The Elusive Neuroendocrine Tumor: Finding the Ectopic ACTH Source 16 Years After the Diagnosis of Cushing Syndrome.

Ectopic adrenocorticotropin hormone (ACTH) syndrome (EAS) accounts for the minority of cases of Cushing syndrome. Up to 20% of these cases remain occult, despite multiple imaging attempts to localize the ACTH-producing tumor. Here we describe long-term follow-up of a 41-year-old woman, with ectopic Cushing syndrome initially classified as occult due to negative localization studies, who had bilateral adrenalectomy to manage hypercortisolism. After 16 years and many computed tomography (CT) scans, magnetic resonance imaging scans, Octreoscans, and 2 exploration surgeries for false positives on imaging, the source of ectopic ACTH production was localized in the pancreas utilizing molecular imaging with gallium-68 somatostatin receptor-targeted positron emission tomography (PET)/CT and fluorine-18 fluorodeoxyglucose PET/CT. She underwent a distal pancreatectomy, and pathology confirmed a 1.7-cm well-differentiated pancreatic neuroendocrine tumor with a moderately strong reactivity to ACTH stain. This case demonstrates the utility of multiple functional imaging modalities in resolving these "cold cases" of occult ectopic Cushing syndrome and the importance of a timely management of hypercortisolism with bilateral adrenalectomy.

Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses.

CONTEXT: Prenatal treatment with dexamethasone to prevent virilization in pregnancies at risk for classical congenital adrenal hyperplasia (CAH) remains controversial. OBJECTIVE: To conduct a systematic review and meta-analyses of studies that evaluated the effects of dexamethasone administration during pregnancies at risk for classical CAH because of 21-hydroxylase deficiency (CYP21A2). DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception through August 2009. Review of reference lists and contact with CAH experts further identified candidate studies. STUDY SELECTION: Reviewers working independently and in duplicate determined trial eligibility. Eligible studies reported the effects on either foetal or maternal outcomes of dexamethasone administered during pregnancy compared to a control group that did not receive any treatment. DATA EXTRACTION: Reviewers working independently and in duplicate determined the methodological quality of studies and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS: We identified only four eligible observational studies (325 pregnancies treated with dexamethasone). The methodological quality of the included studies was overall low. Meta-analysis demonstrates a reduction in foetus virilization measured by Prader score in female foetuses treated with dexamethasone initiated early during pregnancy (weighted mean difference, -2.33, 95% CI, -3.38, -1.27). No deleterious effects of dexamethasone on stillbirths, spontaneous abortions, foetal malformations, neuropsychological or developmental outcomes were found although these data are quite sparse. There was increased oedema and striae in the mothers treated with dexamethasone. There were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone. CONCLUSIONS: The observational nature of the available evidence and the overall small sample size of the whole body of the literature significantly weaken inferences about the benefits and harms of dexamethasone in this setting. Dexamethasone seems to be associated with reduction in foetus virilization without significant maternal or foetal adverse effects. However, this review underscores the current uncertainty and further investigation is clearly needed. The decision about initiating treatment should be based on patients' values and preferences and requires fully informed and consenting parents.

Genetics of type 2 diabetes.

PURPOSE OF REVIEW: To provide an overview of the genetics of type 2 diabetes in the context of recent progress in the understanding of the genetic architecture of the disease and its applicability to the pathogenesis of the disease as well as efforts to individualize therapy in type 2 diabetes. Efforts are underway to understand how these loci alter measurable physiologic processes in nondiabetic humans. However, it is important to understand the potential pitfalls in such studies and the limitations underlying measurement of insulin secretion and action using qualitative methodologies. RECENT FINDINGS: The availability of large population-based cohorts and the ease with which large numbers of common genetic variants can be genotyped has enabled the discovery of multiple loci and pathways associated with type 2 diabetes. Recent efforts examining quantitative traits such as fasting glucose concentrations have led to the discovery of other genes likely to be important in the development of diabetes. SUMMARY: The past 4 years have witnessed a significant increase in our understanding of genetic predisposition to type 2 diabetes. Hopefully more progress will be made in applying this knowledge to the pathophysiology of type 2 diabetes in the coming years.

The effect of a bile acid sequestrant on glucose metabolism in subjects with type 2 diabetes.

We designed an experiment to examine the effect of bile acid sequestration with Colesevelam on fasting and postprandial glucose metabolism in type 2 diabetes. To do so, we tested the hypothesis that Colesevelam increases the disposition index (DI), and this increase is associated with increased glucagon-like peptide-1 (GLP-1) concentrations. Thirty-eight subjects on metformin monotherapy were studied using a double-blind, placebo-controlled, parallel-group design. Subjects were studied before and after 12 weeks of Colesevelam or placebo using a labeled triple-tracer mixed meal to measure the rate of meal appearance (Meal Ra), endogenous glucose production (EGP), and glucose disappearance (Rd). Insulin sensitivity and ß-cell responsivity indices were estimated using the oral minimal model and then used to calculate DI. Therapy with Colesevelam was associated with a decrease in fasting (7.0 ± 0.2 vs. 6.6 ± 0.2 mmol/L; P = 0.004) and postprandial glucose concentrations (3,145 ± 138 vs. 2,896 ± 127 mmol/6 h; P = 0.01) in the absence of a change in insulin concentrations. Minimal model-derived indices of insulin secretion and action were unchanged. Postprandial GLP-1 concentrations were not altered by Colesevelam. Although EGP and Rd were unchanged, integrated Meal Ra was decreased by Colesevelam (5,191 ± 204 vs. 5,817 ± 204 µmol/kg/6 h; P = 0.04), suggesting increased splanchnic sequestration of meal-derived glucose.

Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1.

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1-induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on ß-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion.

Defects in GLP-1 response to an oral challenge do not play a significant role in the pathogenesis of prediabetes.

CONTEXT: There has been much speculation as to whether defects in glucagon-like peptide-1 (GLP-1) secretion play a role in the pathogenesis of type 2 diabetes and the progression from normal glucose tolerance to prediabetes and diabetes. OBJECTIVE: Our objective was to determine whether fasting and postchallenge concentrations of active and total GLP-1 decrease as glucose tolerance and insulin secretion worsen across the spectrum of prediabetes. DESIGN: This was a cross-sectional study. SETTING: The study was performed in the clinical research unit of an academic medical center. PARTICIPANTS: Participants included 165 subjects with a fasting glucose below 7.0 mmol/liter and not taking medications known to affect gastrointestinal motility or glucose metabolism. INTERVENTION: Intervention included a 2-h, 75-g oral glucose tolerance test with insulin, C-peptide, glucagon, and GLP-1 measurements at seven time points. MAIN OUTCOME MEASURE: We evaluated the association of integrated, incremental active, and total GLP-1 concentrations with integrated, incremental glucose response to 75 g oral glucose. RESULTS: After accounting for covariates, there was no evidence of a relationship of incremental glucose concentrations after oral glucose tolerance test with active and total GLP-1 (r(s) = -0.16 and P = 0.14, and r(s) = 0.00 and P > 0.9, respectively). There also was no association of GLP-1 concentrations with insulin secretion and action. CONCLUSIONS: The lack of association of GLP-1 concentrations with glucose tolerance status and with insulin secretion and action in a cohort encompassing the full spectrum of prediabetes strongly argues against a significant contribution of defects in GLP-1 secretion to the pathogenesis of prediabetes.

What is type 2 diabetes?

Type 2 diabetes is a common metabolic disorder characterized by chronic hyperglycaemia. It is associated with a reduced life expectancy owing to a greater risk of heart disease, stroke, peripheral neuropathy, renal disease, blindness and amputation. At present, the best predictors of increased diabetes risk and progression to diabetes are an elevated fasting plasma glucose, an abnormal glucose tolerance test, obesity and evidence of impaired insulin action. However, the mechanisms by which people with impaired fasting glucose and/or abnormal glucose tolerance `progress' to overt type 2 diabetes are not completely understood. Moreover, type 2 diabetes is defined in a `negative' sense (hyperglycaemia occurring in the absence of evidence of autoimmune destruction of islet cells). This has two consequences - one is the heterogeneity of the disease, the other is that the disease is identified purely in terms of hyperglycaemia, to a certain extent ignoring the underlying mechanisms that lead to the disease. In this review, we explore some of these mechanisms in an attempt to remind readers that hyperglycaemia is one of many abnormalities in type 2 diabetes.

Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis.

CONTEXT: Treatment for patients with congenital adrenal hyperplasia (CAH) may affect the final height of these patients. OBJECTIVE: Our objective was to determine the distribution of achieved height in patients with classic CAH diagnosed at infancy or early childhood and treated with glucocorticoids. DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, and Scopus through September 2008; the reference sections of included studies; and expert files. STUDY SELECTION: Eligible studies included patients diagnosed with CAH before age 5 and followed to final height. DATA EXTRACTION: Reviewers working in duplicate independently extracted data on study characteristics and outcomes and determined each study's risk of bias. DATA SYNTHESIS: The sd score (SDS) for final height and corrected height (defined as final height SDS - midparental height SDS) were estimated from each study and pooled using random-effects metaanalysis. The I(2) statistic was used to assess inconsistency in results across studies. RESULTS: We found 35 eligible studies, most of which were retrospective single-cohort studies. The final height SDS achieved by CAH patients was -1.38 (-1.56 to -1.20; I(2) = 90.2%), and the corrected height SDS was -1.03 (-1.20 to -0.86; I(2) = 63.1%). This was not significantly associated with age at diagnosis, gender, type and dose of steroid, and age of onset of puberty. Mineralocorticoid users had a better height outcome in comparison with the nonusers (P = 0.02). CONCLUSION: Evidence derived from observational studies suggests that the final height of CAH patients treated with glucocorticoids is lower than the population norm and is lower than expected given parental height.

Inhibition of dipeptidyl peptidase-4: The mechanisms of action and clinical use of vildagliptin for the management of type 2 diabetes.

Postprandial hyperglycemia in type 2 diabetes is characterized by impaired insulin secretion and action, decreased glucose effectiveness and defective suppression of glucagon secretion. Newly available therapies for type 2 diabetes target the pathway of the incretin hormone glucagon-like peptide-1 (GLP-1). Oral inhibitors of dipeptidyl peptidase-4 (DPP-4) raise the level of endogenous GLP-1 by inhibiting its clearance thereby lowering fasting and postprandial glucose concentrations. Unlike compounds which act as agonists of the GLP-1 receptor, DPP-4 inhibitors are not associated with significant effects on gastrointestinal motility, which led to a controversy around the mechanisms responsible for their glucose-lowering effects. Here we review the evidence in regards to the mechanisms whereby DPP-4 inhibitors lower glucose concentrations. Their effects are most likely mediated by an increase in endogenous GLP-1, although additional mechanisms may be involved. The pharmacology, efficacy and safety of vildagliptin, a novel DPP-4 inhibitor, are also discussed.