Daily Endocrinology Research Analysis
Three impactful endocrinology studies span precision therapeutics, biomarker-driven diagnosis, and practical diabetes technology. A large real-world pharmacogenomic analysis links NBEA variants to weight-loss response with GLP-1 receptor agonists, a JCEM study identifies circulating miR-222-3p as a subtype marker and potential driver in unilateral primary aldosteronism, and a randomized crossover trial shows how Omnipod 5 Activity mode attenuates exercise-related glucose drops.
Summary
Three impactful endocrinology studies span precision therapeutics, biomarker-driven diagnosis, and practical diabetes technology. A large real-world pharmacogenomic analysis links NBEA variants to weight-loss response with GLP-1 receptor agonists, a JCEM study identifies circulating miR-222-3p as a subtype marker and potential driver in unilateral primary aldosteronism, and a randomized crossover trial shows how Omnipod 5 Activity mode attenuates exercise-related glucose drops.
Research Themes
- Pharmacogenomics for obesity therapy
- Circulating microRNA biomarkers in adrenal disease
- Optimizing automated insulin delivery around exercise
Selected Articles
1. Neurobeachin (NBEA) is a novel gene associated with GLP-1 receptor agonist associated weight loss.
Using the NIH All of Us cohort (N=6556) with validation in UK Biobank (N=241), a genetic score based on NBEA variants predicted weight-loss response to GLP-1 receptor agonists over 12–18 months. Individuals above the NBEA-responsive threshold were substantially more likely to achieve top-quintile weight loss and less likely to be non-responders.
Impact: This work advances pharmacogenomics for obesity by providing a validated genetic predictor of response to GLP-1RAs, enabling treatment stratification and potentially improving cost-effectiveness and outcomes.
Clinical Implications: Genotyping for NBEA variation could help select patients most likely to benefit from GLP-1RAs and identify potential non-responders who may need alternative or adjunctive therapies.
Key Findings
- A genetic score derived from NBEA variants predicted 12–18 month weight-loss response to GLP-1RAs in All of Us (N=6556) and was validated in UK Biobank (N=241).
- Individuals above the NBEA response threshold were 82% more likely to be highly responsive (top 20% weight loss).
- The score also reduced odds of non-responsiveness (weight change ≥0%).
Methodological Strengths
- Large real-world development cohort with independent external validation
- Clear, pre-specified outcomes (high responders, non-responders) and appropriate regression modeling
Limitations
- Observational design with potential residual confounding
- Small validation sample size (UK Biobank N=241) may limit precision
Future Directions: Prospective randomized trials stratifying GLP-1RA therapy by NBEA genotype could test clinical utility and cost-effectiveness; mechanistic studies should elucidate NBEA’s role in weight regulation.
AIMS: Nearly 42% of adults in the United States have obesity, a significant risk factor for many cardiometabolic diseases and cancers. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are promising interventions for weight loss, but their efficacy varies significantly across individuals. This study investigates the role of neurobeachin (NBEA), a gene that encodes a protein kinase A anchor protein, on weight loss response in two large, real-world cohorts. MATERIALS AND METHODS: We utilised data from individuals prescribed a GLP-1RA in the NIH All of Us (N = 6556) and validated in the UK Biobank (N = 241). The NBEA genetic score for weight loss (12-18 months) was developed using the NIH All of Us cohort and independently validated in the UK Biobank. Logistic regression modelled associations between the score and outcomes, including high responsiveness (top 20th percentile for weight loss) and non-responsiveness (weight change ≥0%). RESULTS: Individuals meeting the responsive NBEA score threshold were 82% more likely to be highly responsive (FDR p = 1·8 × 10
2. The significance of high expression of circulating miR-222-3p in patients with unilateral primary aldosteronism.
Circulating miR-222-3p was significantly elevated in unilateral primary aldosteronism versus bilateral disease, with higher levels on the tumor-side adrenal vein. miR-222-3p promoted adrenal cell proliferation in vitro and correlated with tumor size and post-saline aldosterone, suggesting utility for subtype diagnosis and pathophysiology.
Impact: Provides a minimally invasive biomarker candidate to distinguish unilateral from bilateral PA, potentially streamlining subtype diagnosis and informing surgical candidacy.
Clinical Implications: Circulating miR-222-3p measurement could complement adrenal vein sampling in subtype diagnosis of PA and identify patients more likely to benefit from adrenalectomy.
Key Findings
- miR-222-3p levels were significantly higher in unilateral PA than bilateral hyperaldosteronism in both adrenal veins and inferior vena cava.
- Within UPA, tumor-side adrenal vein levels exceeded non-tumor side.
- miR-222-3p promoted adrenal cell proliferation, correlated with tumor diameter and post-saline plasma aldosterone; CDKN1B was a predicted target.
Methodological Strengths
- Discovery plus validation workflow across patient samples
- Multiple anatomical compartments assessed (adrenal veins and IVC) and functional in vitro assays
Limitations
- Initial discovery sample size was small; overall numbers not fully detailed in abstract
- CYP11B2 induction by miR-222-3p mimics was not statistically significant
Future Directions: Prospective studies integrating miR-222-3p with clinical and imaging variables could define diagnostic thresholds and evaluate impact on surgical outcomes.
CONTEXT: The significance of circulating miRNAs in primary aldosteronism (PA) is still largely unknown. OBJECTIVE: We compared the profiles of circulating miRNAs between unilateral primary aldosteronism (UPA) and bilateral hyperaldosteronism (BHA) and investigated the potential role of a newly identified UPA-related miRNA in the pathogenesis of PA. METHODS: We initially conducted a comprehensive expression analysis of circulating miRNAs using a qPCR panel in a small number of cases matched for background factors, followed by validation analysis with a larger sample size for the candidate miRNAs. RESULTS: The expression level of one single miRNA, miR-222-3p, was significantly higher in UPA than in BHA, both in the adrenal veins and the inferior vena cava. Moreover, it was significantly higher in the adrenal vein on the tumor side compared to the non-tumor side within the same UPA patients. In primary cultured adrenal cells, miR-222-3p mimics appeared to increase CYP11B2 expression, although the effect was not statistically significant. However, transfection with miR-222-3p mimics significantly increased cell proliferation, while transfection with miR-222-3p inhibitors decreased it. CDKN1B was identified as a predicted target gene of miR-222-3p. Additionally, the expression level of miR-222-3p exhibited a significant positive correlation with tumor diameter and plasma aldosterone concentration after saline infusion test. CONCLUSIONS: The present results demonstrated higher expression of circulating miR-222-3p in UPA than in BHA, providing a biochemical marker for subtype diagnosis of PA. Moreover, the correlation of miR-222-3p with adrenal cell proliferation and aldosterone secretion indicated its significant involvement in the pathogenesis of PA.
3. Use of the Omnipod 5 Automated Insulin Delivery System Activity Feature Reduces Insulin Delivery and Attenuates the Drop in Glycemia Associated With Exercise in a Randomized Controlled Trial.
In a three-way randomized crossover trial of 38 individuals with type 1 diabetes, enabling Omnipod 5’s Activity mode 30–60 minutes pre-exercise reduced insulin delivery before and during exercise and attenuated glucose declines compared with automated mode. Hypoglycemia incidence during exercise did not significantly differ across conditions.
Impact: Provides rigorous RCT evidence to operationalize exercise strategies with automated insulin delivery, informing immediate patient guidance for reducing exercise-related glycemic dips.
Clinical Implications: Advise Omnipod 5 users to enable Activity mode 30–60 minutes before planned moderate-intensity exercise; consider earlier activation and/or carbohydrate intake to further mitigate hypoglycemia risk.
Key Findings
- AF-60 and AF-30 significantly reduced insulin delivery versus Auto in the hour before and during exercise (both P<0.001).
- Glucose decline during exercise was attenuated: Auto −57 mg/dL vs AF-60 −44 mg/dL (P=0.02) and AF-30 −36 mg/dL (P=0.01).
- Incidence of hypoglycemia during exercise did not differ significantly across conditions.
Methodological Strengths
- Randomized three-way crossover design controlling inter-individual variability
- Standardized exercise protocol with postabsorptive state and defined HR targets
Limitations
- Small sample size may limit power to detect differences in hypoglycemia incidence
- Laboratory treadmill setting may not capture free-living exercise variability
Future Directions: Evaluate earlier/longer Activity mode activation, carbohydrate strategies, and free-living trials to optimize protocols for different exercise modalities and durations.
OBJECTIVE: To compare the efficacy of enabling Activity feature 60 (AF-60) or 30 min (AF-30) before prolonged exercise versus the automated mode (Auto) in adults and adolescents with type 1 diabetes wearing the Omnipod 5 System. RESEARCH DESIGN AND METHODS: In this three-way crossover study, 38 participants (age 30 ± 15 years; BMI 24.7 ± 4.1 kg/m2; HbA1c 7.5% ± 0.9% [58 ± 11 mmol/mol]) from the extension phase of the pivotal trial of the Omnipod 5 System completed a 70-min treadmill session at 64-76% maximum heart rate in a postabsorptive state under each of the three conditions. Auto was resumed after exercise, and glycemia and insulin delivery metrics were examined in the 4-h postexercise period. RESULTS: The percentage of participants who developed hypoglycemia during exercise did not differ significantly between Auto (42%) and AF-60 (29%; P = 0.34) or AF-30 (24%; P = 0.14). However, AF-60 and AF-30 reduced insulin delivery compared with Auto in the hour before (P < 0.001) and during exercise (P < 0.001). There was also a favorable attenuation in glucose drop during exercise when comparing Auto (-57 ± -35 mg/dL) with AF-60 (-44 ± -33 mg/dL; P = 0.02) and AF-30 (-36 ± -34 mg/dL; P = 0.01). In the postexercise period, glycemia and insulin delivery were comparable. CONCLUSIONS: Enabling the Activity feature either 60 or 30 min before exercise reduced insulin delivery and attenuated glucose drops relative to Auto, but hypoglycemia incidence was not different across the three conditions. These findings support the use of the Omnipod 5 System for exercise but highlight the importance of using additional strategies, such as earlier use of Activity feature and/or carbohydrate intake to further reduce hypoglycemia risk.