to describe normalcy of the somatotropic axis and the biochemical criteria of "cure" of acromegaly are areas of great debate. Nevertheless, the current international consensus agrees that the diagnosis of acromegaly should be based on both clinical presentation and biochemical data.

Medications designed to act on a specific receptor or group of receptors have helped to target receptors that alter the disease process. Endocrine disorders such as prolactinomas and growth hormone secreting adenomas have been the beneficiary of these endeavors. Although we presently have medications that can effectively treat these disorders, they do not shrink tumors and control hormone over secretion in all cases. The classes of drugs reported here are being developed to treat all patients with acromegaly according to their receptor status and activity. Hopefully, acromegaly will become a disease that can be treated and controlled by medical means and that acromegaly will no longer reduce life expectancy.

This paper presents an overview of the evolution of pituitary surgery for acromegaly. It begins with the first case, attempted in 1893, through the initial transsphenoidal successes in 1907-1910, to the development of effective craniotomy approaches, and ultimately to the resurrection of the transsphenoidal approach in the 1970s and thereafter. Today, the minimally endoscopic transnasal endoscopic approach is fast becoming the norm. Indications for surgery include active acromegaly, visual loss and other forms of mass effect, pituitary tumor apoplexy, and failure of other therapies (medical, radiation). Contraindications include advanced age, debility or other medical conditions increasing the risk of general anaesthesia or surgery. Surgery for acromegaly has the advantage of immediate lowering of the growth hormone excess, with endocrine remission rates of 70% for microadenomas and 50% for macroadenomas. When surgery fails to obtain remission, a program of therapy is designed for the patient to include adjunctive medical therapy (dopamine agonists, somatostatin analogs, and growth hormone receptor antagonists), radiation therapy or radiosurgery (Gamma knife, Cyberknife, etc.).