OBJECTIVE To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12–24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7–193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 μg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845–1.408]; P = 0.5009). However, GAD-alum–treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126–2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose–adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

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CRD42016053457.

Aims Epidemiological data on subclinical atherosclerotic disease in type 1 diabetes mellitus (DM1) are scarce. We aimed to estimate the subclinical atherosclerosis profile of asymptomatic patients with DM1 and an abnormal ankle‐brachial index (ABI). Material and methods In a cross‐sectional design (http://ClinicalTrials.gov Identifier: NCT02910271), we estimated ABI in 289 consecutive asymptomatic patients with DM1. An abnormal ABI led to measurements of toe‐brachial index (TBI) and peripheral doppler ultrasound (DUS) to diagnose peripheral artery disease (PAD) and/or atherosclerotic carotid plaques (ACP). Results A reduced (≤0.9) or increased (>1.2) ABI was detected in 17 (6%) and 75 (26%) patients, respectively. PAD was confirmed by TBI and DUS in 9 (53%) patients with a reduced ABI and 28 (37%) patients with an increased ABI, resulting in a 12.8% (9.4‐17.2) prevalence of asymptomatic PAD. Fourteen patients with an abnormal ABI also exhibited ACP [4.8% (2.9‐7.9)], with 64% of these patients showing bilateral disease. Artery stenosis was mild or moderate in 21% and 29% of patients, respectively. Thus, 46 [16% (12‐21)] patients showed asymptomatic PAD, ACP, or both. According to our data, we would have to explore three asymptomatic patients with DM1 and normal pulses to unmask one case of PAD, and seven asymptomatic patients showing abnormal ABI values to detect one carotid disease. Conclusions Peripheral artery disease is often undiagnosed in asymptomatic patients with DM1. However, its presence may change medical management in a substantial percentage of cases, highlighting the potential benefit of a thorough vascular assessment on these patients.

This study describes the development of a new questionnaire to measure health-related quality of life (HRQoL) in patients with type 1 diabetes (the ViDa1 questionnaire) and provides information on its psychometric properties. For its development, open interviews with patients took place and topics relevant to patients' HRQoL were identified and items were generated. Qualitative analysis of items, expert review, and refinement of the questionnaire followed. A pilot study (N = 150) was conducted to explore the underlying structure of the 40-item ViDa1 questionnaire. A Principal Component Analysis (PCA) was performed and six of the items that did not load on any of the factors were eliminated. The results supported a four-dimensional structure for ViDa1, the dimensions being Interference of diabetes in everyday life, Self-care, Well-being, and Worry about the disease. Subsequently, the PCA was repeated in a larger sample (N = 578) with the reduced 34-item version of the questionnaire, and a Confirmatory Factor Analysis (CFA) was performed (N = 428). Overall fit indices obtained presented adequate values which supported the four-factor model initially proposed [(χ(df=554)2= 2601.93) (p < 0.001); Root Mean Square Error of Approximation = 0.060 (CI = 0.056 −0.064)]. As regards reliability, the four dimensions of the ViDa1 demonstrated good internal consistency, with Cronbach's alphas ranging between 0.71 and 0.86. Evidence of convergent-discriminant validity in the form of high correlations with another specific HRQoL questionnaire for diabetes and low correlations with other constructs such as self-efficacy, anxiety, and depression were presented. The ViDa1 also discriminated between different aspects of clinical interest such as type of insulin treatment, presence of chronic complications, and glycemic control, temporal stability, and sensitivity to change after an intervention. In conclusion, the ViDa1 questionnaire presents adequate psychometric properties and may represent a good alternative for the evaluation of HRQoL in type 1 diabetes.

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Context Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. Objectives (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. Design Randomized, parallel, open-label, clinical trial. Setting Academic hospital. Patients Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. Intervention After a 3-month run-in period of treatment with 35 μg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. Main outcome measures Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin &lt;120 g/L and/or hematocrit &lt;0.36. Results From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: −1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels &lt;120 g/L and hematocrit (Hct) values &lt;0.36, respectively, but none showed Hb &lt;110 g/L or Hct &lt;0.34. Conclusions Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.

Objective To offer a practical guide for the presurgical and anesthetic management of pheochromocytomas and sympathetic paragangliomas (PGLs). Methods This protocol was based on a comprehensive review of the literature and on our own multidisciplinary team's experience from managing pheochromocytoma and sympathetic PGLs at a referral center. Results Patients with pheochromocytomas and sympathetic paragangliomas (PGLs) may develop potentially life-threatening complications, especially during surgical procedures. A complete biochemical, radiological, genetic, and cardiological assessment is recommended in the preoperative stage as it provides an evaluation of the risk of surgical complications and malignancy, allowing individualization of the presurgical treatment. Treatment with α-blockade and proper volume expansion in the preoperative stage significantly reduces the perioperative morbidity. During surgery, the anesthesiologist should look for a deep anesthetic level that inhibits the cardiovascular effects of catecholamines to minimize the risk of intraoperative complications. Conclusions An optimal presurgical evaluation of pheochromocytomas/ sympathetic PGL requires a multidisciplinary approach, including a complete hormonal, radiological, cardiac, genetic, and functioning evaluation in most cases. A proper preoperative evaluation in combination with strict blood pressure and heart rate control, and blood volume status optimization, will significantly reduce the risk of intraoperative and perioperative complications. In those patients who unfortunately develop intraoperative complications, the role of the anesthesiologist is essential since the selection of the appropriate management has a direct impact on morbimortality reduction. Keywords Pheochromocytoma • Paragangliomas • Presurgical management • Anesthetic treatment • α-blockadeThis article was elaborated by the multidisciplinary adrenal/ paraganglioma team of the Hospital Ramón y Cajal. Madrid (Spain).