Treatments in Endocrinology最新文献

The prevalence of obesity is increasing rapidly and the associated morbidity and mortality has led to an urgent need for potential therapeutic targets to reduce appetite and food intake. Gut hormones released after eating that coordinate digestive activity and promote satiety are novel potential treatments for obesity. Oxyntomodulin is a gut hormone that is produced by the L cells in the small intestine and reduces food intake. It is timely to review some of the original literature on oxyntomodulin, to evaluate what is already known about the peptide, and also to set the recent findings on its effects on food intake and bodyweight into context.Recent studies have shown that long-term peripheral administration of oxyntomodulin to rats leads to reduced food intake and reduced weight gain. Studies in humans have demonstrated that acute administration reduces food intake by 19%. When given preprandially by subcutaneous injection three times daily, oxyntomodulin resulted in a reduction in food intake and mean weight loss of 2.8kg over 4 weeks. Oxyntomodulin thus represents a potential therapy for obesity.The mechanism of action of oxyntomodulin is not known. Current evidence suggests that it acts via the glucagon-like peptide 1 (GLP-1) receptor. There may be an additional receptor in the gastric mucosa mediating its effects on gastric acid secretion. Although oxyntomodulin probably acts via the GLP-1 receptor, the two peptides differentially regulate food intake and energy expenditure in the mouse.Oxyntomodulin represents a potential therapy for obesity. Further work will help to clarify its mechanisms of action.

Obesity and type 2 diabetes mellitus have reached epidemic proportions in the US, and indeed, globally. While microvascular complications contribute to considerable morbidity, much of the excess mortality (around 70%) is due to macrovascular disease. Hyperglycemia has predictable toxic effects on multiple organs ('glucotoxicity') including the pancreas, where it impairs insulin secretion and insulin gene expression through mechanisms that lead to glucose densensitization and beta-cell exhaustion, eventually resulting in irreversible beta-cell failure. There is robust evidence to suggest that strict glycemic control reduces diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) in both primary- and secondary-prevention settings. While unequivocal evidence that intensive glycemic control reduces the risk of death due to macrovascular disease is lacking, meta-analytic data and controlled clinical trial data suggest there may still be clinically significant lowering of the risk for macrovascular endpoints through strict glycemic control. Cardiovascular disease in a diabetic patient is a collusion of several factors besides hyperglycemia, such as hypertension, dyslipidemia, diffuse endothelial dysfunction, hypercoagulability, and inflammation. It is important to address lifestyle issues such as maintenance of ideal bodyweight, good dietary practice, smoking cessation, and regular exercise in the comprehensive risk management of a diabetic patient, in order to reduce the vascular complications. Large, ongoing clinical trials such as ACCORD (Action to Control Cardiovascular Risk in Diabetes) are likely to establish the potential benefits of glycemic control in preventing or postponing macrovascular complications of diabetes.

Inhaled human insulin (Exubera((R)) [insulin human (rDNA origin)] Inhalation Powder) has recently been approved in the EU and the US for preprandial use in adult patients with diabetes mellitus. This formulation of insulin has a more rapid onset, but similar duration, of glucose-lowering activity compared with subcutaneously administered regular human insulin.Preprandial inhaled human insulin provided glycemic control that was comparable to preprandial subcutaneous regular insulin when added to long- or intermediate-acting subcutaneous basal insulin in patients with type 1 diabetes. Inhaled human insulin is also effective when administered alone, when combined with oral antihyperglycemic therapy, or when combined with basal subcutaneous insulin in patients with type 2 diabetes. Comparable rates of hypoglycemia occurred in patients treated with inhaled human insulin and in those treated with subcutaneous regular human insulin. Patients treated with inhaled human insulin demonstrated a greater decline in pulmonary function (forced expiratory volume in 1 second, carbon monoxide diffusing capacity) than patients treated with comparator antihyperglycemic agents; the mean difference between the treatment groups that favored the comparators was noted within the first several weeks of treatment, and did not change over a 2-year treatment period. This agent has also been associated with significant improvements in some quality-of-life and treatment satisfaction scores, especially when compared with subcutaneous mealtime insulin regimens.

Extremely low birth-weight newborns (<1000g) experience low levels of thyroid hormone that vary inversely with the severity of neonatal illness and the extent of developmental immaturity with levels reaching a nadir at approximate, equals7 days after birth; this phenomenon can persist for several weeks. In the absence of transplacental passage, 30-50% of these neonates cannot generate sufficient quantities of thyroid hormone to meet postnatal demands, placing them at an increased risk for developmental delay and cerebral palsy. Population surveys and interventional trials suggest that a therapeutic opening exists during a 'window of opportunity' corresponding to this period of diminished capacity. Variables to consider before intervention focus on the consideration that supplementation of both the substrate thyroxine and the active hormone triiodothyronine may be necessary in quantities that do not suppress thyroid-stimulating hormone release, yet overcome the persistence of increased conversion to 3,3'5'-triodo-L-thyronine, terminal deiodination, and activity of the sulfation inactivation pathways, as well as the diminished capacity of the newborn to accommodate postnatal physiologic changes. Single daily replacement doses may suppress levels of converting enzymes in the brain, suggesting that physiologic 'mimicry' provided by a constant infusion may be the preferred dosing option. Properly powered clinical trials targeting long-term developmental outcomes are needed to discern whether these interventions will do more than simply elevate blood levels of thyroid hormones to the target values of either the fetus or developing neonate. Identifying the appropriate indications for supplementation may alleviate individual pain and distress due to disability for several hundred extremely low birth-weight neonates each year in the US alone, and save society a pro-rated lifetime cost of nearly $US1 million per child.

Type 2 diabetes mellitus is usually preceded by impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), which are often referred to as pre-diabetes. Individuals with IGT demonstrate beta-cell dysfunction, insulin resistance, and increased hepatic glucose production; IGT and IFG are risk factors for both diabetes and cardiovascular disease. Type 2 diabetes is associated with micro- and macrovascular complications that lead to excessive mortality and morbidity and the risk of microvascular complications extends to people with pre-diabetes. Maintaining good glycemic control in type 2 diabetes can reduce the risk of developing chronic disease-associated complications. Most individuals who develop type 2 diabetes appear to pass through a stage of IFG or IGT; thus, early intervention (lifestyle and/or pharmacologic) in individuals with pre-diabetes may help prevent cardiovascular disease and the development of type 2 diabetes.The use of exogenous insulin treatment offers the potential to reduce the cardiovascular risk in individuals with type 2 diabetes or pre-diabetes through effective reductions in blood glucose and lipid levels, and in the associated tissue damage resulting from their chronic elevations. However, there are barriers associated with insulin initiation in both type 2 diabetes and pre-diabetes (e.g. hypoglycemia, weight gain, the possible unpredictable action of long-acting insulin, and the need for injections). Insulin glargine, with its flat time-action profile, near 24-hour duration of action, reduced risk of hypoglycemia, and improved glycemic control compared with insulin suspension isophane (neutral protamine hagedorn [NPH] insulin), may help to overcome some of these barriers.Initial results from a small study have indicated the feasibility of treating individuals with pre-diabetes to near-normoglycemia using a regimen of low-dose insulin glargine plus caloric restriction. This is being followed up in the ongoing ORIGIN (Outcomes Reduction with Initial Glargine INtervention) study, which will investigate whether treatment to near-normoglycemia with insulin glargine in individuals with IGT, IFG, or new-onset type 2 diabetes can reduce cardiovascular morbidity and mortality compared with conventional management of these conditions, and whether the rate of progression to type 2 diabetes can be similarly reduced.Further studies are needed to investigate the potential benefits of insulin therapy in individuals with pre-diabetes.

New treatments and treatment protocols for endocrine disorders are evolving rapidly, and research and development activity in the endocrinology field is high. Optimal therapy remains contentious in some areas. To help you keep up to date with the latest advances worldwide on all aspects of drug therapy and management of endocrine disorders, this section of the journal brings you information selected from the rapid drug news alerting service Inpharma WeeklyInpharma Weekly provides rapid alerts to news on drugs and drug therapy. Summarizing information selected from over 1600 biomedical journals, this newsletter is produced by Adis International Limited and is available in a variety of formats. Please contact your nearest Adis office for subscription details. The use of trade names, identified by ['~'] or the use of a registered (((R))) or trademark (trade mark) symbol, is for product identification purposes only and does not imply endorsement.. Each issue contains easy-to-read summaries of the most important research and development news, clinical studies, treatment guidelines, pharmacoeconomic and adverse drug reaction news, and expert opinion pieces published in the world's top endocrinology journals.

Our knowledge and understanding of the role played by peroxisome proliferator-activated gamma receptors in physiology and pathophysiology has expanded dramatically over the past 5 years. Originally described as having important functions in adipogenesis and glucose homeostasis, their pharmacologic agonists, the thiazolidinediones, were introduced as antihyperglycemic, insulin-sensitizing agents for the management of type 2 diabetes mellitus. However, it was to some degree inevitable that the thiazolidinediones would be rapidly recognized as having vasculoprotective properties beyond glycemic control that might also be beneficial. First, diabetic complications are vascular in nature, the earliest feature of these is endothelial dysfunction. Second, it is being increasingly appreciated that these complications develop through inflammatory and procoagulant pathways in which increased oxidative stress is considered a major etiologic mechanism, and which are closely linked to the presence of insulin resistance, visceral obesity, and hyperglycemia. Early appreciation that the thiazolidinediones have antioxidant, anti-inflammatory, anti-procoagulant, and antiproliferative properties in addition to their insulin-sensitizing, anti-lipotoxic properties created a marriage of investigative pathways that has not only led to a very large body of literature on the pleiotropic effects of thiazolidinediones, but also to the development of new understandings of the connections between insulin resistance, obesity, and hyperglycemia and the onset of vascular disease. Understandably, most of the focus has been directed at the macrovascular complications of diabetes, since these are the major causes of morbidity and mortality in this population. However, there is evidence that these agents may have benefits for the microvascular complications as well, and their potential role for cardiovascular disease prevention in non-diabetic patients with the metabolic syndrome is a logical extension of the work performed in diabetes. The recently reported results of the effects of pioglitazone versus placebo on cardiovascular events in patients with type 2 diabetes support the contention that these agents have vasculoprotective effects.

Objective: To evaluate the efficacy of a gastric stimulation procedure for the treatment of morbid obesity.

Methods: All implantable gastric stimulator systems were implanted in a laparoscopic procedure. We focused on the results of the LOSS (Laparoscopic Obesity Stimulation Survey) study, which was a multicenter European survey of 16 hospitals. To date, 91 patients have undergone implantable gastric stimulator implantation in the LOSS study.

Results: The patient population was comprised of 62 (68%) women and 29 (32%) men. The mean age was 41 years, mean weight was 116kg, and mean body mass index was 41 kg/m(2). All surgical procedures were successfully completed. There were no deaths, and no severe peri- or postoperative complications. The mean excess weight loss (EWL) was 20% at 12 months after surgery and about 25% at 2 years after implantation. Baroscreen-selected patients achieved a 31.4% EWL, which was significantly different to the EWL of those patients who were not selected by this screening (15% EWL) [p < 0.01].

Conclusion: Gastric pacing is a promising, minimally invasive, safe, and effective surgical method that results in very little impairment of the patient. Patient selection for gastric stimulation therapy seems to be an important determinant of treatment outcome.

Gonadotropin-releasing hormone (GnRH) analog therapy relies primarily on the ability of these compounds to bind to and modulate GnRH-receptor activity. GnRH analogs have been used in pediatric patients where endogenous gonadotropin release is undesirable or potentially harmful, such as in: (i) patients with central precocious puberty (CPP); (ii) healthy short children where pubertal delay would provide an opportunity to supplement pre-pubertal linear growth; and (iii) children with malignancies and other disorders where treatment requires the use of gonadotoxic compounds. In the first two groups of patients, GnRH agonists may be used alone or in conjunction with somatropin (growth hormone [GH]) to prevent early skeletal maturation and increase the subsequent adult height, while in the latter case, GnRH agonists are used alone or in conjunction with GnRH antagonists in an attempt to preserve gonadal function.In children and adolescents with CPP, timely use of GnRH agonists alone can result in an adult height within the genetic potential of the individual (target height); however, minimal height is gained when GnRH agonist therapy is commenced after a marked advancement of skeletal age. This provides the rationale for combined therapy with GnRH agonists and somatropin in such patients, and studies have shown improved growth with this approach compared with GnRH agonists alone. Combination therapy with GnRH agonists and somatropin has also been shown to increase adult heights to a greater extent than GnRH agonists alone in pediatric patients with concomitant CPP and GH deficiency, those with idiopathic short stature, and those born small for gestational age; however, such combination therapy has shown no increased benefit over somatropin alone in pediatric patients with GH deficiency. Limited results in children and adolescents with congenital adrenal hyperplasia and chronic primary hypothyroidism have also shown increased growth rates, while no growth benefit was seen in pediatric renal transplant recipients.GnRH analogs also have potential as gonadoprotective agents; studies of GnRH agonists used alone and in combination with GnRH antagonists in women undergoing cytotoxic therapy have shown increased preservation of reproductive potential in patients who were receiving GnRH analog therapy versus those who were not.The adverse effects of GnRH analogs mainly consist of menopausal-like complaints. Increases in bodyweight and body mass index in children receiving GnRH agonist therapy have been shown; however, these increases do not persist after discontinuation of therapy. Adult bone mineral density and fertility are also not adversely affected by childhood GnRH agonist therapy.GnRH analog therapy appears to be both well tolerated and effective in pediatric patients, as it allows the preservation or improvement of adult height, and shows no longstanding negative effects on body composition, bone density, reproductive function, or endocrine physi