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Context: Current guidelines for distinguishing Cushing's disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients., Objective: To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters., Design: Retrospective study., Setting: University hospitals., Patients: Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation., Results: Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92-.99] in the primary study and .99 [95% CI, .98-1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index .99 [95% CI, .97-1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3-10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value., Conclusion: UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Aims: Few studies have compared arm and ankle blood pressures (BPs) with regard to peripheral artery disease (PAD) and mortality. These relationships were assessed using data from three large prospective clinical trials., Methods: Baseline BP indices included arm systolic BP (SBP), diastolic BP (DBP), pulse pressure (arm SBP minus DBP), ankle SBP, ankle-brachial index (ABI, ankle SBP divided by arm SBP), and ankle-pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). These measurements were categorized into four groups using quartiles. The outcomes were PAD (the first occurrence of either peripheral revascularization or lower-limb amputation for vascular disease), the composite of PAD or death, and all-cause death., Results: Among 40 747 participants without baseline PAD (age 65.6 years, men 68.3%, diabetes 50.2%) from 53 countries, 1071 (2.6%) developed PAD, and 4955 (12.2%) died during 5 years of follow-up. Incident PAD progressively rose with higher arm BP indices and fell with ankle BP indices. The strongest relationships were noted for ankle BP indices. Compared with people whose ankle BP indices were in the highest fourth, adjusted hazard ratios (95% confidence interval) for each lower fourth were 1.64 (1.31-2.04), 2.59 (2.10-3.20), and 4.23 (3.44-5.21) for ankle SBP; 1.19 (0.95-1.50), 1.66 (1.34-2.05), and 3.34 (2.75-4.06) for ABI; and 1.41 (1.11-1.78), 2.04 (1.64-2.54), and 3.63 (2.96-4.45) for APPD. Similar patterns were observed for mortality. Ankle BP indices provided the highest c-statistics and classification indices in predicting future PAD beyond established risk factors., Conclusions: Ankle BP indices including the ankle SBP and the APPD best predicted PAD and mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches., Objective: To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO., Design: A double-blind multicenter superiority randomized clinical in trial in two parallel arms., Setting: Eleven French University Hospital Centers., Participants: Adults with CRO (body mass index > 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year., Interventions: Exenatide or placebo injected subcutaneously twice a day during 26 weeks., Main Outcomes and Measures: The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile., Results: At week 26, weight decreased from baseline by a mean of -3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. The adjusted mean treatment difference was -3.1 kg (95% confidence interval [CI] -7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: -2.3, 95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events)., Conclusions and Relevance: Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity., Competing Interests: Conflict of interest: G.R. is on the editorial board of EJE. He was not involved in the review or editorial process for this paper, on which he is listed as an author. The other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: Cortisol-lowering drugs may not restore a normal cortisol secretion in Cushing disease (CD)., Objective: This work aimed to assess the long-term cortisol exposure in medically treated CD patients using hair-cortisol (HF) and hair-cortisone (HE) measurement., Methods: This multicenter prospective study included 3 groups of female patients: CushMed = 16 treated with a stable cortisol-lowering drug dosage and normal urinary free cortisol (UFC); CushSurg = 13 cured by pituitary surgery; CushBla = 15 receiving stable recommended doses of hydrocortisone following bilateral adrenalectomy. Patients were evaluated for 3 months with their usual treatments. Two late-night saliva and 24-hour urine samples were collected monthly in CushMed, and at study end in CushSurg and CushBla patients. A 3-cm hair sample was collected at study end from all patients. Main outcome measures included clinical score and centralized measurement of UFC, late-night salivary cortisol (LNSF), late-night salivary cortisone (LNSE), HE, HF., Results: Despite having almost all UFCs normalized, CushMed patients exhibited increased HE as compared to CushSurg controls (P = .003). CushMed patients also had increased clinical score (P = .001), UFC (P = .03), LNSF, LNSE (P = .0001), and variability in the latter parameters (P = .004). CushBla patients had increased HF and HE, contrasting with LNSEs similar to CushSurg patients. Six of 15 CushMed patients exhibited increased HE concentrations and had increased antihypertensive drug dosage compared to CushMed patients with normal HE (P = .05)., Conclusion: Despite normalized UFCs, a subset of medically treated CD patients displays an altered circadian rhythm of serum cortisol. A single HE measurement identifies chronic mild persistent hypercortisolism and could replace multiple saliva analyzes to monitor medical treatments in CD patients once UFC is normalized., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Cushing's disease (CD) may recur despite corticotropic insufficiency (COI) following pituitary surgery. The predictive value of the desmopressin test (DT) for recurrence in this setting remains controversial. We have evaluated whether the disappearance of the response to DT predicts a low probability recurrence in a large cohort of patients with post-operative COI., Design: Multicentre retrospective study., Methods: Ninety-five patients with CD (women 82%, age 41 ± 14 years), responding preoperatively to DT and with early post-operative COI (08 00 am cortisol: <138 nmol/L), underwent a DT within 3 months post-surgery. Association between DT findings and the prediction of recurrence was tested using regression and ROC analyses., Results: Recurrence occurred in 17/95 patients within 29 to 91 months. The cortisol peak (327, 95% CI (237-417) vs 121 (79-164) nmol/L, P = 0.0001) and absolute increment during DT (208 (136-280) vs 56 (22-90) nmol/L, P = 0.005) were greater in the recurrence vs remission group. Cortisol peak (AUC: 0.786 (0.670-0.902)) and increment (0.793 (0.672-0.914)) yielded a higher prognostic performance for recurrence than did the early post-operative 08 00 am cortisol (0.655 (0.505-0.804)). In the context of COI, cortisol peak >100 nmol/L and increment >30 nmol/L had a high negative predictive value (94, 95% CI (88-100) and 94, (88-100), respectively). Patients with a cortisol peak ≤100 nmol/L (vs >100) or an increment ≤30 nmol/L (vs >30) were less likely to have CD recurrence (odds ratios: 0.12, 95% CI (0.03-0.41) and 0.11 (0.02-0.36), respectively)., Conclusion: The disappearance of the response to the post-operative DT was independently associated with a lower odds of CD recurrence and offers an incremental prognostic value, which may help to stratify patients with COI and refine their follow-up according to the risk of recurrence.

Background: Hyperglycaemia impairs tubulo-glomerular feedback. We tested whether variable tubulo-glomerular feedback during hyperglycaemia contributes to renal risk heterogeneity seen in Type 1 diabetes., Methods: During the period 1990-92, we studied the tubulo-glomerular feedback in Type 1 diabetic patients at high or low renal risk [21 of 54 with glomerular hyperfiltration and/or microalbuminuria against 11 of 55 with normal glomerular filtration rate (GFR) and urinary albumin despite uncontrolled diabetes]. The GFR, effective renal plasma flow, mean arterial pressure and fractional reabsorptions of glucose, osmols, sodium and lithium were measured sequentially during normo- and hyperglycaemia. All patients were followed up until 2016 for incident proteinuria, estimated GFR <60 mL/min/1.73 m2, doubling of serum creatinine, end-stage renal disease or all-cause death., Results: Glycaemia increased from 6.1 ± 1.3 to 15.1 ± 1.9 mmol/L in both high-risk and low-risk patients. Glycosuria was lower in the high- versus low-risk patients: 0.34 ± 0.25 versus 0.64 ± 0.44 mmol/min (P = 0.03). Both groups displayed similar kidney function during normoglycaemia. Hyperglycaemia increased more importantly GFR and fractional reabsorptions, and pre-glomerular vasodilatation in the high- than in the low-risk patients (all P < 0.05). Over 21 years, 31.5% high- versus 12.7% low-risk patients developed endpoints (adjusted P = 0.006). In a multi-adjusted survival analysis of patients having undergone renal tests, each 0.10 mmol/min glycosuria during hyperglycaemia reduced the outcome risk by 0.72 (95% confidence interval 0.49-0.97, P = 0.03)., Conclusions: Reduced tubulo-glomerular feedback and glycosuria during hyperglycaemia indicate high renal risk for Type 1 diabetic patients. Inter-individual variability in tubulo-glomerular feedback activity determines renal risk in Type 1 diabetes., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: High plasma adiponectin levels are associated with diabetic nephropathy (DN). T-cadherin gene (CDH13) variants have been shown to be associated with adiponectin levels. We investigated associations between allelic variations of CDH13 and DN in subjects with type 1 diabetes., Methods: Two CDH13 polymorphisms were analysed in 1297 Caucasian subjects with type 1 diabetes from the 'Survival Genetic Nephropathy' (SURGENE) (n = 340, 10-year follow-up), 'Genesis France-Belgium' (GENESIS) (n = 501, 5-year follow-up for n = 462) and 'Génétique de la Néphropathie Diabétique' (GENEDIAB) (n = 456, 9-year follow-up for n = 283) cohorts. Adiponectin levels were measured in plasma samples from GENESIS and GENEDIAB cohorts., Results: Pooled analysis of GENEDIAB and GENESIS studies showed that baseline plasma adiponectin levels were higher in subjects with established/advanced DN at inclusion (P < 0.0001) and in subjects who developed end-stage renal disease (ESRD) at follow-up (P < 0.0001). The minor allele of rs3865188 was associated with lower adiponectin levels (P = 0.006). rs11646213 [odds ratio (OR) 1.47; 95% confidence interval (CI) 1.18-1.85; P = 0.0009] and rs3865188 (OR 0.71; 95% CI 0.57-0.90; P = 0.004) were associated with baseline prevalence of established/advanced DN. These polymorphisms were also associated with the risk of ESRD (0.006 < P < 0.03). The association between rs11646213 (but not rs3865188) and renal function remained significant after adjustment for plasma adiponectin. In SURGENE, rs11646213 [hazard ratio (HR) 1.69; 95% CI 1.01-2.71; P = 0.04] and rs3865188 (HR 0.74; 95% CI 0.55-0.99; P = 0.04) were associated with risk of renal events (defined as progression to more severe DN stages)., Conclusions: Plasma adiponectin levels are associated with the prevalence of DN and the incidence of ESRD in patients with type 1 diabetes. CDH13 polymorphisms are also associated with the prevalence and incidence of DN, and with the incidence of ESRD in these patients. The association between CDH13 and DN may be due to pleiotropic effects, both dependent and independent of plasma adiponectin levels., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Context: Experimental data support a role for vasopressin in metabolic disorders., Objective: We investigated associations of plasma copeptin, a surrogate of vasopressin, and of allelic variations in the arginine vasopressin-neurophysin II gene with insulin secretion, insulin sensitivity, and the risk for impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM)., Design, Setting, and Participants: We studied 5110 unrelated French men and women from a prospective cohort of the general population (Data from Epidemiological Study on the Insulin Resistance Syndrome cohort, 9-y follow-up). Six single nucleotide polymorphisms were genotyped., Main Outcome Measure: Incidence of IFG or T2DM during follow-up., Results: The incidence of hyperglycemia (IFG/T2DM) during follow-up by quartiles of baseline plasma copeptin was 11.0% (Q1), 14.5% (Q2), 17.0% (Q3), and 23.5% (Q4), log-rank test P = .003. Participants in the upper quartile of plasma copeptin had significantly lower insulin sensitivity (homeostasis model assessment index) at baseline and during follow-up, as compared with other participants. Cox proportional hazards regression analyses showed significant associations of the CC genotype of rs6084264, the TT genotype of rs2282018, the C-allele of rs2770381, and the CC genotype of rs1410713 with the incidence of hyperglycemia. The genotypes associated with an increased risk of hyperglycemia were also associated with increased plasma copeptin in men but not in women., Conclusions: High plasma copeptin was associated with reduced insulin sensitivity and an increased risk for IFG/T2DM diabetes in this community-based cohort. Moreover, in men, allelic associations support a causal role for vasopressin in these disorders.

Diabetes is one of the most chronic diseases in Western populations. Mortality rates in diabetic patients are higher than in the general population and their prognosis following any cardiovascular event is generally worse. Type 1 diabetic patients' acute complications-related mortality decreases with time and the interval free from the diagnosis of diabetes until the development of chronic complications is larger although global mortality is still higher than that of sex- and age matched healthy individuals. As a consequence of better primary and secondary prevention, recent data in the general population show that there is a trend towards decreased cardiovascular events and increased life expectancy. The same thing applies for type 2 diabetic patients. However, increased survival in the general population associated to epidemic bursts of obesity and sedentary lifestyle all over the globe, leads to a higher incidence of type 2 diabetes worldwide. This counteracts the diminution of diabetes-related mortality that would move forward on an ascending slope in the next decades.

Context: Type B insulin resistance syndrome is a rare condition characterized by the presence of autoantibodies directed against the insulin receptor. It has been reported in association with autoimmune diseases such as systemic lupus erythematosus., Objective: We report a case of type B insulin resistance syndrome in a patient with HIV infection on highly active antiretroviral therapy (HAART)., Patient and Methods: A 27-yr-old African woman with ketosis-prone diabetes and HIV infection developed severe insulin resistance after the initiation of HAART. Standard oral glucose tolerance tests using 75 g of glucose performed 1, 2, and 3 months after the initiation of HAART showed severe hyperinsulinemia and hypoglycemia. Six months later, she developed symptomatic hyperglycemia resistant to high-dose insulin therapy. To determine the cause of insulin resistance, we assayed the titer of insulin receptor autoantibodies in the serum of the patient., Results: Plasma insulin receptor autoantibodies were present at the time of marked hyperglycemia and insulin resistance, confirming the diagnosis of type B insulin resistance syndrome. Simultaneously the diagnosis of immune reconstitution inflammatory syndrome was established according to increased CD4 T cell count, decreased plasma HIV1-RNA level, and tuberculosis reactivation, shortly after institution of HAART. Corticosteroid therapy improved insulin resistance and hyperglycemia., Conclusion: We report the first case of type B insulin resistance syndrome associated with immune reconstitution inflammatory syndrome in an HIV-infected patient.

Introduction: High total adiponectin (ADPN) levels were reported in type 1 diabetes (T1D) and related to long diabetes duration and nephropathy. We studied whether ADPN and its specific isoforms were elevated in T1D without microangiopathy and whether they were related to kidney function., Materials and Methods: Total, high, medium, and low molecular weight ADPN and insulin levels were measured in 47 consecutive normoalbuminuric, normotensive T1D patients without retinopathy and in 47 age-, sex-, and body mass index-matched controls. Glomerular filtration rate was estimated by (51)Cr-EDTA plasma clearance., Results: Total and high molecular weight ADPN ratio were higher in T1D patients than in controls. ADPN levels were not related to anthropometric measures, whereas they were in controls. In T1D, ADPN levels were not related to glycosylated hemoglobin, diabetes duration, or glomerular filtration rate. Peripheral insulin levels were higher in T1D patients than in controls, but they were not related to ADPN levels. In controls, insulin levels were positively related to total ADPN., Conclusion: In T1D without microangiopathy, high ADPN levels could not be related to anthropometric diabetes parameters, kidney function, or high insulin levels. The nature of this elevation remains unknown.

Background: Aldosterone can affect both blood pressure (BP) and glucose metabolism. We assessed the association of two polymorphisms -344 T>C and the 3097 G>A in the aldosterone synthase gene (CYP11B2) with prevalent and incident hypertension (HT), type 2 diabetes (T2D), and the metabolic syndrome (MetS)., Methods: We studied the 5,212 participants to D.E.S.I.R. (Data from Epidemiologic Study on the Insulin Resistance syndrome), a cohort from French general population. Genotyping was done by a TaqMan assay. Analysis of covariance, multivariate logistic regression (adjusted for age, MetS components) and haplotype analysis were performed., Results: The prevalences and 9-year incidences were 16.7 and 36.1% for HT, 2.6 and 6.2% for T2D, and 19.3 and 25.1% for the MetS. Risk for incident HT was reduced with the AA genotype of 3097 G>A, adjusted odds ratios (OR): 0.67; p = 0.04. The prevalence of HT was lower in women carrying the C allele of -344 T>C, OR 0.75; p = 0.03 for the TC genotype and 0.69; p = 0.03 for the CC genotype. In men, incident T2D was associated with both polymorphisms, adjusted OR for -344 T>C: 1.63; p = 0.04 for TC genotype and 2.12; p = 0.008 for CC genotype; for the 3097 G>A: the AA genotype was associated with a lower risk, OR 0.23; p = 0.02. In men, incident MetS was associated with 3097 G>A, OR: 0.57; p = 0.02 for AA genotype. Significant associations between haplotype combinations and the prevalence or incidence of the three diseases were also found., Conclusion: The -344 T>C and 3097 G>A polymorphisms in the CYP11B2 are associated with T2D, hypertension and the MetS in European subjects with gender variations.