Faculty Bibliography

PURPOSE/OBJECTIVE:Primary aldosteronism (PA) is an underdiagnosed cause of secondary hypertension with significant health consequences. Expanding screening criteria may improve case detection and reduce the number of untreated patients. METHODS:We assessed PA screening rates in a cohort of 457 adults with comorbid obstructive sleep apnea (OSA) and hypertension (HTN). PA screening in a subset of the cohort (n = 97, 21%) was conducted using serum aldosterone, aldosterone-to-plasma renin activity ratio (ARR), and plasma renin activity (PRA). Screening results were compared between the 2016 Endocrine Society guidelines (serum aldosterone and ARR) and the Vaidya & Carey algorithm (serum aldosterone and PRA). RESULTS:The screened patients were predominantly male (mean age 58.6 years), with common comorbidities including hyperlipidemia (80%) and diabetes mellitus (31%). PA positivity rates differed significantly between screening criteria: 7% tested positive using Endocrine Society guidelines, while 33% screened positive using the Vaidya & Carey algorithm. Notably, 26% of patients with negative screens by Endocrine Society criteria were reclassified as positive, and 11 previously indeterminate cases were classified as negative due to absent renin suppression. Using the Vaidya & Carey algorithm with a stricter PRA suppression threshold, 25% of patients screened positive. CONCLUSION/CONCLUSIONS:The Vaidya & Carey algorithm may be an important tool in increasing detection of previously unidentified cases and clarifying the diagnosis of cases that were previously deemed indeterminate. Given the morbidity of untreated PA, more robust screening approaches are warranted. Prospective studies are needed to validate these findings across diverse populations.

OBJECTIVE:This study examined racial and ethnic differences in percent total weight loss (%TWL) and glycemic improvement following sleeve gastrectomy (SG) and explored the role of socioeconomic and psychosocial factors in postsurgical outcomes. METHODS:This longitudinal study included patients who underwent SG between 2017 and 2020, with follow-up visits over 24 months. RESULTS:Non-Hispanic Black (NHB) participants had lower %TWL at 3, 12, and 24 months compared with Hispanic (H) and non-Hispanic White (NHW) participants. Fat mass index was initially lower in NHB, with smaller reductions over time and significant group differences persisting at 24 months. NHB participants had higher baseline fat-free mass index values; by 24 months, fat-free mass index values were lower in H participants. Hemoglobin A1c decreased across all groups but remained consistently higher in NHB and H compared with NHW at 24 months. NHB participants reported higher perceived discrimination, sleep disturbance, and perceived stress than H and NHW participants at all time points. Employment status predicted %TWL at 12 months. There was a significant interaction between race and ethnicity and employment status observed at 12 and 24 months, suggesting that employment-related disparities could impact surgical outcomes. CONCLUSIONS:NHB participants experienced less favorable outcomes following SG, emphasizing the need for tailored interventions addressing socioeconomic and psychosocial disparities.

AIMS/OBJECTIVE:To characterize changes in continuous glucose monitoring (CGM)-derived time in tight range (TIR) measures in individuals with prediabetes or non-insulin-treated type 2 diabetes undergoing dietary weight loss intervention and to quantify the association between weight loss and TIR improvement. METHODS:) were analysed. The association between weight change and TIR change adjusted for demographic and clinical covariates was computed using linear regression. RESULTS:. There were no associations between weight loss and change in any overnight TIR measure. CONCLUSION/CONCLUSIONS:in individuals with prediabetes and non-insulin-treated type 2 diabetes undergoing dietary intervention. The daytime time in tight range measures can complement traditional markers like HbA1c, offering a more comprehensive view of glycaemic variations during dietary weight loss programmes for individuals with prediabetes and type 2 diabetes not on insulin.

DIAPH1 is a member of the family of Diaphanous Related Formins (DRFs) implicated in cell migration and cytokinesis. DRFs are maintained in an autoinhibited state by the intramolecular association between diaphanous inhibitory (DID) and diaphanous autoregulatory (DAD) domains. Actin polymerization requires the binding of activated RhoA to the GTPase binding domain (GBD) of DIAPH1 and the dissociation of DAD. In the presence of excess RhoA, actin polymerization is only partially activated. Using monomeric domain constructs of DIAPH1, the sequential binding affinities of RhoA and DAD to GBD-DID were characterized. Binding of RhoA and DAD were negatively cooperative requiring a 100-fold greater concentration of DAD to achieve saturation when RhoA binding site was occupied. The unimolecular architecture of full length DIAPH1 establishes an effective concentration of DAD in the micromolar range, which is 100-fold larger than the intrinsic affinity of DAD for DID. The effective concentration is large enough to maintain DIAPH1 autoinhibition, yet small enough to permit partial activation of DIAPH1 after RhoA binding. By exploiting negative cooperativity, DIAPH1 maintains a reserve of inactivated molecules enabling gradual responses to cellular processes that require prolonged and sustained regulation. The proposed mechanism is extended to other DIAPH1 activating ligands and broadly applicable to all DRFs.

Angiopoietin-like 3 (ANGPTL3) inhibits lipases that hydrolyze triglycerides (TGs) in TG-rich lipoproteins (TRLs). We evaluated TRL-TGs, TRL particle (apolipoprotein B), palmitate, and glucose kinetics during a mixed-meal test that included intravenous and oral tracer administrations in people with extremely rare compound heterozygous ANGTPL3 loss-of-function mutations (ANGPTL3^-/- group, n = 3) and matched control participants (n = 7). Multi-organ (liver, muscle, and adipose tissue) insulin sensitivity was evaluated with a two-step hyperinsulinemic-euglycemic clamp procedure and glucose and palmitate tracer infusions. We find that plasma TG and TRL particle concentrations are more than 10-fold lower in the ANGPTL3^-/- than in the control group due to both markedly reduced liver-derived TRL particle and TG secretion rates combined with increased plasma clearance of both liver- and gut-derived TRLs. Palmitate and glucose kinetics during the meal test are not different between the groups. We conclude that the biological function of ANGPTL3 reaches beyond inhibiting intravascular lipase activity.

BACKGROUND:Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neuroendocrine tumors. PitNETs can be challenging to classify, and current recommendations include a large immunohistochemical panel to differentiate among 14 WHO-recognized categories. METHODS:In this study, we analyzed clinical, immunohistochemical and DNA methylation data of 118 PitNETs to develop a clinico-molecular approach to classifying PitNETs and identify epigenetic classes. RESULTS:CNS DNA methylation classifier has an excellent performance in recognizing PitNETs and distinguishing the three lineages when the calibrated score is ≥0.3. Unsupervised DNA methylation analysis separated PitNETs into two major clusters. The first was composed of silent gonadotrophs, which form a biologically distinct group of PitNETs characterized by clinical silencing, weak hormonal expression on immunohistochemistry, and simple copy number profile. The second major cluster was composed of corticotrophs and Pit1 lineage PitNETs, which could be further classified using DNA methylation into distinct subclusters that corresponded to clinically functioning and silent tumors and are consistent with transcription factor expression. Analysis of promoter methylation patterns correlated with lineage for corticotrophs and Pit1 lineage subtypes. However, the gonadotrophic genes did not show a distinct promoter methylation pattern in gonadotroph tumors compared to other lineages. Promoter of the NR5A1 gene, which encodes SF1, was hypermethylated across all PitNETs clinical and molecular subtypes including gonadotrophs with strong SF1 protein expression indicating alternative epigenetic regulation. CONCLUSION/CONCLUSIONS:Our findings suggest that classification of PitNETs may benefit from DNA methylation for clinicopathological stratification.

Alzheimer's and Parkinson's disease are the most common neurodegenerative diseases, significantly affecting the elderly with no current cure available. With the rapidly aging global population, advancing research on these diseases becomes increasingly critical. Both disorders are often studied using model organisms, which enable researchers to investigate disease phenotypes and their underlying molecular mechanisms. In this review, we critically discuss the strengths and limitations of using Drosophila, zebrafish, and mice as models for Alzheimer's and Parkinson's research. A focus is the application of single-cell RNA sequencing, which has revolutionized the field by providing novel insights into the cellular and transcriptomic landscapes characterizing these diseases. We assess how combining animal disease modeling with high-throughput sequencing and computational approaches has advanced the field of Alzheimer's and Parkinson's disease research. Thereby, we highlight the importance of integrative multidisciplinary approaches to further our understanding of disease mechanisms and thus accelerating the development of successful therapeutic interventions.

Diabetes is a major risk factor for cardiovascular diseases. Patients with diabetes are at greater risk for morbidity and mortality post myocardial infarction. As the epidemic of diabetes continues at an alarming pace, identification of specific therapeutic interventions to protect diabetic patients from the devastating consequences of myocardial infarction is an urgent need. Advanced glycation end products (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids, accumulate in the diabetic circulation and heart. The interaction of AGEs with its key receptor, receptor for AGE or RAGE, contributes to cardiac injury and dysfunction. The discovery that intracellular domain of RAGE binds to the formin, DIAPH1, and that DIAPH1 is essential for RAGE ligand-mediated signal transduction, unveiled the specific cellular means by which RAGE functions and highlights a new target for therapeutic interruption of pathological RAGE signaling during myocardial infarction. This review delves into intrinsic mechanisms by which AGE-RAGE axis via RAGE-DIAPH1 driven DIAPH1-Mitofusin2 (MFN2) interaction modulates pathogenic inter-organelle communications and opens opportunities for intensive studies to uncover the comprehensive mechanisms that drive injury-provoking actions from the intracellular space. This review illustrates the potential therapeutic cardioprotective benefits of antagonism of RAGE-DIAPH1interactions in the diabetic heart.