Purpose of review To summarize major factors affecting fertility in obesity. Recent findings Fertility can be negatively affected by obesity. In women, early onset of obesity favours the development of menses irregularities, chronic oligo-anovulation and infertility in the adult age. Obesity in women can also increase risk of miscarriages and impair the outcomes of assisted reproductive technologies and pregnancy, when the body mass index exceeds 30 kg/m2. The main factors implicated in the association may be insulin excess and insulin resistance. These adverse effects of obesity are specifically evident in polycystic ovary syndrome. In men, obesity is associated with low testosterone levels. In massively obese individuals, reduced spermatogenesis associated with severe hypotestosteronemia may favour infertility. Moreover, the frequency of erectile dysfunction increases with increasing body mass index. Summary Much more attention should be paid to the impact of obesity on fertility in both women and men. This appears to be particularly important for women before assisted reproductive technologies are used. Treatment of obesity may improve androgen imbalance and erectile dysfunction, the major causes of infertility in obese men.
Purpose of review Recent studies have suggested that mineralocorticoid receptor activation leads to cardiovascular and renovascular injury through mechanisms that are largely independent of aldosterone's classic effects on fluid and electrolyte balance. This review provides an overview of this literature and discusses the possible role for mineralocorticoid receptor in the pathogenesis of cardiovascular and renovascular injury in diabetes mellitus. Recent findings Mineralocorticoid receptor activation has multiple adverse effects on the cardiovascular system, including the promotion of vascular injury and inflammation, atherosclerosis, myocardial necrosis and inflammation, cardiac fibrosis and remodeling, renal injury, proteinuria, stroke and hypertension. Studies examining these effects of mineralocorticoid receptor have focused on patients with cardiac dysfunction and on non-diabetic animal models of cardiovascular and renovascular injury. Diabetic individuals with heart failure show a beneficial response to mineralocorticoid receptor antagonists. Mineralocorticoid receptor antagonists also reduce proteinuria in patients with diabetes, and reduce renal injury in diabetic animal models. Mineralocorticoid receptor antagonists may, however, have adverse effects in diabetes, including the induction of hyperkalemia, endothelial dysfunction and autonomic dysfunction. Summary There is strong evidence that mineralocorticoid receptor activation contributes to the pathophysiology of cardiovascular and renovascular injury, although few studies have shown these effects in diabetic populations. There is thus a need for large-scale prospective studies to determine the role of mineralocorticoid receptor antagonists in the treatment of patients with diabetes.
Purpose of review Thus far more than 30 peptides have been identified as being expressed within the digestive tract, making the gut the largest endocrine organ in the body. Understanding of the physiology of many of these peptides has progressed rapidly. This paper provides an overview of advances in our understanding of the physiology of ghrelin, motilin, cholecystokinin, glucagon-like peptide-1 and oxyntomodulin, glucose-dependent insulinotropic peptide, gastrin-releasing peptide, enterostatin, galanin, and gut leptin. Recent findings The review highlights how, in anticipation of and in response to food intake of a particular amount and composition, changes in gastrointestinal hormone synthesis and release occur in order to regulate and coordinate gastrointestinal function, appetite control, and intermediary metabolism. Abnormalities of gut hormones in disorders such as diabetes mellitus, disorders of body weight, and eating disorders are highlighted. The paucity of data relating to the human physiology of enterostatin, galanin, and gut leptin stands in contrast to the other hormones discussed and highlights areas for further investigation. Summary An increase in the understanding of the physiology of gut hormones and their role in integrating food intake and intermediary metabolism have led to novel therapies for the management of diabetes mellitus and also has the potential for new approaches for the management of disorders of food intake and body weight.
Purpose of reviewPeptide YY, released from the gastrointestinal tract, has been shown to reduce food intake and bodyweight in rodents and to reduce food intake after intravenous infusion in humans. The purpose of this review is to highlight recent advances in the peptide YY field with regard to energy balance in both rodent and human models. Recent findingsThe anorexigenic effect of peripherally administered peptide YY3–36 in rodents has been confirmed by others. A number of groups have been unable to reproduce these original findings. Recent studies have suggested that the failure of an anorexigenic response to peptide YY3–36 may be explained, at least partly, by interference by incidental extraneous experimental stress. Peptide YY3–36 was initially hypothesized to alter food intake inhibiting neuropeptide Y appetite-stimulating pathways in the hypothalamus. If these pathways were already inhibited by incidental stress, peptide YY3–36 would have nothing further to inhibit. There is conflicting evidence as to whether peptide YY3–36 alters food intake via a direct circulation/hypothalamic interaction or via the vagal pathway. Recent studies have found that plasma peptide YY levels are elevated post-gastric bypass in obese individuals, which may be the cause of the resulting appetite loss post-surgery. Finally, peptide YY, when administered in combination with glucagon-like peptide-1, reduces food intake to a greater extent than either alone in rodent and human models, suggesting a possible combination therapy for reducing bodyweight. SummaryPeptide YY reduces food intake in rodent and human models and plays a role in the homeostatic mechanisms underpinning energy balance.
Purpose of review Non-alcoholic fatty liver disease is an increasingly prevalent form of chronic liver disease that progresses to cirrhosis and hepatocellular carcinoma in a fraction of the overweight and sedentary population. Knowledge is advancing rapidly in describing the magnitude of the problem, how non-alcoholic fatty liver disease should be diagnosed, and what treatment options are available. This review examines data from the past year on key clinical aspects of non-alcoholic fatty liver disease. Recent findings New data on the epidemiology of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and insulin resistance is constantly emerging, and new treatment options are being evaluated. Using serum alanine aminotransferase elevations to identify patients with possible chronic liver diseases is unreliable and should possibly be abandoned. Similarly, ultrasound is unreliable in detecting non-alcoholic fatty liver disease in severely obese patients. Imaging by computed tomography or magnetic resonance may be used in high-risk groups, such as those with features of the metabolic syndrome, but cost-effective means of identifying patients with non-alcoholic steatohepatitis are not available. Treatment options include weight loss, exercise and drugs. Bariatric surgery may be beneficial with respect to liver disease. Summary The presence of non-alcoholic steatohepatitis should be sought in individuals with features of insulin resistance and other features of the metabolic syndrome, because these patients are most at risk of developing advanced liver disease. Current data indicate that lifestyle modifications that include weight loss and exercise should be the primary treatment option.
Purpose of review This article highlights recent information regarding the physiology of ghrelin and how derangements in it contribute to human diseases. Recent findings Ghrelin is a brain–gut peptide with growth hormone-releasing and appetite-inducing activities. Experimental evidence has confirmed a role for endogenous ghrelin in regulating growth hormone secretion, but studies in humans have not yet pinpointed the exact role of ghrelin in this respect. Accumulating evidence supports the notion that the ghrelin/growth hormone secretagogue receptor axis is part of the complex of neuroendocrine factors that affect feeding behavior and energy metabolism, and that ghrelin might act to provide the calories that growth hormone requires for growth and repair. Environmental factors may modulate ghrelin's activity and have a role in obesity. Furthermore, constitutive activation of the growth hormone secretagogue receptor, polymorphisms in the gene for this receptor, and dysregulation of postprandial ghrelin suppression may contribute to the obese phenotype. A new and important psychiatric issue is the role of ghrelin in the weight gain, insulin resistance and diabetes type 2 associated with the use of atypical antipsychotic drugs. The novel role of ghrelin is in the adaptive response to caloric restriction and loss of body fat by induction of tissue-specific changes in lipid metabolism that favor triglyceride deposition in liver over skeletal muscle. New insights into ghrelin's effects on the pancreas and liver provide evidence for its role in glucose metabolism. Summary Recent studies have confirmed a role for ghrelin as a marker of changes in energy balance, and the role of the growth hormone secretagogue receptor as a modest amplifier of its biological function. A ghrelin antagonist may provide further insights with regard to ghrelin physiology and its involvement in the etiology of obesity.
Purpose of review Chronic kidney disease is a major cause of morbidity and mortality in patients with diabetes. Chronic kidney disease is associated with multiple co-morbidities, and anemia is one of the most frequent. Anemia leads to reduced quality of life and many hemodynamic changes that may impact the outcome of diabetic patients with chronic kidney disease. Anemia is readily identified and treated in diabetic patients with chronic kidney disease. Recent findings This past year has been marked by many studies highlighting the negative impact of chronic kidney disease on individuals with diabetes, specifically that it is associated with excess cardiovascular disease and mortality. Studies have detailed the frequency and severity of anemia in diabetic patients. Many studies have demonstrated the efficacy of treatment for anemia in diabetic patients and suggested benefits beyond correction of the hematocrit. Summary Effective options are available for the correction of anemia in diabetic patients with chronic kidney disease. Early, aggressive and effective treatment will improve the quality of life and can possibly reduce morbidity and mortality in patients with diabetes and chronic kidney disease.
Purpose of review Obesity and type 2 diabetes are becoming more prevalent worldwide. These related diseases are potentially life threatening, increasing the risk and development of co-morbid diseases such as heart disease and certain cancers. This review aims to discuss the findings that peptide YY inhibits food intake, decreases adiposity and promotes insulin action, which may have important implications for obesity and type 2 diabetes. Recent findings Recent studies in rodents and humans have established an important role for peptide YY in reducing food intake, body weight and adiposity. There are also emerging data to suggest that peptide YY is involved in regulating insulin release and glucose homeostasis. As hyperinsulinemia is causally associated with the etiology of obese and insulin-resistant states, peptide YY may be an important link between obesity and type 2 diabetes. Summary Peptide YY is a gut-derived hormone that appears to have major effects on energy balance and glucose homeostasis. Insights into the mechanisms by which Peptide YY affects food intake, body weight, adiposity and glucose homeostasis from transgenic mouse models may be useful in developing long-term therapies for the treatment of obesity and type 2 diabetes.
Purpose of review The importance of parathyroid hormone in maintaining bone health has long been appreciated. Recent advances in the understanding of the cellular and molecular actions of this hormone have enhanced our treatment of parathyroid disorders and osteoporosis. Recent findings Parathyroid hormone has been shown to act at the cellular level through the activation of the RANK ligand system, which is a new target for drug development for osteoporosis. Our understanding of the natural history of primary hyperparathyroidism and the potential for medical management has recently come under greater scrutiny. An increased recognition of vitamin D inadequacy is changing our understanding of secondary hyperparathyroidism. Newer calcimimetic drugs are enhancing our therapy of both primary and secondary hyperparathyroidism. Synthetic parathyroid hormone has been shown to be both safe and effective in the treatment of osteoporosis. Summary Synthetic parathyroid hormone, the first anabolic agent for osteoporosis, has changed the therapeutic approach in severe osteoporosis. Although newer drugs have been used for primary hyperparathyroidism, surgery remains the definitive therapy. Increased understanding of the molecular biology of parathyroid hormone has allowed the development of new classes of therapeutic agents for osteoporosis.
Purpose of reviewVitamin D is an important determinant of bone health and neuromuscular function. This article discusses recent research findings about the association of vitamin D and skeletal health with respect to parathyroid hormone, bone mineral density, physical performance, falls, and fracture. Recent findingsThe critical threshold to maximize adequate calcium absorption and suppress excess parathyroid hormone secretion is a 25-hydroxyvitamin D level of 30 ng/ml or 75 nmol/l. In a study of postmenopausal women on osteoporosis therapy, 45% of women taking 400 IU or more of vitamin D daily had serum 25-hydroxyvitamin D levels lower than 30 ng/ml compared with 63% taking less than 400 IU of vitamin D supplementation daily. In community-dwelling adults, a significant positive association was shown between 25-hydroxyvitamin D levels and total hip bone mineral density and lower extremity function. A meta-analysis of hip fractures demonstrated a 26% lowering of risk with doses of greater than 700 IU of vitamin D supplementation. Subsequent clinical trials showed similar reductions but were not statistically significant. SummaryThe inexpensive and simple practice of maintaining adequate vitamin D can contribute to decreasing fracture risk through skeletal and neuromuscular effects. Prevention strategies for fracture risk reduction should include vitamin D supplementation, particularly in the elderly.
Purpose of review Automated insulin delivery using the subcutaneous site for both glucose sensing and insulin delivery, while not commercially available, is starting to be implemented in the research environment. Here, we review issues with glucose sensing and insulin delivery algorithms that need to be resolved in order to achieve a closed-loop system. Recent findings Glucose sensing technology is improving. New studies demonstrating minimal delay in the subcutaneous interstitial fluid glucose response are reviewed, together with early studies indicating longer delay. The pharmacokinetics/pharmacodynamics of subcutaneous insulin, which pose a significant obstacle to closing the delivery loop, are also reviewed, together with approaches being used to develop algorithms to overcome the delay in insulin absorption from this site. Closed-loop data using the Medtronic MiniMed external Physiologic Insulin Delivery system are presented. Summary Initial closed-loop data in both animals and humans suggest that a completely automated insulin delivery system is attainable, although substantial research remains to be conducted prior to such a system being available for home patient use.
In this issue of Current Opinion in Endocrinology and Diabetes, we present several summaries of current topics that underscore the expanding role of diet and nutrition within the traditional subspecialty of endocrinology and metabolism. With an increasing prevalence of dietrelated chronic diseases, it is important that physicians and other healthcare providers acquire competency in this underrecognized area of medicine. Unfortunately, most physicians do not feel they have the expertise to nutritionally manage disorders brought about or affected by diet. The diseases with the highest mortality rates in the US, cardiovascular disease, type 2 diabetes and some forms of cancer, are strongly correlated with lifestyle factors. Recent reviews on trans fatty acids [1], soy protein and isoflavones [2], management of abnormal blood lipids [3], dietary approaches to prevent and treat hypertension [4], and diet and lifestyle modification [5] draw attention to the essential role of diet and nutrition in the prevention and management of cardiovascular disease. In nonhuman primates, type 2 diabetes can be entirely prevented by restricted food intake [6]. We are able to achieve similar treatment results in patients with severe obesity utilizing bariatric surgery techniques [7,8]. A lifetime high intake of fruits and vegetables, moderate alcohol, and low intake of red meats can prevent colon cancer [9].
Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA Correspondence to Dr Allison B. Goldfine, MD, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA Tel: +1 617 732 2643; fax: +1 617 713 3403; e-mail: [email protected]
Purpose of review Ligands that bind to peroxisome proliferator-activated receptors (PPARs) have been shown to modify lipid metabolism and reduce insulin resistance – a common underlying physiologic abnormality associated with central obesity, type 2 diabetes, and cardiovascular disease. This review focuses on the different molecular mechanisms of PPARs, and potential metabolic and clinical benefits. Recent findings To date, three subtypes of PPARs (PPARα, PPARδ, and PPARγ) have been identified. Activation of PPARα by fibrates and polyunsaturated fatty acids alters lipid metabolism, resulting in an increase in high-density lipoprotein cholesterol and reduction of triglycerides. Activation of PPARγ by thiazolidinediones decreases peripheral insulin resistance, yielding beneficial antihyperglycemic properties. This class has also been shown to play a key role in the regulation of adipose tissue differentiation and proliferation. Both PPARα and PPARγ reduce levels of inflammatory markers, including cytokines and metalloproteinases. Dual PPAR agonists (glitazar class) are currently undergoing clinical studies to determine whether activation of both PPARα and PPARγ results in additive effects on lipid metabolism, insulin sensitivity and inflammation. PPARδ appears to be a regulator of lipid metabolism, increasing fatty acid oxidation in muscle and adipose tissue and reducing adiposity. The clinical benefit of PPARδ has yet to be established. Summary Activation of cell signaling pathways regulated by PPARs alters lipid and glucose metabolism, as well as lowering insulin resistance. The potential metabolic and clinical benefits of PPAR activation continue to be demonstrated in clinical studies, making this an area of intense research focus for years to come.
Department of Metabolic Medicine, Hammersmith Hospital, Imperial College London, London, UK Correspondence to Stephen R. Bloom, Department of Metabolic Medicine, Hammersmith Campus, Imperial College London, 6th Floor Commonwealth Building, Du Cane Road, London W12 0NN, UK Tel: +44 020 8383 3242; fax: +44 020 8383 3142; e-mail: [email protected]
Purpose of review Bone growth in width and cross-sectional size is a crucial but long-neglected determinant of bone strength throughout life. Paediatric bone research is just starting to rediscover the importance of bone geometry. The present review highlights some recent developments in this fledgling field. Recent findings Pubertal bone development is characterized by a rapid increase in bone size, which is faster in boys than in girls. This sex difference is at least partly explained by differences in muscle development. During female puberty, bone apposition is known to occur also at the inner (endocortical) surface of the second metacarpal bone. New data suggest that the same may happen at the lower extremity. Bone size development is sensitive to mechanical loads, with high-impact activity leading to larger bones. A number of non-mechanical factors (for example testosterone, oestrogen, parathyroid hormone, calcium intake) also influence bone size in a direct or indirect way. Genetic research has revealed genomic regions that are linked to cross-sectional bone size development, but no specific genes have yet been singled out as major contributors. Summary As accurate methods to determine bone size and geometry are becoming more widely available, research is starting to elucidate the effects of genetic, mechanical, hormonal and nutritional factors that influence the growth of bone size and geometry. Looking at bones in terms of structure rather than just mass or density opens up a new field for endocrinologists who have an interest in bone development.
Purpose of reviewRathke's cleft cysts arise from embryonic remnants of Rathke's cleft. The purpose of this paper is to review the current knowledge pertaining to Rathke's cleft cysts. Recent studies regarding the management of Rathke's cleft cysts are also discussed. Recent findingsRathke's cleft cysts generally exhibit a benign clinical course. Magnetic resonance imaging is the diagnostic imaging study of choice. Although the most consistent sign to differentiate Rathke's cleft cysts is the lack of enhancement of the cyst wall on contrast-enhanced magnetic resonance images, the presence of an intracystic nodule of low signal intensity on T2-weighted images and possibly high signal intensity on T1-weighted images is highly characteristic of Rathke's cleft cysts. Surgical management is the treatment for symptomatic Rathke's cleft cysts, although asymptomatic lesions may be followed conservatively. Drainage of the cyst contents is the primary goal of surgery; aggressive total resection of the cyst wall, however, may be associated with greater endocrine morbidity. Recurrence may be more common than previously noted when a longer follow-up period is observed. SummaryIncidental Rathke's cleft cysts may be followed with serial imaging. Symptomatic Rathke's cleft cysts are best removed via the transsphenoidal route. Extended postoperative follow-up is indicated in all patients.
Purpose of review To examine the potential of incretin hormones, glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, for the treatment of type 2 diabetes, with emphasis on glucagon-like peptide 1 receptor agonists and inhibitors of the enzyme dipeptidyl peptidase IV. Recent findings Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are released from the gut after meal ingestion; the release of glucagon-like peptide 1 is slightly impaired in individuals with type 2 diabetes. Both incretin hormones stimulate insulin secretion in a glucose-dependent manner and inhibit apoptosis in β cells, and glucagon-like peptide 1 inhibits glucagon secretion. Both incretins are rapidly inactivated by dipeptidyl peptidase IV. The enzyme inactivates the two incretins by removing their two N-terminal amino acids. This process is rapid, resulting in short circulating half-lives of the incretins. The combined action of glucagon-like peptide 1 to stimulate insulin secretion and inhibit glucagon secretion has formed the basis for the development of type 2 diabetes treatment. Two strategies of glucagon-like peptide 1-based therapy have been successful: one strategy uses dipeptidyl peptidase IV-resistant glucagon-like peptide 1 mimetics, whereas the other uses the inhibition of dipeptidyl peptidase IV. Both work in patients with type 2 diabetes, resulting in improved metabolic control. Summary Glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase IV inhibitors are beneficial in type 2 diabetes, which shows that an endogenous physiological pathway may be successful in treating one of the current major diseases.
