Division Of Endocrinology Research Articles

Exploring the Interplay between Emotional Attitudes toward Diabetes, Eating Behavior, and Glycemic Control in Patients with Type 2 Diabetes Mellitus.

This study aimed to assess the association between emotional attitudes toward diabetes, eating behavior styles, and glycemic control in outpatients with type 2 diabetes. Observational study. Endocrinology Division of Hospital de Clínicas de Porto Alegre, Brazil. 91 outpatients diagnosed with type 2 diabetes. Baseline assessments included data on clinical parameters, lifestyle factors, laboratory results, eating behavior styles, and emotional attitudes. All patients received nutritional counseling following diabetes recommendations. A follow-up visit was scheduled approximately 90 days later to evaluate changes in weight, medication dosages, and glycated hemoglobin values. Patients were categorized based on their emotional attitude scores towards diabetes (positive or negative), and their characteristics were compared using appropriate statistical tests. At baseline, no differences were observed in the proportion of patients with good glycemic control, eating behavior styles, and emotional attitudes. However, patients with a positive attitude towards the disease exhibited a significantly better response in glycemic control compared to the reference group (OR=3.47; 95%CI=1.12-10.75), after adjusting for diabetes duration, sex, and medication effect score. However, when BMI was included in the model, the association did not reach statistical significance. Therefore, these results should be interpreted with caution. Patients with a positive attitude towards diabetes showed a greater reduction in glycated hemoglobin levels following nutritional counseling. However, baseline BMI could be a potential confounding factor.

6482 Knowledge and comfort in addressing eating disorders in people living with Type 1 Diabetes in an academic Endocrinology center

Abstract Disclosure: N. Viera Felicino: None. D. Lam: None. Background: Eating disorders(ED) occur at twice the rate in people living with type 1 diabetes(PWT1D) compared to the general population. Early detection and prevention necessitate a high level of clinical suspicion, as the coexistence of ED and T1D is linked to compromised metabolic control, earlier onset of microvascular complications, elevated mortality rates and diminished quality of life. Despite this, healthcare providers often encounter multiple challenges, such as the tendency for ED/DEB to be well hidden and/or denied, as well as a general discomfort in broaching this sensitive topic. Compounding the issue is the scarcity of literature offering optimal methods for supporting and treating individuals suffering from this dual diagnosis. Here, we conducted a survey at an academic center to assess providers’ overall knowledge and comfort level regarding the intersection of ED/DEB in PWT1D. Methods: A 15 question anonymous survey was distributed to members of our Endocrinology division, including fellows, attendings, and advanced practice providers (APPs) across four practices within an academic center in New York City. The primary objectives of the survey were to gauge participants' understanding in three key areas: general knowledge regarding the prevalence of this dual diagnosis, awareness of associated morbidity, and their professional experiences in providing care to this population. Results: The survey was distributed to a total of 40 participants with 29 responses: 38% Endocrine fellows, 41% attending physicians, and 21% APPs. 97% acknowledged that ED are more prevalent in PWT1D compared to the general population and 25% could identify validated screening tools for ED. Regarding the association between ED in PWT1D and health outcomes, 67% accurately identified the increased risk of developing microvascular complications and 36% recognized the increase in the risk of all-cause mortality. 71% reported caring for a PWT1D who expressed concerns about insulin and weight gain. When asked to rate their comfort level in addressing these concerns, 13.8% and 3.4% reported feeling comfortable and very comfortable, respectively. 86% of respondents expressed unfamiliarity with available resources for providing support to individuals in this group. Discussion: The results of the survey show general acknowledgment of the heightened prevalence of ED among PWT1D and association with morbidity and mortality, but emphasizes gaps in knowledge, a general sense of discomfort, and a shortage of resources to effectively manage individuals within this patient demographic. Our survey highlights the need for enhanced education and resources to better equip healthcare professionals in managing the complex intersection of both disorders. Given that diabetes outcomes are heavily dependent on behavioral adherence, strategies for addressing ED are crucial for comprehensive patient care. Presentation: 6/2/2024

6889 Potential Impact of Parental Origin of Inheritance in Presentation of Familial Partial Lipodystrophy

Abstract Disclosure: D. Gilio: None. M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. Speaker; Self; Amryt. O. Besci: None. M. Celik Guler: None. A. Neidert: None. I. Yildirim: None. B. Akinci: Advisory Board Member; Self; Amryt. Consulting Fee; Self; Regeneron Pharmaceuticals, Alnylam Pharmaceuticals, Amryt, AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novartis Pharmaceuticals, Novo Nordisk, Sanofi-Aventis, Servier, Third Rock Ventures. E.A. Oral: Advisory Board Member; Self; Amryt, Regeneron Pharmaceuticals. Consulting Fee; Self; Regeneron Pharmaceuticals, Amryt, Third Rock Ventures. Grant Recipient; Self; Regeneron Pharmaceuticals, Amryt. Research Investigator; Self; Novo Nordisk, Fractyl, Ionis Pharmaceuticals Inc., GI Dynamics, Rhythm Pharmaceuticals. Other; Self; Amryt. Background: Familial partial lipodystrophy Type 2 (FPLD2) caused by autosomal dominant LMNA variants is characterized by partial loss of subcutaneous adipose tissue in the limbs, trunk, and gluteal region with accumulation in other parts of the body, such as the face and neck. It is usually associated with different degrees of insulin resistance and hypertriglyceridemia and body composition patterns. We wanted to know the contributing factors for the different metabolic abnormalities and body composition presentations of FPLD2. We hypothesized that parental inheritance line may be a contributory factor to the expression of the metabolic phenotype and body composition characteristics. Methods: We retrospectively collected clinical data of 77 FPLD2 cases from the Divisions of Metabolism and Endocrinology of 3 different sites: the University of Michigan, the University of São Paulo and The Turkish Lipodystrophy Study Group (TuLip). We further selected 53 published cases curated from 15 studies in the literature. For inclusion of the studies, we used web search tools including PubMed, OMIM and Google Scholar. Only patients where we could assess the genetic inheritance were included in this study. Data collected included demographic information, medical history and laboratory results. Results: 79 patients inherited the LMNA variant from the mother (Group 1; 18 males and 61 females), and 51 patients inherited it from the father (Group 2; 14 males and 37 females). The median age at lipodystrophy diagnosis was lower in Group 1 than in Group 2. Diabetes was reported in more than half of the groups; however, the prevalence rates were not significantly different. The mean age (± SEM) at first diagnosis of diabetes was 30 ± 15 years in Group 1 and 32 ± 11 years in Group 2; the microvascular complications were present in 8 patients with diabetes in Group 1 (36.3%) and in 5 patients in Group 2 (23.8%). Both groups' mean triglycerides levels were >150 mg/dL, with a trend of higher triglycerides in Group 2 than in Group 1. Episodes of acute pancreatitis were identified in 9 patients (19.5%) of Group 1 and 10 patients (31.2%) of Group 2; however, patients in Group 1 showed 1.7 episodes of pancreatitis per person while Group 2 showed 8.1 episodes per person on average. The fatty liver disease was the most common liver abnormality identified and it seemed to be more frequent in Group 2 than in Group 1. There was no difference between the two groups in relation to the body mass index (BMI) and the ratio of percent fat mass of the trunk to percent fat mass of the legs (FMR); however, the DEXA (dual x-ray absorptiometry) showed a higher total fat mass in Group 1 compared to Group 2 (22.2 versus 17.3 Kg, p=0.040) in the presence of comparable total lean mass. Conclusion: Our data suggest that there is a difference in body fat mass according to the genetic inheritance, however the metabolic impact is not completely clear and require more detailed analysis. Presentation: 6/1/2024

7341 Establishing a Multidisciplinary Care Program for patients with Klinefelter Syndrome and other Aneuploidy X and Y Variations

Abstract Disclosure: C.J. Romero: None. N.R. Malhotra: None. A. Norris-Brilliant: None. C. Mintz: None. Objectives: Klinefelter syndrome (KS) is one of the most common genetic aneuploidies denoted by a XXY karyotype and affects up to 1 in 600 patients. Most patients are not diagnosed until adolescent years or adulthood. KS is one of the leading causes of male infertility and testosterone insufficiency. KS is also associated with developmental delays, particularly speech and language delay. Advances in genetics screenings has led to early identification of KS and other aneuploidy X and Y variations, access to neurodevelopmental screening and fertility preservation resources during adolescence and young adulthood. We believe a multidisciplinary program for KS can provide the necessary resources for patients and families at any age from infancy to young adulthood. Methods: A group of faculty from the divisions of pediatric endocrinology, genetics, urology and psychiatry assembled in 2023 to establish a multidisciplinary clinic (MDC) to provide comprehensive care to patients/parents; this ranged from prenatal diagnosis to young adulthood. Two major challenges of care are access to neuro-psychological evaluations and fertility preservation options. Testosterone supplementation requires appropriate referral to endocrinology and timing of treatment remains controversial. Our goals include: expertise guidance and planning after prenatal diagnosis or later in age; access to cost effective neuro-psychological testing during early childhood years; urological consultation beginning in early puberty to educate and prepare patients for choices of surgical and non-surgical options of fertility preservation. Results: Our current center cares for 12 patents ranging from ages 3 months to 21 years. Of this cohort, 3 (25%) of the patients had initial consultations with the parents during pregnancy. 7 (58%) of the patients were of pubertal age that one would consider testosterone replacement, but only 3 (43%) were taking testosterone. Only 1 patient of school age reported neuro-psychological evaluation that was completed at a different institution. No patients received testosterone supplementation during year one of life. Conclusions: A multidisciplinary team can offer simultaneous assessment, anticipatory guidance and management for KS patients and their families. It is a comprehensive resource to our community. Prenatal genetic screenings bring awareness to this diagnosis and therefore timely education toward understanding the lifelong management of KS. Identifying developmental delays early in childhood will help with scholastic success. Monitoring of pubertal development will ensure appropriate pubertal progression in addition to education and management of fertility preservation. Undoubtedly future urological advances will assist patients more effectively. We believe our model provides the access to resources that allow our patients and family to successfully thrive. Presentation: 6/2/2024

Expanding the Spectrum of Endocrine Abnormalities Associated with SOX11-related Disorders.

SOX11 variants cause Coffin-Siris Syndrome (CSS), characterized by developmental delay, hypogonadotropic hypogonadism (HH), skeletal and facial defects. To examine the contribution of SOX11 variants to the pathogenesis of Idiopathic Hypogonadotropic Hypogonadism (IHH), a disorder caused by hypothalamic GnRH deficiency. The Reproductive Endocrine Unit and the Pediatric Endocrinology Division, Massachusetts General Hospital. A cohort of 1810 unrelated IHH probands. Exome sequencing data from the entire cohort were examined for SOX11 rare single nucleotide variants (SNVs) [minor allele frequency in the gnomAD database <0.1%]. Rare SOX11 variant association testing was performed between the IHH and gnomAD population. Phenotyping of individuals harboring pathogenic/likely pathogenic SNVs (determined by the ACMG criteria) was performed. Four pathogenic SOX11 SNVs were identified in 5 IHH probands. The IHH cohort was enriched for SOX11 protein truncating SNVs (frameshift/nonsense) across the entire protein (2 SNVs in 3 IHH cases [p.S303X (de-novo); p.S345Afs*13]; p 0.0004981) and for SOX11 missense SNVs within the SOX11-high-mobility group (HMG) domain (2 SNVs in 2 IHH cases p.G84D[de-novo]; p.P114S; p=0.00313922). The phenotypic spectrum of SOX11 variant carriers revealed additional endocrine defects including anosmic and normosmic forms of IHH, growth-hormone deficiency, pituitary and hypothalamic structural defects, and hypothyroidism. A pathogenic SOX11 SNV was also identified in a patient with functional HH (FHH, p.R100Q). CSS-associated features were present in 4/5 probands. Deleterious SOX11 variants cause IHH and other pituitary hormone deficiencies, suggesting that the human SOX11-associated disorder may stem from both hypothalamic and pituitary level defects.

Novel approach for oligospermia (NAPO) - Protocol for a randomized controlled trial

BackgroundInfertility affects millions of couples globally, with up to 40–50 % of cases linked to impaired semen quality. Insemination or in vitro fertilization are used frequently, regardless of the cause of infertility due to the lack of specific medical interventions for male infertility. Denosumab, an antibody blocking RANKL signaling, may enhance semen quality in infertile men. This randomized controlled trial evaluates if denosumab improves spermatogenesis in men with severely impaired semen quality identified by serum AMH levels as a predictive marker. MethodsNAPO is a single-center, sponsor-investigator-initiated, placebo-controlled, double-blinded randomized trial. Subjects will be randomized in a 2:1 fashion to receive either denosumab 60 mg subcutaneously or a placebo. The study will be carried out at the Division of Translational Endocrinology, Copenhagen University Hospital, Herlev, Denmark. The primary outcome of the study is defined as the difference in sperm concentration (millions/mL) at one spermatogenesis (80 days) after inclusion. DiscussionAn important step in addressing infertility is establishing a viable treatment option for male infertility. With this study, we describe the protocol for a planned RCT aimed at evaluating whether treatment with denosumab can improve sperm concentration in men with severely impaired semen quality. The results of this study will provide evidence crucial for future treatment in a patient group where treatment options are minimal at best. Trial registrationClinical Trials: NCT06300229. Registered on March 12, 2024. Clinical Trials Information System (CTIS): 2023-508325-27-00. Approved on December 19, 2023.

Clinical features most frequently present in patients with concomitant diabetic kidney disease and diabetic retinopathy.

To evaluate the profile of patients with diabetic kidney disease (DKD) with and without concomitant diabetic retinopathy (DR) to identify clinical predictors of the development of both complications together. Cross-sectional study including patients with type 1 and type 2 diabetes and DKD followed at the endocrinology division of a public hospital in Southern Brazil and referred for retinography assessment. The definition of DR was the occurrence of any diabetes-related damage identified in color fundus photographs under mydriasis. Urinary albumin excretion ≥ 14 mg/L and/or glomerular filtration rate < 60 mL/min/1.73 m2 (CKD-EPI equation) were used to define DKD. Factors evaluated included the clinical differences of the participants according to the presence or absence of DR. Multiple regression models were used to identify predictors of DR presence according to the clinical characteristics evaluated. The study included 517 patients with DKD, 433 (83.7%) of whom had type 2 diabetes (median age 64.7 years [interquartile range 59-73 years] years, 59.8% women, 83.4% white) and 84 (16.3%) had type 1 diabetes (median age 46.6 years [interquartile range 33.5-54.2 years], 46.4% women, 91.7% white). Patients with type 2 diabetes and DR (versus those without DR) were more often on insulin (odds ratio [OR] 3.63, 95% confidence interval [CI] 1.89-7.00), had diabetes for longer (OR 1.04, 95% CI 1.02-1.07), and had higher systolic blood pressure (OR 1.01, 95% CI 1.00-1.02). No predictors of DR presence were identified in participants with type 1 diabetes. Among patients with DKD and type 2 diabetes, insulin use, longer diabetes duration, and higher systolic blood pressure level were associated with the presence of DR.

Assessment of the Incidence of Müllerian Anomalies in Central Illinois

Introduction: Müllerian anomalies include a spectrum of malformations resulting from the underdevelopment of the Müllerian duct during embryological development. This results in a malformed vagina, uterus or both. Complete agenesis of one or both of these structures in a subset of these cases is known as Mayer‐Rokitansky‐Küster‐Hauser (MRKH) syndrome. There are two types of Müllerian agenesis: Type I MRKH only affects the upper vagina, cervix and uterus, whereas Type II MRKH has associated malformations affecting the renal, auditory and skeletal systems. The reported prevalence is approximately 1 in 5,000 for MRKH syndrome and ~5.5 in 100 for all Müllerian anomalies; however, there is a broad range in the described incidence rates. Purpose: We hypothesized the patient population served by the Department of Ob/Gyn, Division of Reproduction, Endocrinology and Infertility (REI) at Southern Illinois University (SIU) School of Medicine has a higher incidence of Müllerian anomalies and MRKH. Our objective was to assess the incidence of these Müllerian anomalies and describe the types of anomalies that affect women in Central Illinois. Methods: All patients receiving care at SIU Ob/Gyn, Division of REI from 01/1/2010-07/31/2021 were queried using specific ICD-9 and 10 codes and further screened to verify eligibility. A retrospective review (IRB# 21-893) was then conducted on all eligible subjects and relevant health information was extracted from the electronic health record. Continuous variables were measured by central tendency (mean or median) and dispersion (standard deviation or range). Categorical variables were described using frequencies and percentages. Results: The initial query identified 282 individuals of which 81 were deemed eligible (i.e., confirmed Müllerian anomaly). The total number of unique patients who underwent an ultrasound at REI during that time of study approval was 697. Based on these data, the calculated incidence of Müllerian anomalies in the REI patient population is ~11.6% and the incidence of MRKH is 57 in 5000. Demographics included: 74 subjects were White (91.4%), two Black or African American (2.5%), one Asian (1.2%) and 4 declined to report their race or identified as more than one race (4.9%); two subjects were of Hispanic ethnicity (2.5%). Mean ages at menarche and diagnosis were 12.7 ± 1.7 and 27.8 ± 6.4 years, respectively. Eight subjects diagnosed with MRKH had Type I MRKH. The specific type of anomalies identified included: uterine septum (29.1%), arcuate uterus (25.3%), unicornuate uterus (19.0%), agenesis (10.1%), bicornuate uterus (6.3%), uterus didelphys (6.3%) and 3.8% had another type of anomaly. The majority of patients underwent surgery within approximately one year of diagnosis (74%). Postoperative complications were rare (~7%) and included mild constipation, urinary retention and bleeding from the incision site. Pregnancy outcomes were as follows: prior to diagnosis, 3 (30%) infants were preterm vs. 7 (70%) term and those were spontaneous conceptions; after diagnosis 4 (30%) infants were preterm vs 9 (70%) term deliveries and the most common methods of conception were spontaneous and ovulation induction; post-surgery 11 (31%) infants were born preterm vs 24 (69%) term deliveries, and the most common methods of conception were ovulation induction and in-vitro fertilization. Conclusions: From this initial investigation, we found the incidence of Müllerian anomalies in the SIU Ob/Gyn, REI population is higher than the wide range of reported values. As expected, the vast majority of these patients underwent surgical management with little or no complications. We aim to further study what factors/exposures may be impacting the development of female fetuses resulting in Müllerian anomalies.

Novel Autologous Dendritic Cell Therapy AVT001 for Type 1 Diabetes

BackgroundCD8+ T regulatory (Treg) cells that recognize the nonclassical class 1b molecule Qa-1/human leukocyte antigen E (Q/E CD8+ Treg cells) are important in maintaining self-tolerance. We sought to investigate the role that these T cells play in type 1 diabetes (T1D) pathogenesis and whether an intervention targeting this mechanism may delay T1D progression.MethodsWe conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose.ResultsSixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were −0.17% (95% CI, −0.60 to 0.26%) for HbA1c and −0.06 U/kg/day (95% CI, −0.14 to 0.02) for daily insulin dose.ConclusionsIn this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.)

Ten years' real-life experience on the use of multikinase inhibitors in patients with advanced differentiated thyroid cancer.

To evaluate objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) associated with tyrosine kinase inhibitors (TKIs) in patients with radioiodine refractory differentiated thyroid cancer (RR-DTC). Additionally, to compare: (i) ORR and PFS among patients treated with lenvatinib and sorafenib; (ii) ORR and PFS among patients receiving lenvatinib as first-line vs. second-line and; (iii) adverse effects (AEs) observed in patients treated with these medications. Retrospective analysis of RR-DTC adult patients treated with TKIs at the Division of Endocrinology, Hospital de Clinicas, University of Buenos Aires (March 2011-November 2023). Among 43 patients included in the study, 32 received sorafenib (30 as first-line and 2 as second-line), while 29 received lenvatinib (12 as first-line and 17 as second-line). The median PFS and OS for the entire cohort were 32.7 and 39.0 months, respectively. Lenvatinib demonstrated a significantly higher ORR compared to sorafenib (37.9% vs. 9.4%, p = 0.008). However, both drugs exhibited similar median PFS (23.2 vs. 16.0 months, p = 0.419). No significant difference was observed in ORR and PFS between patients receiving first-line vs. second-line lenvatinib. Sorafenib-treated patients experienced higher rates of hand-foot skin syndrome (69% vs. 41%, p = 0.032) and alopecia (25% vs. 3%, p = 0.018), whereas lenvatinib-treated patients had higher rates of proteinuria (31% vs. 0%, p < 0.001) and grade 3 hypertension (31% vs. 9%, p = 0.034). TKIs demonstrated efficacy and tolerability comparable to real-world data in RR-DTC. PFS was not statistically different between sorafenib and lenvatinib. Our study will help guide physicians in making informed decisions regarding treatment sequencing with TKIs in these patients.

Sex-driven factors associated with anxiety and depression in autoimmune diabetes.

To analyze the prevalence of anxiety and depression in a large cohort of adults with autoimmune diabetes, identifying sex-driven associated factors. In this cross-sectional study, we enrolled 553 consecutive adults with Type 1 diabetes mellitus or latent autoimmune diabetes in adults who came to the Division of Endocrinology of the S.Orsola-Malpighi Polyclinic, Bologna (Italy),to receive their second dose of SARS-CoV-2 vaccine. We administered the questionnaires: Hospital Anxiety and Depression Scale, Diabetes Distress Scale, Diabetes-related Quality of Life, Diabetes Treatment Satisfaction Questionnaire. We collected clinical and biochemical data and 14 days glucose metrics in patients with sensor use > 70% in a time span of ± 4months from the questionnaires' administration. We excluded 119 patients from our analyses with missing data (final cohort n = 434: 79% of those enrolled). Anxiety and depression prevalence was respectively 30.4% and 10.8%. According to the multivariate analysis, higher diabete-related emotional burden, lower treatment satisfaction, but not physician-related distress, were risk factors for anxiety and depression; female sex was associated with anxiety (OR 0.51, 95% 0.31-0.81; p = 0.005); in women, depression was associated with increasing age (males vs. females OR 0.96 per 1year increase, 95% CI 0.92-1.00; p = 0.036), whilst in men with HbA1c (OR 1.08 per 1mmol/mol increase, 95% CI 1.03-1.13; p = 0.002). Nearly 1/3 of patients with autoimmune diabetes suffers from anxiety and 1/10 from depression. These conditions are associated with independent modifiable and non-modifiable characteristics. For depression, these characteristics differ between males and females.

The people behind the papers – J. Guillermo Sanchez and Jim Wells

During development, the gastrointestinal tract undergoes patterning along its anterior-posterior axis to define regions with distinct organs and functions. A new paper in Development derives human intestinal organoids from an individual with duodenal defects and a compound heterozygous variant in the gene encoding the transcription factor RFX6. By studying these organoids, the authors identify novel roles for RFX6 in intestinal patterning. To learn more about the story behind the paper, we caught up with first author J. Guillermo Sanchez and corresponding author Jim Wells, an endowed professor in the Division of Developmental Biology at Cincinnati Children's Hospital, USA, where he is also the Director for Basic Research in the Division of Endocrinology.

Protocol for preliminary, multicenteric validation of "PoCOsteo device": A point of care tool for proteomic and genomic study of osteoporosis.

One of the goals of the HORIZON 2020 project PoCOsteo was to develop a medical device, which would measure and/or quantify proteomic as well as genomic factors as present in whole blood samples collected through finger prick. After validating the tool in the clinical setting, the next step would be its clinical validation based on the existing guidelines. This article presents the protocol of a validation study to be carried out independently at two different centers (Division of Endocrinology and Diabetology at the Medical University of Graz as a clinic-based cohort, and the Endocrinology and Metabolism Research Institute at the Tehran University of Medical Sciences as a population-based cohort). It aims to assess the tool according to the Clinical & Laboratory Standards Institute guidelines, confirming if the proteomics and genomics measurements provided by the tool are accurate and reproducible compared with the existing state-of-the-art tests. This is the first time that such a detailed protocol for lab validation of a medical tool for proteomics and genomic measurement is designed based on the existing guidelines and thus could be used as a template for clinical validation of future point-of-care tools. Moreover, the multicentric cohort design will allow the study of a large number of diverse individuals, which will improve the validity and generalizability of the results for different settings.

ASSOCIATION OF LEVEL OF EDUCATION AND OCCUPATION WITH DIABETIC FOOT ULCER IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Objective: Diabetic foot ulcer (DFU) is a well-known microvascular complication of Type 2 Diabetes mellitus (T2DM) with several risk factors. This study intended to determine the association of the level of education and occupation with the severity and outcome of DFU in diabetic patients. Materials and Methods: This study was conducted from 1st January 2023 to 25th January 2023 in the Endocrinology Division of the Department of Medical Specialties, Khyber Teaching Hospital, Peshawar. Adult diabetic patients with DFU were enrolled in the study. All the relevant demographic, clinical, and biochemical characteristics were measured. Results: Out of 148 patients, only 50 (33.8%) patients were educated. The study participants had a mean age, BMI, HbA1c, and duration of DM of 56.48 years, 27.3 kg/m2, 10.3 % and 9.4 years, respectively. There was a substantial association between the level of education and occupation with the severity of DFU which was statistically significant (p-value = 0.001 and p-value = 0.01, respectively). Regarding the outcome of DFU, it was found that patients with medium and high levels of literacy and skilled occupation had lower rates of major amputations. These results were statistically non-significant however they were found to be clinically significant. Conclusion: A significant association was observed between the education level and occupation with the severity and outcome of DFU. This underpins the significance of structured education of patients with low and medium literacy levels and those with unskilled and semiskilled jobs regarding their foot care. Keywords: Type 2 Diabetes Mellitus, Diabetic Foot ulcer, Occupation

NIH Fifth Artificial Pancreas Workshop 2023: Meeting Report: The Fifth Artificial Pancreas Workshop: Enabling Fully Automation, Access, and Adoption.

The Fifth Artificial Pancreas Workshop: Enabling Fully Automation, Access, and Adoption was held at the National Institutes of Health (NIH) Campus in Bethesda, Maryland on May 1 to 2, 2023. The organizing Committee included representatives of NIH, the US Food and Drug Administration (FDA), Diabetes Technology Society, Juvenile Diabetes Research Foundation (JDRF), and the Leona M. and Harry B. Helmsley Charitable Trust. In previous years, the NIH Division of Diabetes, Endocrinology, and Metabolic Diseases along with other diabetes organizations had organized periodic workshops, and it had been seven years since the NIH hosted the Fourth Artificial Pancreas in July 2016. Since then, significant improvements in insulin delivery have occurred. Several automated insulin delivery (AID) systems are now commercially available. The workshop featured sessions on: (1) Lessons Learned from Recent Advanced Clinical Trials and Real-World Data Analysis, (2) Interoperability, Data Management, Integration of Systems, and Cybersecurity, Challenges and Regulatory Considerations, (3) Adaptation of Systems Through the Lifespan and Special Populations: Are Specific Algorithms Needed, (4) Development of Adaptive Algorithms for Insulin Only and for Multihormonal Systems or Combination with Adjuvant Therapies and Drugs: Clinical Expected Outcomes and Public Health Impact, (5) Novel Artificial Intelligence Strategies to Develop Smarter, More Automated, Personalized Diabetes Management Systems, (6) Novel Sensing Strategies, Hormone Formulations and Delivery to Optimize Close-loop Systems, (7) Special Topic: Clinical and Real-world Viability of IP-IP Systems. "Fully automated closed-loop insulin delivery using the IP route," (8) Round-table Panel: Closed-loop performance: What to Expect and What are the Best Metrics to Assess it, and (9) Round-table Discussion: What is Needed for More Adaptable, Accessible, and Usable Future Generation of Systems? How to Promote Equitable Innovation? This article summarizes the discussions of the Workshop.

SAT339 Osteopenia In The Setting of Mild Autonomous Cortisol Secretion

Abstract Disclosure: J.J. Mao: None. K.C. McCowen: None. C. Choe: None. Jimmy J. Mao, MD (1); Karen C. McCowen (1); Charles H. Choe (1)(1) Division of Endocrinology, Diabetes, and Metabolism, University of California San Diego, La Jolla, CA. Background: Over 80% of adrenal incidentalomas are benign adrenal cortical adenomas, of which 30-50% are found to have mild autonomous cortisol secretion (MACS). Bone fragility is a known complication of MACS. Clinical Case: A 57-year-old postmenopausal female with no prior history of fracture, venous thromboembolism, and atherosclerotic cardiovascular disease, was referred for incidental bilateral adrenal nodules. Body mass index was normal at 21 kg/m2, and no clinical stigmata of Cushing syndrome were noted on physical exam. Unenhanced computed tomography scan revealed a 4.6 cm right adrenal nodule and a 3.3 cm left adrenal nodule; both nodules measured less than -18 Hounsfield Units. Biochemical work-up for pheochromocytoma, primary aldosteronism, and non-classical congenital adrenal hyperplasia was negative. Evaluation for hypercortisolism revealed a morning cortisol of 20.3 mcg/dL (ref. 4-22 mcg/dL) with concurrent adrenocorticotropic hormone of &amp;lt;5 pg/mL (ref. 6-50 pg/mL), 24-hour urine free cortisol of 16.9 mcg (ref. 4-50 mcg), and midnight salivary cortisol of 0.07 mcg/dL (ref. &amp;lt;0.09 mcg/dL). A 1 mg dexamethasone suppression test measured on two separate occasions was elevated at 6.3 mcg/dL and 7.9 mcg/dL (ref. &amp;lt;1.8 mcg/dL). A subsequent 8 mg dexamethasone suppression test was also elevated at 6.1 mcg/dL (ref. &amp;lt;1.8 mcg/dL). The diagnosis of MACS was made. A bone mineral density (BMD) scan revealed T-scores at the right femoral neck, left femoral neck, and lumbar spine at -1.6, -1.3, and -0.8, respectively. Ten-year probability of major osteoporotic fracture and hip fracture were 8.3% and 1.0%, respectively. To reduce the risk for future fractures, the decision was made to proceed with adrenal vein sampling (AVS) in preparation for potential adrenalectomy. Conclusion: MACS is the most frequent hormonal abnormality in adrenal incidentalomas, with an estimated prevalence of 0.8-2 cases per 1000 persons. A previous prospective study found that surgical cure of unilateral MACS may lead to a substantial risk reduction (up to 15-fold) of future incident asymptomatic vertebral fractures. Additionally, the highest risk for clinical fracture in those with adrenal adenomas (either nonfunctional or with cortisol hypersecretion) appears to occur at 7-10 years after initial diagnosis. BMD does not perfectly correlate with fracture risk, so unilateral adrenalectomy (if lateralization is observed on AVS) and/or pharmacotherapy should be strongly considered in patients with an expected longevity of &amp;gt;10 years even with mild osteopenia and low fracture risk assessment tool scores. Presentation: Saturday, June 17, 2023

SAT227 A 17-year old Teenager With Recurrent Syncopes In The Setting of Hypocalcemia

Abstract Disclosure: D.V. Chartoumpekis: None. P. Bountouris: None. K. Dimitropoulos: None. I.G. Habeos: None. Background: One of the main reasons of syncope is the long QT syndrome. The exercise-induced hypocalcemia in a background of primary hypoparathyroidism is sometimes overlooked in the differential diagnosis. Clinical Case: A 17-year old female was transferred to the emergency room of the University Hospital of Patras after having experienced a syncope while swimming. She described in the past 6 months similar episodes during exercise (running, cycling). A basic investigation with full blood count, sodium, potassium, cortisol and TSH levels along with a brain MRI and an ECG were performed at her primary care physician. Due to a discovered long QT she was addressed to a cardiology private office for further investigation. However, before the planned appointment she had this episode while swimming and she was admitted to the cardiology department. During her hospitalization a serum calcium of 4.7 mg/dl and a serum P of 9.4 mg/dl were discovered with a non-detectable PTH. The endocrinology division was called for further evaluation. Chvostek and Trousseau’s signs were positive. The patient was administered a calcium gluconate drip and in parallel a treatment with calcium carbonate and alphacalcidol was initiated. The possibility of an autoimmune polyendocrine syndrome was excluded as the patient did not present candidiasis, adrenal insufficiency, autoimmune thyroid disease or diabetes. After her exit from the hospital she was followed up at the outpatient endocrinology clinic and her daily doses of calcium carbonate and alphacalcidol was modified several times as the [CaxP] was always higher than 55 mg2/dl2 and when the dose of calcium carbonate was lowered she developed symptomatic hypocalcemia. During the first month of her follow-up a cataract in the right eye was discovered and a brain MRI unveiled basal ganglia calcifications. No signs of renal stones or nephrocalcinosis were seen in the ultrasound. As the calcium and phosphate levels, after almost 9 months of changes in the treatment schemes, were not optimal, a treatment with recombinant PTH was initiated. This treatment aided the patient to reach low normal levels of calcium and [CaxP] lower than 55 mg2/dl2. The patient is followed up every six months in the endocrinology outpatient clinic. Conclusion: This is an interesting case of primary hypoparathyroidism possibly of autoimmune origin. The presence of syncopes during exercise could be due to a further drop of calcium levels due to transient respiratory alkalosis. This case can be useful in the teaching of differential diagnosis of long QT syndrome, the management and evaluation of an hypocalcemia and the rule out of autoimmune polyendocrine syndromes in the context of a primary hypoparathyroidism. Presentation: Saturday, June 17, 2023

Sexual dysfunction in women with PCOS: a case control study.

What is the relationship of sex steroid levels with sexual function in women with and without polycystic ovary syndrome (PCOS)? Women with PCOS reported more sexual dysfunction and more sexual distress compared to those without PCOS, but only few and weak associations between androgen levels and sexual function were observed. The literature shows that women with PCOS report lower levels of sexual function and sexual satisfactionand more sexual distress. Contributing factors seem to be obesity, alopecia, hirsutism, acne, infertility, anxiety, depression, and low self-esteem. In women with PCOS clinical and/or biochemical hyperandrogenism is common; its relationship with sexualfunction is, however, inconclusive. This observational prospective case control study with 135 women (68 PCOS, 67 control) was conductedfrom March 2017 until March 2020. Heterosexual women with and without PCOS, aged 18-40 years, in a steady relationshipand without any comorbidities, underwent an extensive medical and endocrine screening using liquid chromatography-tandem mass spectrometry and validated sexual function questionnaires. Women with PCOS reported significantly lower sexual function (Female Sexual Function Index (FSFI) P < 0.001, partial η2 = 0.104), higher levels of sexual distress (Female Sexual Distress Scale-Revised P < 0.001, partial η2 = 0.090), and they more often complied with the definition of sexual dysfunction (41.2% vs 11.9%, P < 0.001, Phi V = 0.331) and clinical sexual distress (51.5% vs 19.4%, P < 0.001, Phi V = 0.335). Regression analysis adjusted for confounders showed only few and weak associations between androgen levels and sexual function, with each model explaining a maximum of 15% sexual function. Following significant Group × Hormone interactions, analyses for both groups separately showed no significant associations in the PCOS group. The control group showed only weak negative associations between testosterone and FSFI pain (β = -6.022, P = 0.044, Adj R2 = 0.050), between FAI and FSFI orgasm (β = -3.360, P = 0.023, Adj R2 = 0.049) and between androstenedione and clinical sexual distress (β = -7.293, P = 0.036, exp(β) = 0.001). The focus of the study on sexual functioning potentially creates selection bias. Possibly women with more severe sexual disturbances did or did not choose to participate. Differences between women with PCOS and controls in relationship duration and hormonal contraceptive use might have skewed the sexual function outcomes. Sexual function is impaired in women with PCOS. However, endocrine perturbations seem to have minimal direct impact on sexual function. Addressing sexuality and offering psychosexual counseling is important in the clinical care for women with PCOS. This study was funded by the departments of the participating centers: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Psychosomatic OBGYN and Sexology, Leiden University Medical Center, Leiden, the Netherlands; and Department of Sexology and Psychosomatic OBGYN, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands. J.S.E.L. received unrestricted research grants from the following companies (in alphabetical order): Ansh Labs, Ferring, Merck Serono and Roche Diagnostics. He also received consultancy fees from Ansh Labs, Ferring, Titus Healthcare and Roche Diagnostics. The other authors have no conflicts of interest. CCMO register, registration number: NL55484.078.16, 10 March 2016. https://www.toetsingonline.nl/to/ccmo_search.nsf/Searchform?OpenForm.

Evaluation of etiology and clinical feature of precocious puberty among children presenting in a pediatric endocrinology department in a tertiary care hospital.

Objective: To find the frequency of precocious puberty in children and to compare the clinical and laboratory parameters of central &amp; peripheral precocious puberty. Study Design: Cross-sectional study. Setting: Karachi's National Institute of Child Health's Paediatric &amp; endocrinology Division. Period: December 2016 and 2021. Material &amp; Methods: All patients with precocious puberty will be taken from files through non-probability convenience sampling method. Data was analyzed on SPSS version 22.0. Results: Total 65 patients were included. The mean age was 6+3.35years. Precocious puberty was classified as peripheral precocious puberty in 38 (58.4%), central precocious puberty in 20 (30.76%), premature thelarche in 5(7.69%) and premature1pubarche in 2 (3.07%). In the peripheral precocious1puberty group, CAH was found in 22(78.5%), out of which 2 patients were of rare mutation of CAH presenting with peripheral precocious puberty (DAX mutation and 11 B hydroxylase mutation, adenocarcinoma was observed in 2(7.14%) followed by Mu-cane- Albright syndrome was in 4(14.28%) and van wykgrumbach syndrome in 10 patients. Central precocious puberty was found in 20 patients hypothalamic harmartoma in 4(20%), craniopharyngioma 3(15%), hypothalamic astrocytoma 1(5.0%), genetically proven neurofibromatosis in 1(5.0%) patient and hydrocephalus 1(5.0%) and in 10(50%) patients no cause was found. Conclusion: The conclusion of the study that Peripheral precocious puberty was more common than central precocious puberty. The common cause of peripheral precocious puberty was CAH, while central precocious puberty was idiopathic. Children with central precocious puberty had greater height SDS, weight SDS, FSH, and LH levels compared to children who had peripheral precocious puberty.

Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: a randomised crossover trial

Aims/hypothesisThis study compared the frequency of hypoglycaemia, time to hypoglycaemia and recovery from hypoglycaemia after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100. Furthermore, the symptomatic and counterregulatory responses to hypoglycaemia were compared between icodec and glargine U100 treatment.MethodsIn a randomised, single-centre (Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria), open-label, two-period crossover trial, individuals with type 2 diabetes (age 18–72 years, BMI 18.5–37.9 kg/m2, HbA1c ≤75 mmol/mol [≤9.0%]) treated with basal insulin with or without oral glucose-lowering drugs received once-weekly icodec (for 6 weeks) and once-daily glargine U100 (for 11 days). Total weekly doses were equimolar based on individual titration of daily glargine U100 during the run-in period (target fasting plasma glucose [PG]: 4.4–7.2 mmol/l). Randomisation was carried out by assigning a randomisation number to each participant in ascending order, which encoded to one of two treatment sequences via a randomisation list prepared prior to the start of the trial. At steady state, double and triple doses of icodec and glargine U100 were administered followed by hypoglycaemia induction: first, euglycaemia was maintained at 5.5 mmol/l by variable i.v. infusion of glucose; glucose infusion was then terminated, allowing PG to decrease to no less than 2.5 mmol/l (target PGnadir). The PGnadir was maintained for 15 min. Euglycaemia was restored by constant i.v. glucose (5.5 mg kg−1 min−1). Hypoglycaemic symptoms score (HSS), counterregulatory hormones, vital signs and cognitive function were assessed at predefined PG levels towards the PGnadir.ResultsHypoglycaemia induction was initiated in 43 and 42 participants after double dose of icodec and glargine U100, respectively, and in 38 and 40 participants after triple doses, respectively. Clinically significant hypoglycaemia, defined as PGnadir <3.0 mmol/l, occurred in comparable proportions of individuals treated with icodec vs glargine U100 after double (17 [39.5%] vs 15 [35.7%]; p=0.63) and triple (20 [52.6%] vs 28 [70.0%]; p=0.14) doses. No statistically significant treatment differences were observed in the time to decline from PG values of 5.5 mmol/l to 3.0 mmol/l (2.9–4.5 h after double dose and 2.2–2.4 h after triple dose of the insulin products). The proportion of participants with PGnadir ≤2.5 mmol/l was comparable between treatments after double dose (2 [4.7%] for icodec vs 3 [7.1%] for glargine U100; p=0.63) but higher for glargine U100 after triple dose (1 [2.6%] vs 10 [25.0%]; p=0.03). Recovery from hypoglycaemia by constant i.v. glucose infusion took <30 min for all treatments. Analyses of the physiological response to hypoglycaemia only included data from participants with PGnadir <3.0 mmol/l and/or the presence of hypoglycaemic symptoms; in total 20 (46.5%) and 19 (45.2%) individuals were included after a double dose of icodec and glargine U100, respectively, and 20 (52.6%) and 29 (72.5%) individuals were included after a triple dose of icodec and glargine U100, respectively. All counterregulatory hormones (glucagon, adrenaline [epinephrine], noradrenaline [norepinephrine], cortisol and growth hormone) increased during hypoglycaemia induction with both insulin products at both doses. Following triple doses, the hormone response was greater with icodec vs glargine U100 for adrenaline at PG3.0 mmol/l (treatment ratio 2.54 [95% CI 1.69, 3.82]; p<0.001), and cortisol at PG3.0 mmol/l (treatment ratio 1.64 [95% CI 1.13, 2.38]; p=0.01) and PGnadir (treatment ratio 1.80 [95% CI 1.09, 2.97]; p=0.02). There were no statistically significant treatment differences in the HSS, vital signs and cognitive function.Conclusions/interpretationDouble or triple doses of once-weekly icodec lead to a similar risk of hypoglycaemia compared with double or triple doses of once-daily glargine U100. During hypoglycaemia, comparable symptomatic and moderately greater endocrine responses are elicited by icodec vs glargine U100.Trial registrationClinicalTrials.gov NCT03945656.FundingThis study was funded by Novo Nordisk A/S.Graphical