Nature Reviews Endocrinology

Published by Nature Publishing Group
Online ISSN: 1759-5037
Publications
Article
I PET identifies more foci suggestive of residual thyroid tissue or metastases than ¹³¹I planar whole-body imaging in patients with well-differentiated thyroid cancer.Van Nostrand et al.¹³¹I whole-body dosimetry.
 
Article
Interleukin 13 (IL-13) has a key role in the regulation of hepatic glucose production in mice, new data reveal.
 
Article
The radioiodine (¹³¹I) activities that are as high as safely administrable (AHASA) for the treatment of children with advanced differentiated thyroid cancer (DTC) are twice as high as those previously estimated, Verburg et al. report.
 
Article
The use of stem cells in regenerative medicine holds great promise for the cure of many diseases, including type 1 diabetes mellitus (T1DM). Any potential stem-cell-based cure for T1DM should address the need for beta-cell replacement, as well as control of the autoimmune response to cells which express insulin. The ex vivo generation of beta cells suitable for transplantation to reconstitute a functional beta-cell mass has used pluripotent cells from diverse sources, as well as organ-specific facultative progenitor cells from the liver and the pancreas. The most effective protocols to date have produced cells that express insulin and have molecular characteristics that closely resemble bona fide insulin-secreting cells; however, these cells are often unresponsive to glucose, a characteristic that should be addressed in future protocols. The use of mesenchymal stromal cells or umbilical cord blood to modulate the immune response is already in clinical trials; however, definitive results are still pending. This Review focuses on current strategies to obtain cells which express insulin from different progenitor sources and highlights the main pathways and genes involved, as well as the different approaches for the modulation of the immune response in patients with T1DM.
 
Article
18-Oxocortisol measurement from adrenal vein blood samples may provide a helpful biomarker for the subtype differentiation of primary aldosteronism.
 
Article
Background. A 5-year-old white girl with a history of hypothyroidism in infancy presented to the endocrinology clinic of a tertiary hospital. Her physical examination noted a stocky physique, broad chest, short neck and short digits. Two years later, skin examination revealed subcutaneous nodules and acanthosis nigricans. Investigations. Measurement of levels of serum phosphate, parathyroid hormone, ionized calcium and insulin; measurement of peak growth hormone by the arginine-levodopa stimulation test; calculation of homeostasis model assessment of insulin resistance; assessment of bone age; DNA analysis of the GNAS gene. Diagnosis. Pseudohypoparathyroidism type 1a in a patient with Albright hereditary osteodystrophy, characterized by hypocalcemia, hypothyroidism, growth-hormone deficiency and insulin resistance. Management. The child continued to take levothyroxine 25 microg once daily, and at 5 years of age she was started on 40 mg/kg elemental calcium as calcium carbonate daily, and calcitriol (active vitamin D) 0.25 microg twice daily. Lifestyle modifications were also recommended for weight control. At 6 years and 4 months of age, treatment with growth hormone was initiated at a dose of 0.3 mg/kg weekly.
 
Article
An HbA1c level ≥6.5% is recommended as a criterion for the diagnosis of diabetes mellitus. A recent study has assessed the sensitivity and specificity of HbA1c levels for distinguishing between new onset type 1 diabetes mellitus and transient hyperglycemia in children. Do the results have implications for current pediatric clinical practice?
 
Article
A novel study published in The Lancet suggests a U-shaped association between HbA1c levels and mortality in patients with type 2 diabetes mellitus. But is a revision of current guidelines to include a minimum HbA1c target advisable on the basis of these findings?
 
Article
The purpose of a diagnostic test is to identify individuals who have a disorder and reassure those who do not. An HbA₁(c)-based diagnosis of diabetes mellitus or prediabetes fails to meet that purpose. Diabetes mellitus is a disorder of glucose, not HbA₁(c), metabolism. Microvascular complications in diabetes mellitus are driven by chronic hyperglycemia. The correlation of these complications with HbA₁(c) levels is convenient; however, unlike the direct information provided by glucose, HbA₁(c) values reflect glycemic and nonglycemic factors. The latter include modulators of glucose transport across the erythrocyte membrane, intracellular protein glycation and deglycation, erythrocyte turnover, systemic illness and hematological and medical disorders, among others. Genetic rather than glycemic factors explain most of the variance in HbA₁(c) levels. Finally, HbA₁(c) values are misleading as a measure of average blood glucose among persons of African, Asian, Hispanic and other non-European ancestry. Given the numerous pitfalls, the use of HbA₁(c) levels for diagnosing diabetes mellitus or prediabetes is ill-advised.
 
Article
The development of a true reference measurement system by the International Federation for Clinical Chemistry (IFCC) for the first time allows reporting of true HbA(1c) results, standardized to an absolute value, worldwide. Regression equations between the IFCC assay and current harmonization assays, including the Diabetes Control and Complications Trial (DCCT) assay, are linear, tight, and stable over time. National and international setting of targets, audit and benchmarking of services will be easier than before, as will translation of research into clinical practice. Nevertheless, the main disadvantage of the IFCC assay is that the numbers and units reported (mmol/mol) are very different from the DCCT value (percentage). An extensive education program for patients and health-care professionals is, therefore, needed to prevent confusion and consequent deterioration in glycemic control. Furthermore, the IFCC system does not overcome difficulties inherent in the measurement and interpretation of HbA(1c), such as in the presence of abnormal turnover of red blood cells and hemoglobinopathies.
 
Article
We read with interest the Perspectives article by Dagogo-Jack (Pitfalls in the use of HbA1c as a diagnostic test: the ethnic conundrum. Nat. Rev. Endocrinol. 6, 589–593 (2010)
 
Article
Treatment with agonists of the glucagon-like peptide 1 receptor (GLP-1R) induces weight loss in patients with overweight or obesity irrespective of the presence of type 2 diabetes mellitus, report Danish researchers.
 
Article
In a recent article, Strosberg and colleagues report on a multi-institutional, phase II open-label study of ganitumab, a human monoclonal antibody against insulin-like growth factor 1 receptor (IGF-1R), for the treatment of advanced carcinoid and pancreatic neuroendocrine tumours (NETs).¹ The researchers administered ganitumab at a dose of 18 mg/kg every 3 weeks to 60 patients with metastatic, progressive NETs (30 with carcinoid NETs and 30 with pancreatic NETs); patients received a median of six cycles of treatment.
 
Article
Landmark studies published in 2010 have shed new light on the biology of thyroid cancer. From cooperation between various genetic lesions during thyroid carcinogenesis to identification of the cell type primarily affected, the results of these studies offer a solid framework for future development of targeted thyroid cancer therapies.
 
Article
Safe, effective treatments that are more widely available than surgery are needed to combat obesity. Nonetheless, the FDA has voted against two new drugs and withdrawn another in 2010. Despite the uphill battle faced by those developing medical therapies, a number of studies demonstrate the variety of biological targets for obesity treatment.
 
Article
The majority of patients with type 2 diabetes mellitus have uncontrolled glycemia, blood pressure and lipid levels and struggle to achieve targets set by current guidelines. In 2010, subgroup analyses of the ACCORD trial further underscored the need to tailor treatment to each individual.
 
Article
Vitamin D deficiency increases the risk of autoimmune, cardiovascular and infectious diseases, type 2 diabetes mellitus, as well as the risk of falls and fractures. Several prospective, randomized, controlled trials published in 2010 highlight the importance of improving vitamin D status in children and adults to reduce the risk of upper respiratory tract infections and cardiovascular disease, amongst other disorders.
 
Article
The medical management of pituitary tumors is entering a new era. Novel compounds that directly target the pituitary tumor have shown promise in patients with treatment-refractory or recurrent Cushing disease and acromegaly. Furthermore, the alkylating agent temozolomide provides clinical benefit for patients with aggressive pituitary adenomas or carcinomas.
 
Article
Clinical and experimental studies suggest that early life experiences, perhaps spanning multiple generations, affect lifelong risk of metabolic dysfunction through epigenetic mechanisms. Data published in 2011 suggest that epigenetic analysis could potentially have utility as a marker of early metabolic pathology and might enable early life prophylaxis.
 
Article
The complex relationship between pregnancy and thyroid function, and its clinical effect on mother and baby, continued to stimulate research in 2011. Key advances were made on three important issues: how long maternal thyroid function affects fetal thyroid hormone levels; whether thyroid autoimmunity affects pregnancy outcome; and the prevalence of permanent hypothyroidism after postpartum thyroiditis.
 
Article
Polycystic ovary syndrome (PCOS) is a complex genetic disease that affects approximately 7% of women of reproductive age worldwide. From novel pathways implicated in the etiology of PCOS through genome-wide association to characterization of the reproductive and metabolic changes that occur in ageing women with PCOS, the year 2011 has seen a number of studies published that highlight the intricacies of this condition.
 
Article
Over the past decade, investigators have actively searched for safer therapeutic approaches to replace or complement the use of bisphosphonates and/or parathyroid hormone, exploring both antiresorptive and osteoanabolic pathways. Besides marked progress in basic research, the year 2011 has seen several compounds for the treatment of osteoporosis enter or progress within clinical trials.
 
Article
With primary aldosteronism now widely acknowledged as common and associated with both hypertension-related and non-hypertension-related pathology, research interest into its causes and consequences continues to grow. In 2011, major breakthroughs occurred in understanding the role and nature of underlying genetic disturbances and elucidating the pathophysiology of its cardiovascular sequelae.
 
Article
In 2012, we learned that functional thyroid tissue can be generated in vitro, and that thyroid hormones stimulate autophagy. Patients with defects in TRα have been identified, and di-iodothyropropionic acid has been shown to ameliorate MCT8 deficiency. Finally, we found that gene expression profiling can identify benign thyroid nodules.
 
Article
Worldwide, >366 million people with type 2 diabetes mellitus remain at excess risk of cardiovascular disease and face a lifetime of treatment escalation for this progressive disorder. Studies in 2012 have re-affirmed the safety of early insulin treatment, metformin use in renal impairment, and shown β-cell function preservation over several years.
 
Article
Researchers are trying to develop more efficient and safer antifracture treatments. Besides the ongoing promising clinical trials involving antibodies to the Wnt antagonist sclerostin or inhibition of the osteoclast enzyme cathepsin K, the year 2012 has seen several novel osteoporosis targets identified by using different methodological approaches.
 
Article
Systemic administration of anti-PCSK9 antibodies induces dramatic reductions in LDL-cholesterol levels, and the effect of this therapy on LDL-receptor activity seems to be additive to that of statin therapy. Inhibition of PCSK9 is potentially very important to the clinician, and should enable more patients to achieve their LDL-cholesterol-level goal.
 
Article
2012 has been a rewarding year for adipocyte research. A new type of brown-like adipocyte—the beige adipocyte—and irisin, a previously unknown hormone that stimulates the formation of such cells, have been discovered. A bipotential adipocyte progenitor giving rise to both brown and white adipocytes has also been identified.
 
Article
Neuroendocrine tumours are a heterogeneous group of neoplasms with various clinical presentations, growth rates and responses to available therapies. Studies published in 2012 have provided insights into tumour-cell signalling that will increase our knowledge of tumour biology and molecular genetics, making it possible to personalize patient care.
 
Article
2013 was a good year for adrenocortical cancer, as the new knowledge gained holds great promise for patients. Advances were made in genetics, epigenetics, the advent of related technological and bioinformatic tools, and the feasibility of massive screening of people and samples.
 
Article
2013 has revealed interesting mechanisms that explain how glucocorticoid signalling responses can be influenced by childhood trauma, activity of other signalling molecules, glucocorticoid circadian rhythms and the sequence of DNA regulatory regions. In particular, studies this year highlight how different signalling environments can determine the molecular and physiological responses of glucocorticoids themselves, and how glucocorticoids can affect other signalling systems.
 
Article
Studies published in 2013 have addressed the question of whether the rising incidence of differentiated thyroid cancer is actually the result of overdiagnosis. Advances have also been made in the treatment of differentiated thyroid cancer, including improvements in radioiodine therapy.
 
Article
Metabolic surgery has been proven to be effective in inducing remission of type 2 diabetes mellitus prior to any significant weight reduction. Studies in 2013 have investigated the mechanisms of action of these procedures and have highlighted a central role of the small intestine in the effects on glucose homeostasis.
 
Article
In 2013, studies in rodents and humans have reaffirmed the essential role of the gut microbiota in host metabolism. More importantly, several converging results have increased our knowledge regarding the taxa and functions of the gut microbiota that contribute to the management of energy homeostasis, glucose metabolism and metabolic inflammation.
 
Article
In 2013, considerable progress was made towards deciphering the molecular foundations of puberty. Loss of transcriptional repression was identified as a core mechanism underlying the onset of puberty, and this loss was found to be precipitated by epigenetic cues. It was also discovered that nutritional deprivation delays puberty by repressing reproductive neuroendocrine function.
 
Article
2014 has seen advances in our understanding of benign and malignant tumours of the adrenal cortex, particularly in Cushing syndrome. Modern genetics has generated a flurry of data. The challenge is to give sense to them; however, the difficulties of collecting the clinical data must not be underestimated.
 
Article
In 2014, two phase II clinical studies reported rapid, impressive increases in BMD in women with low bone mass who were treated with sclerostin inhibitors for 1 year. The antifracture efficacy and tolerability of these new, bone-building therapies are currently being investigated in phase III clinical trials.
 
Article
Studies published in 2014 have helped in our understanding of the epigenetic mechanisms by which suboptimal nutritional exposures during in utero development are transmitted to subsequent generations through the maternal and the paternal germlines. Advances include identification of common genetic loci that are vulnerable to the effects of in utero undernutrition and overnutrition, as well as those that are epigenetically modified tissue-wide.
 
Article
In 2014, numerous noteworthy papers focusing on adipose tissue physiology were published. Many of these articles showed the promise of adipose-tissue-targeted approaches for therapeutic intervention in obesity and type 2 diabetes mellitus. Here, we highlight advances in the development and maintenance of brown and/or beige adipocytes and the metabolic implications of inflammation in adipose tissues.
 
Article
2014 was a good year for developments in automated insulin delivery systems for patients with diabetes mellitus. Clinical trials shifted from research units to the outpatient setting, included both adult and adolescent individuals and were conducted over periods from overnight to 24 h, with improvements seen in time spent in the target glycaemic range and reduced risk of hypoglycaemia.
 
Article
Phenylketonuria is the most prevalent inherited defect in amino acid metabolism. Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. Untreated, phenylketonuria causes severe mental retardation, epilepsy and behavioral problems. The combined effect of neonatal screening and treatment has, however, meant that phenylketonuria is now a biochemical rather than a clinical diagnosis. Treatment consists of stringent dietary restriction of natural protein intake and supplementation of amino acids other than phenylalanine by a chemically manufactured protein substitute. Although clinical outcome on a phenylalanine-restricted diet is good, neuropsychological deficits are now known to exist in dietary-treated patients with phenylketonuria, and quality of life, nutritional condition and psychosocial outcome could probably also be improved. The need for new therapeutic approaches is being met by supplementation with tetrahydrobiopterin or large neutral amino acids, whilst development of the use of phenylalanine ammonia lyase, and, in the longer term, gene therapy and chaperone treatment holds promise. This Review provides an overview of the history of phenylketonuria, the challenges of treatment today and the treatment possibilities in the near future.
 
Article
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease with a strong inflammatory component. The latest studies indicate that innate immunity and inflammatory mediators have a much broader role in T1DM than initially assumed. Inflammation might contribute to early induction and amplification of the immune assault against pancreatic beta cells and, at later stages, to the stabilization and maintenance of insulitis. Inflammatory mediators probably contribute to the suppression of beta-cell function and subsequent apoptosis; they may also inhibit or stimulate beta-cell regeneration and might cause peripheral insulin resistance. The different effects of inflammation take place in different phases of the course of T1DM, and should be considered in the context of a 'dialog' between invading immune cells and the target beta cells. This dialog is mediated both by cytokines and chemokines that are released by beta cells and immune cells, and by putative, immunogenic signals that are delivered by dying beta cells. In this Review, we divided the role of inflammation in T1DM into three arbitrary stages: induction, amplification and maintenance or resolution of insulitis. These stages, and their progression or resolution, might depend on a patient's genetic background, which contributes to disease heterogeneity.
 
| Accuracy of using HbA 1c ≥6.5% for detecting undiagnosed diabetes as defined by OGTT 
Article
Over the past three decades, the number of people with diabetes mellitus has more than doubled globally, making it one of the most important public health challenges to all nations. Type 2 diabetes mellitus (T2DM) and prediabetes are increasingly observed among children, adolescents and younger adults. The causes of the epidemic of T2DM are embedded in a very complex group of genetic and epigenetic systems interacting within an equally complex societal framework that determines behavior and environmental influences. This complexity is reflected in the diverse topics discussed in this Review. In the past few years considerable emphasis has been placed on the effect of the intrauterine environment in the epidemic of T2DM, particularly in the early onset of T2DM and obesity. Prevention of T2DM is a 'whole-of-life' task and requires an integrated approach operating from the origin of the disease. Future research is necessary to better understand the potential role of remaining factors, such as genetic predisposition and maternal environment, to help shape prevention programs. The potential effect on global diabetes surveillance of using HbA(1c) rather than glucose values in the diagnosis of T2DM is also discussed.
 
Article
The discovery of fibroblast growth factor 23 (FGF-23) has expanded our understanding of phosphate and vitamin D homeostasis and provided new insights into the pathogenesis of hereditary hypophosphatemic and hyperphosphatemic disorders, as well as acquired disorders of phosphate metabolism, such as chronic kidney disease. FGF-23 is secreted by osteoblasts and osteocytes in bone and principally targets the kidney to regulate the reabsorption of phosphate, the production and catabolism of 1,25-dihydroxyvitamin D and the expression of α-Klotho, an anti-ageing hormone. Secreted FGF-23 plays a central role in complex endocrine networks involving local bone-derived factors that regulate mineralization of extracellular matrix and systemic hormones involved in mineral metabolism. Inactivating mutations of PHEX, DMP1 and ENPP1, which cause hereditary hypophosphatemic disorders and primary defects in bone mineralization, stimulate FGF23 gene transcription in osteoblasts and osteocytes, at least in part, through canonical and intracrine FGF receptor pathways. These FGF-23 regulatory pathways may enable systemic phosphate and vitamin D homeostasis to be coordinated with bone mineralization. FGF-23 also functions as a counter-regulatory hormone for 1,25-dihydroxyvitamin D in a bone-kidney endocrine loop. FGF-23, through regulation of additional genes in the kidney and extrarenal tissues, probably has broader physiological functions beyond regulation of mineral metabolism that account for the association between FGF-23 and increased mortality and morbidity in chronic kidney disease.
 
Article
An endogenous selective estrogen receptor modulator, 27-hydroxycholesterol, has a negative influence on bone homeostasis, according to a research team from the USA.“Osteoporosis is an important public health concern, and it is well known that estrogens have a protective role in bone,” explain lead researchers Carolyn Dusell and Erik Nelson (Duke University Medical Centre, Durham, USA).
 
Article
Trends in the presentation and management of insulinoma observed at the Mayo Clinic over the past 20 years have been reviewed in a new study. The findings shed light on poorly known and new findings of insulinoma and enable critical appraisal of current guidelines for the diagnosis and management of this condition.
 
Article
In the past few years, several interleukins (ILs) attracted considerable attention as potential effectors in the pathology and physiology of insulin resistance associated with type 2 diabetes mellitus (T2DM) and obesity. IL-1, a major proinflammatory cytokine, is present at increased levels in patients with diabetes mellitus, and could promote beta-cell destruction and alter insulin sensitivity. The effects of IL-1 are likely to be counteracted by IL-1 receptor antagonist protein (IL-1ra), as suggested by interventional studies in patients with T2DM who were treated with a recombinant form of this protein. However, studies in IL-1ra-deficient mice provided controversial results on the exact effect of the IL-1 signaling pathway on insulin secretion, insulin sensitivity and accumulation of adipose tissue. Likewise, IL-6 has been suggested to be involved in the development of obesity-related and T2DM-related insulin resistance. The action of IL-6 on glucose homeostasis is also complex and integrates central and peripheral mechanisms. Both experimental and clinical studies now converge to show that several ILs contribute to the pathology and physiology of T2DM through their interaction with insulin signaling pathways and beta-cell function.
 
Article
Adrenocortical carcinoma is a rare heterogeneous neoplasm with an incompletely understood pathogenesis and a poor prognosis. Previous studies have identified overexpression of insulin-like growth factor 2 (IGF-2) and constitutive activation of β-catenin as key factors involved in the development of adrenocortical carcinoma. Most patients present with steroid hormone excess, for example Cushing syndrome or virilization, or abdominal mass effects, but a growing proportion of patients with adrenocortical carcinoma (currently >15%) is initially diagnosed incidentally. No general consensus on the diagnostic and therapeutic measures for adrenocortical carcinoma exists, but collaborative efforts, such as international conferences and networks, including the European Network for the Study of Adrenal Tumors (ENSAT), have substantially advanced the field. In patients with suspected adrenocortical carcinoma, a thorough endocrine and imaging work-up is recommended to guide the surgical approach aimed at complete resection of the tumor. To establish an adequate basis for treatment decisions, pathology reports include the Weiss score to assess malignancy, the resection status and the Ki67 index. As recurrence is frequent, close follow-up initially every 3 months is mandatory. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Results of a large phase III trial in advanced adrenocortical carcinoma are anticipated for 2011 and will hopefully establish a benchmark therapy. New targeted therapies, for example, IGF-1 receptor inhibitors, are under investigation and may soon improve current treatment options.
 
Article
Protecting the functional mass of insulin-producing β cells of the pancreas is a major therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). The gonadal hormone 17β-oestradiol (E2) is involved in reproductive, bone, cardiovascular and neuronal physiology. In rodent models of T1DM and T2DM, treatment with E2 protects pancreatic β cells against oxidative stress, amyloid polypeptide toxicity, lipotoxicity and apoptosis. Three oestrogen receptors (ERs)--ERα, ERβ and the G protein-coupled ER (GPER)--have been identified in rodent and human β cells. Whereas activation of ERα enhances glucose-stimulated insulin biosynthesis, reduces islet toxic lipid accumulation and promotes β-cell survival from proapoptotic stimuli, activation of ERβ increases glucose-stimulated insulin secretion. However, activation of GPER protects β cells from apoptosis, raises glucose-stimulated insulin secretion and lipid homeostasis without affecting insulin biosynthesis. Oestrogens are also improving islet engraftment in rodent models of pancreatic islet transplantation. This Review describes developments in the role of ERs in islet insulin biosynthesis and secretion, lipid homeostasis and survival. Moreover, we discuss why and how enhancing ER action in β cells without the undesirable effect of general oestrogen therapy is a therapeutic avenue to preserve functional β-cell mass in patients with diabetes mellitus.
 
Article
Peptide hormones and proteins control body weight and glucose homeostasis by engaging peripheral and central metabolic signalling pathways responsible for the maintenance of body weight and euglycaemia. The development of obesity, often in association with type 2 diabetes mellitus (T2DM), reflects a dysregulation of metabolic, anorectic and orexigenic pathways in multiple organs. Notably, therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists, or single co-agonists, for the treatment of obesity and T2DM. Here, we review advances in the science of co-agonist therapy, and highlight promising areas and challenges in co-agonist development. We describe mechanisms of action for combinations of glucagon-like peptide 1, glucagon, gastric inhibitory polypeptide, gastrin, islet amyloid polypeptide and leptin, which enhance weight loss whilst preserving glucoregulatory efficacy in experimental models of obesity and T2DM. Although substantial progress has been achieved in preclinical studies, the putative success and safety of co-agonist therapy for the treatment of patients with obesity and T2DM remains uncertain and requires extensive additional clinical validation.
 
Top-cited authors
Sylvia H Ley
  • Harvard Medical School
Dianna J Magliano
  • Baker Heart and Diabetes Institute
George Chrousos
  • National and Kapodistrian University of Athens
Mark A Febbraio
  • Baker Heart and Diabetes Institute
Ellen Blaak
  • Maastricht University