Daily Endocrinology Research Analysis
Analyzed 82 papers and selected 3 impactful papers.
Summary
Three papers stand out in endocrinology today: age-adjusted HbA1c thresholds markedly improve type 1 diabetes progression risk stratification in autoantibody-positive adults; CYP11B2 immunohistochemistry reveals frequent discordance with cross-sectional imaging in lateralized primary aldosteronism; and a mechanistic study identifies OGR1 as the proton sensor linking extracellular acidity to parathyroid hormone secretion.
Research Themes
- Risk stratification and diagnostic accuracy in endocrine disorders
- Tissue-based phenotyping versus imaging for surgical decision-making
- Mechanistic endocrine physiology linking pH sensing to hormone secretion
Selected Articles
1. Accounting for Age-Related Increases in HbA1c More Accurately Quantifies Risk of Type 1 Diabetes Progression in Islet Autoantibody-Positive Adults.
In islet autoantibody-positive relatives, applying age-adjusted HbA1c or a higher adult threshold (≥6.0%) aligned adult progression risk with children, especially in those ≥30 years. This resolves age-related misclassification inherent to the standard HbA1c ≥5.7% threshold and supports tailored prevention trial enrollment.
Impact: This large, prospective analysis operationalizes age-specific HbA1c criteria for dysglycemia, directly improving risk enrichment for T1D prevention trials and clinical monitoring in adults.
Clinical Implications: Use age-adjusted HbA1c or an HbA1c ≥6.0% threshold in autoantibody-positive adults (particularly ≥30 years) to identify high-risk individuals comparable to children, guiding surveillance intensity and prevention trial eligibility.
Key Findings
- In TrialNet (n=5,024), standard HbA1c ≥5.7% yielded higher 1-year progression risk in children than adults; age adjustment attenuated these differences.
- An HbA1c threshold ≥6.0% produced comparable progression risks between adults and children across autoantibody strata.
- Adults <30 years had risks similar to children in post hoc analyses.
- Age-related HbA1c modeling leveraged 6,273 adults from the Exeter 10000 cohort.
Methodological Strengths
- Large, multicenter prospective cohort (TrialNet) with external population modeling (Exeter 10000)
- Direct comparison of standard vs. age-adjusted and higher HbA1c thresholds with quantified progression risks
Limitations
- Observational design without interventional validation of thresholds
- Generalizability may be limited to relatives of individuals with T1D and specific age strata
Future Directions: Prospective validation of age-adjusted or ≥6.0% HbA1c thresholds in diverse adult at-risk cohorts and their integration into adaptive prevention trials and monitoring algorithms.
OBJECTIVE: HbA1c thresholds used to define dysglycemia in autoantibody-positive individuals at risk for type 1 diabetes do not account for age-related increases in HbA1c and may overestimate progression risk in adults. We evaluated whether age-adjusted HbA1c or a higher HbA1c threshold improves risk stratification across age-groups. RESEARCH DESIGN AND METHODS: We analyzed 5,024 autoantibody-positive relatives (3,720 children and 1,304 adults) participating in the TrialNet Pathway to Prevention study. Age-related HbA1c effects were modeled using 6,273 adults from the population-based Exeter 10000 cohort. Progression risk was compared using the standard dysglycemia threshold (HbA1c ≥5.7% [39 mmol/mol]), age-adjusted HbA1c, and an alternative threshold of HbA1c ≥6.0% (42 mmol/mol). RESULTS: Using HbA1c ≥5.7% (39 mmol/mol), children had higher 1-year progression risk than adults among single autoantibody-positive participants (38% [95% CI 28, 47] vs. 13% [7.2, 19]) and multiple autoantibody-positive participants (55% [49, 60] vs. 38% [27, 47]) (both P < 0.001). Age adjustment reduced these differences; progression risk was similar among single autoantibody-positive participants (38% [28, 47] vs. 27% [13, 39]; P = 0.32), with attenuated differences among multiple autoantibody-positive participants. An HbA1c threshold ≥6.0% (42 mmol/mol) yielded comparable progression risk between adults and children across autoantibody subgroups. In post hoc analyses, adults aged <30 years had progression risk similar to children (P = 0.1). CONCLUSIONS: Age-related variation in HbA1c influences dysglycemia classification in adults at risk for type 1 diabetes. Age-adjusted HbA1c or a higher HbA1c threshold (≥6.0% [42 mmol/mol]) in adults aged ≥30 years identifies individuals with progression risk comparable to children and may improve age-specific risk stratification in prevention settings.
2. Acidic extracellular pH-induced PTH secretion in male mouse parathyroids is OGR1-dependent.
Using a novel 5-ALA–guided isolation of mouse parathyroids, the study shows that extracellular acidosis directly stimulates PTH secretion via OGR1 (GPR68). Low extracellular calcium both acidifies the milieu and synergizes with acidosis, mechanistically linking metabolic acidosis to secondary hyperparathyroidism and nominating OGR1 as a target.
Impact: This is the first mechanistic demonstration that OGR1 is the proton sensor mediating acidosis-driven PTH release, providing a concrete pathway connecting acid–base balance to parathyroid physiology.
Clinical Implications: Identifying OGR1 as essential for acid-stimulated PTH secretion suggests therapeutic modulation of OGR1 signaling in secondary hyperparathyroidism, particularly in chronic kidney disease with metabolic acidosis.
Key Findings
- Developed a reliable 5-ALA fluorescence method to identify and isolate mouse parathyroid glands ex vivo.
- Extracellular acidic pH significantly increased PTH secretion; this response was abolished in OGR1 knockout glands.
- Low extracellular Ca2+ promoted extracellular acidification and synergized with acidic pH to enhance PTH secretion in wild-type but not OGR1-deficient PTGs.
- No compensatory upregulation of other proton-sensing receptors was observed in OGR1-deficient glands.
Methodological Strengths
- Introduction of a novel ex vivo parathyroid isolation method enabling reproducible functional assays
- Use of genetic knockout (OGR1−/−) to establish causality for proton sensing in PTH secretion
Limitations
- Ex vivo mouse model; in vivo validation in disease states (e.g., CKD) is lacking
- Male mice only; sex differences not assessed
Future Directions: Test OGR1 modulation in in vivo models of metabolic acidosis and CKD-related secondary hyperparathyroidism; assess sex differences and translational relevance in human parathyroid tissue.
The role of extracellular acidity in regulating parathyroid hormone (PTH) secretion in cultured mouse parathyroid glands (PTGs) has not studied to date, largely due to the technical difficulty of isolating mouse PTGs. We hypothesized that acidic extracellular pH directly stimulates PTH secretion through activation of a proton-sensing receptor, specifically ovarian cancer G protein-coupled receptor 1 (OGR1, also known as GPR68). To test this, we developed a method to reliably identify and isolate PTGs from male mice by administering 5-aminolevulinic acid (5-ALA), which induced selective fluorescence in these glands. Using this model, we demonstrate that acidic extracellular pH significantly stimulates PTH secretion in cultured mouse PTGs. Mechanistically, we identify OGR1 as the primary proton sensor mediating this response, as PTGs from OGR1 knockout mice failed to increase PTH secretion under acidic conditions, with no evidence of compensatory upregulation of other proton-sensing receptors. In addition, we found that low extracellular Ca2+ not only stimulates PTH secretion but also promotes extracellular acidification. Notably, low Ca2+ and acidic pH act synergistically to enhance PTH secretion in wild-type PTGs, an effect markedly attenuated in OGR1-deficient glands. Together, these findings establish a direct, OGR1-dependent mechanism by which extracellular acidity regulates PTH secretion and reveal an interaction between calcium and pH signaling in this process. This work provides a robust ex vivo model for studying PTG physiology and offers new insight into how metabolic acidosis may contribute to secondary hyperparathyroidism in chronic kidney disease, highlighting OGR1 signaling as a potential therapeutic target.
3. Aldosterone Synthase Expression vs. Cross-Sectional Imaging in Lateralized Primary Aldosteronism.
In 173 surgically treated, lateralized PA cases, CYP11B2 IHC agreed with cross-sectional imaging in only about half of patients, with 47.4% showing discordance driven by nonfunctional nodules, occult CYP11B2-positive foci, or multifocal disease. Findings caution against image-guided targeting without AVS or tissue mapping.
Impact: Direct tissue mapping against imaging reveals frequent mislocalization risks, challenging current imaging-driven practices and underscoring the need for functional localization in PA.
Clinical Implications: Avoid relying solely on CT/MRI to guide adrenalectomy in PA; prioritize AVS and consider the potential for multifocal aldosterone production that imaging may miss or misclassify.
Key Findings
- Among 173 lateralized PA patients, only 31% had a single APA/APN concordant on both imaging and CYP11B2 IHC; overall, about half were concordant when including thickening.
- Discordance (47.4%) included nonfunctional imaging nodules, imaging-normal glands with discrete CYP11B2-positive foci, and additional CYP11B2-positive areas beyond the imaged lesion.
- KCNJ5 mutations were enriched in concordant cases, while CACNA1D mutations were more frequent in discordant cases.
Methodological Strengths
- Blinded radiologic interpretation paired with CYP11B2 IHC as a tissue gold standard
- Mutation profiling (KCNJ5, CACNA1D) to explore biological correlates of concordance
Limitations
- Single-center retrospective cohort with potential selection bias
- Functional outcomes post-surgery were not the primary endpoint and not correlated to discordance patterns
Future Directions: Prospective multicenter studies integrating AVS, imaging, CYP11B2 IHC, and surgical outcomes to refine localization algorithms and reduce misdirected therapy.
CONTEXT: Adrenal vein sampling (AVS) is the standard of care for guiding surgery in primary aldosteronism (PA). Because of its technical complexity and limited availability, however, many centers still use cross-sectional imaging for surgical guidance. DESIGN: Single referral-center retrospective cohort study of patients with PA who underwent unilateral adrenalectomy between 2012-2024. Blinded cross-sectional imaging interpretation was corroborated with CYP11B2 immunohistochemistry (IHC) of formalin-fixed paraffin-embedded adrenal tissue. RESULTS: Of 173 patients, age 52.6±11.8 years, 119 (68.8%) were men, 134 (77.5%) White, 30 (17.3%) Black, and 9 (5.2%) other races. CYP11B2 IHC identified a single aldosterone-producing adenoma (APA) or nodule (APN) in 87 (50.3%) and 38 (22.0%) patients, respectively; multiple CYP11B2-positive foci in 45 (26.0%) patients, and no CYP11B2-positive lesions in 3 patients. A single corresponding APA or APN on both IHC and imaging was found in only 53/173 (31%) patients, and an additional 38/173 (22%) patients also had adrenal thickening. Discrepant IHC-imaging findings were observed in 82 (47.4%) patients, including: 1) additional nodule(s) on imaging (ipsilateral non-functional adenoma, n=21; bilateral nodules, n=29; or contralateral nodule(s), n=6); 2) normal adrenals (n=2) or unilateral adrenal hyperplasia (n=4), but discrete CYP11B2-positive foci on IHC; and 3) corresponding APA/APN on imaging-IHC with additional CYP11B2-positive area(s) (n=20). Patients with IHC-imaging concordance had the highest proportion of women and KCNJ5 mutations, while CACNA1D mutations were most frequent in the discordant group. CONCLUSIONS: Even in patients with lateralized PA, IHC mapping of aldosterone sources corresponded with imaging findings in approximately half of the cases. These data caution against targeted therapy guided by cross-sectional imaging.