Daily Endocrinology Research Analysis
Three papers stood out in endocrinology today: a multi-omics study identifying circulating proteins/metabolites linked to 1-year progression or remission of prediabetes; a large retrospective cohort showing post–captopril challenge aldosterone predicts cardiac remodeling and diastolic dysfunction in primary aldosteronism; and a human comparative study clarifying how endurance training enhances muscle insulin sensitivity despite high intramyocellular lipids. Together, they advance risk stratifica
Summary
Three papers stood out in endocrinology today: a multi-omics study identifying circulating proteins/metabolites linked to 1-year progression or remission of prediabetes; a large retrospective cohort showing post–captopril challenge aldosterone predicts cardiac remodeling and diastolic dysfunction in primary aldosteronism; and a human comparative study clarifying how endurance training enhances muscle insulin sensitivity despite high intramyocellular lipids. Together, they advance risk stratification and mechanistic understanding in metabolic and endocrine hypertension care.
Research Themes
- Biomarker-guided prediction of glycemic trajectories in prediabetes
- Functional endocrine testing to prognosticate organ remodeling in hormone-mediated hypertension
- Mechanistic basis of exercise-enhanced insulin sensitivity and lipid signaling
Selected Articles
1. Proteomic and Metabolomic Signatures in Prediabetes Progressing to Diabetes or Reversing to Normoglycemia Within 1 Year.
In a longitudinal multi-omics analysis of up to 134 individuals (108 with paired 1-year data), higher prediabetic levels of DCXR and GSTA3, elevated OGTT AUCs for IDL particles/apolipoprotein B/cholesterol, and rising glutamate were associated with progression to type 2 diabetes, while immune-response pathways differentiated trajectories a year prior. The signatures correlated with insulin sensitivity metrics.
Impact: Provides mechanistically anchored, blood-based candidates to predict short-term prediabetes outcomes, enabling earlier risk stratification beyond glucose alone.
Clinical Implications: If validated, these markers (e.g., DCXR, GSTA3, IDL-related measures, glutamate) could inform targeted prevention, personalized OGTT interpretation, and selection for intensive lifestyle/drug interventions.
Key Findings
- Higher prediabetic DCXR and GSTA3 levels predicted 1-year progression to diabetes.
- Immune-response pathways distinguished diabetes vs. normoglycemia trajectories already in the prediabetic state a year earlier.
- OGTT AUCs of IDL particles, IDL apoB, and IDL cholesterol were elevated in new-onset diabetes; glutamate increased in progressors.
- Protein differences correlated with indices of insulin sensitivity.
Methodological Strengths
- Paired longitudinal sampling over 1 year with multi-timepoint OGTT metabolomics.
- Integrated proteomics (1,389 proteins) and metabolomics (152 metabolites) with pathway analysis.
Limitations
- Modest sample size may limit generalizability.
- Observational design cannot prove causality; external validation is needed.
Future Directions: Validate signatures in larger, diverse cohorts; test predictive utility for selecting preventive interventions; mechanistically dissect immune pathways and lipid particle biology in progression.
OBJECTIVE: Progression of prediabetes to type 2 diabetes has been associated with β-cell dysfunction, whereas its remission to normoglycemia has been related to improvement of insulin sensitivity. To understand the mechanisms and identify potential biomarkers related to prediabetes trajectories, we compared the proteomics and metabolomics profile of people with prediabetes progressing to diabetes or reversing to normoglycemia within 1 year. RESEARCH DESIGN AND METHODS: The fasting plasma concentrations of 1,389 proteins and the fasting, 30-min, and 120-min post-oral glucose tolerance test (OGTT) plasma concentrations of 152 metabolites were measured in up to 134 individuals with new-onset diabetes, prediabetes, or normal glucose tolerance. For 108 participants, the analysis was repeated with samples from 1 year before, when all had prediabetes. RESULTS: The plasma concentrations of 14 proteins were higher in diabetes compared with normoglycemia in a population with prediabetes 1 year before, and they correlated with indices of insulin sensitivity. Higher levels of dicarbonyl/L-xylulose reductase and glutathione S-transferase A3 in the prediabetic state were associated with an increased risk of diabetes 1 year later. Pathway analysis pointed toward differences in immune response between diabetes and normoglycemia that were already recognizable in the prediabetic state 1 year prior at baseline. The area under the curve during OGTT of the concentrations of IDL particles, IDL apolipoprotein B, and IDL cholesterol was higher in new-onset diabetes compared with normoglycemia. The concentration of glutamate increased in prediabetes progressing to diabetes. CONCLUSIONS: We identify new candidates associated with the progression of prediabetes to diabetes or its remission to normoglycemia. Pathways regulating the immune response are related to prediabetes trajectories.
2. Determinants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals.
Compared with sedentary peers, endurance-trained individuals had higher insulin sensitivity and mitochondrial content/capacity while exhibiting lower activation of nPKC isoforms despite higher intramyocellular DAG. Findings implicate lipid compartmentalization and signaling context—rather than bulk lipid content—as key determinants of muscle insulin sensitivity.
Impact: Addresses the athlete’s paradox in humans with mechanistic insight, shifting focus from lipid quantity to subcellular localization/signaling as therapeutic targets.
Clinical Implications: Supports endurance training to enhance insulin sensitivity and highlights nPKC signaling and lipid compartmentalization as potential drug targets to mimic exercise benefits.
Key Findings
- Endurance-trained participants had higher insulin sensitivity and mitochondrial content/capacity than sedentary individuals.
- Despite higher intramyocellular diacylglycerol, activation of novel PKC isoforms was lower in trained subjects.
- Data suggest lipid compartmentalization and signaling context, not bulk DAG/TG content, drive insulin sensitivity differences.
Methodological Strengths
- Direct human comparison across trained and sedentary groups including both sexes.
- Multidimensional phenotyping of insulin sensitivity, mitochondrial metrics, and lipid signaling.
Limitations
- Observational design limits causal inference.
- Sample size and detailed methods are not specified in the abstract; potential selection bias.
Future Directions: Intervention trials modulating nPKC activity or lipid compartmentalization; longitudinal training studies to track remodeling of lipid signaling and insulin action.
The athlete's paradox states that intramyocellular triglyceride accumulation associates with insulin resistance in sedentary but not in endurance-trained humans. Underlying mechanisms and the role of muscle lipid distribution and composition on glucose metabolism remain unclear. We compared highly trained athletes (ATHL) with sedentary normal weight (LEAN) and overweight-to-obese (OVWE) male and female individuals. This observational study found that ATHL show higher insulin sensitivity, muscle mitochondrial content, and capacity, but lower activation of novel protein kinase C (nPKC) isoforms, despite higher diacylglycerol concentrations. Notably, sedentary but insulin sensitive OVWE feature lower plasma membrane-to-mitochondria
3. The Captopril Challenge Test Predicts Cardiac Structure and Dysfunction in Primary Aldosteronism.
In 540 patients with primary aldosteronism, higher post–captopril challenge plasma aldosterone was linearly associated with worse LV mass, diastolic indices (E/e'), and LAVI at baseline and predicted larger improvements in these measures after targeted therapy over 1 year. Baseline aldosterone lacked similar associations for diastolic function.
Impact: Elevates a widely used confirmatory test (CCT) into a prognostic tool for cardiac remodeling and therapeutic benefit in PA, supporting risk-based treatment decisions.
Clinical Implications: Post-CCT PAC can help prioritize timely subtype work-up and definitive therapy (adrenalectomy/mineralocorticoid receptor antagonists) in those at highest cardiac risk and inform follow-up intensity.
Key Findings
- Post–CCT aldosterone showed a linear association with LVMI, E/e', and LAVI, indicating a continuous risk spectrum.
- Patients with higher post–CCT PAC experienced the greatest improvements in LVMI, E/e', and LAVI after 1 year of PA-targeted therapy.
- Baseline aldosterone was not associated with diastolic indices, underscoring the added value of post–CCT measurements.
Methodological Strengths
- Large sample size (n=540) with standardized echocardiographic assessments at baseline and 1 year.
- Robust statistical approaches (restricted cubic splines, multivariable regression) with adjustments.
Limitations
- Retrospective design with potential selection and treatment biases.
- Lack of randomized assignment to specific PA therapies may confound improvement estimates.
Future Directions: Prospective validation and integration of post–CCT PAC into risk scores; assess thresholds to guide timing and intensity of PA therapy; explore pathophysiologic links to diastolic dysfunction.
CONTEXT: The captopril challenge test (CCT) is a commonly used confirmation test that identifies the magnitude of renin- and angiotensin II-independent aldosterone production and thus the presence and severity of primary aldosteronism (PA). OBJECTIVE: This study investigated the association between the post-CCT plasma aldosterone concentration (PAC) and cardiovascular remodeling and diastolic dysfunction. METHODS: A total of 540 PA patients with complete CCT and echocardiographic data were retrospectively analyzed. Clinical and echocardiographic parameters were assessed at baseline and 1 year after PA-targeted treatment. RESULTS: The post-CCT PAC showed a significant linear association with both left ventricular mass index (LVMI) and the ratio of early diastolic transmitral and myocardial velocity on tissue Doppler imaging (E/e') in restricted cubic spline analyses, indicating a continuum of risk linked to postcaptopril aldosterone levels. In linear regression analyses, post-CCT PAC was significantly associated with baseline LVMI, E/e', and left atrial volume index (LAVI), regardless of multiple model adjustments. One year after PA-targeted treatment, patients with higher post-CCT PAC experienced the greatest improvements in LVMI, E/e', and LAVI. In contrast, baseline aldosterone levels were associated only with baseline LVMI and its improvement after treatment but not with the baseline or improvement of E/e' or LAVI. CONCLUSION: Higher post-CCT PAC was significantly associated with worse left ventricular remodeling and diastolic dysfunction but also greater improvements in cardiac structure and dysfunction following targeted treatment. These findings highlight the prognostic and therapeutic values of the CCT that the post-CCT PAC predicts the severity of cardiac disease and also the potential for therapeutic benefits in PA.