Daily Endocrinology Research Analysis
Three high-impact studies advance endocrine-metabolic science and care: a Nature Communications analysis decomposes fasting insulin genetics into mechanistic clusters with distinct cardiometabolic risks; a Nature Metabolism study identifies a SIRT5–TBK1 desuccinylation axis that protects primate skeletal muscle from ageing; and a Movement Disorders cohort reframes MCT8 deficiency as childhood parkinsonism responsive to levodopa/carbidopa.
Summary
Three high-impact studies advance endocrine-metabolic science and care: a Nature Communications analysis decomposes fasting insulin genetics into mechanistic clusters with distinct cardiometabolic risks; a Nature Metabolism study identifies a SIRT5–TBK1 desuccinylation axis that protects primate skeletal muscle from ageing; and a Movement Disorders cohort reframes MCT8 deficiency as childhood parkinsonism responsive to levodopa/carbidopa.
Research Themes
- Heterogeneity of insulin resistance and cardiometabolic risk
- Mitochondrial and inflammatory signaling in muscle ageing
- Translational therapeutics in rare endocrine-neurologic disorders
Selected Articles
1. Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes.
FI-associated variants cluster into seven mechanistic groups that differentially link to T2D and cardiovascular outcomes. Polygenic scores derived from “diabetogenic” clusters predict variable risks for CAD, MI, and stroke, with a sex-specific MI risk in the visceral adiposity cluster among men without T2D. Findings decouple elevated FI from uniform disease risk, enabling process-specific risk stratification.
Impact: This large multi-ancestry genomic analysis redefines insulin resistance heterogeneity and provides cluster-specific risk signatures for cardiometabolic disease.
Clinical Implications: Risk prediction and prevention strategies can incorporate cluster-specific polygenic scores and phenotypes (e.g., visceral adiposity vs. inflammation) rather than relying on fasting insulin alone.
Key Findings
- Seven FI-associated genetic clusters were identified with distinct mechanisms.
- Clusters split into non-diabetogenic vs. diabetogenic hyperinsulinemia.
- In >1.1M individuals, cluster-specific polygenic scores showed varying risks for CAD, MI, and stroke.
- Visceral adiposity cluster conferred a sex-specific MI risk in males without T2D.
- Processes can decouple elevated FI from T2D and cardiovascular risk.
Methodological Strengths
- Very large multi-ancestry sample size (>1.1 million)
- Mechanism-informed clustering with polygenic risk evaluation across diseases
Limitations
- Observational genetic design cannot establish causality for all pathways
- Potential heterogeneity in phenotype definitions and cohort ascertainment
Future Directions: Integrate cluster-specific PRS into clinical risk tools; test targeted interventions (e.g., adiposity vs. inflammation pathways) in precision prevention trials.
2. SIRT5 safeguards against primate skeletal muscle ageing via desuccinylation of TBK1.
SIRT5 expression declines with age in primate skeletal muscle. SIRT5 desuccinylates TBK1 (K137), dampening inflammatory signaling and preserving function; SIRT5 gene therapy improves performance and mitigates age-related muscle dysfunction in mice.
Impact: Reveals a previously unrecognized SIRT5–TBK1 post-translational modification axis governing muscle ageing, offering a tractable therapeutic target.
Clinical Implications: Although preclinical, targeting the SIRT5–TBK1 pathway could inform future interventions to prevent or treat sarcopenia and frailty.
Key Findings
- SIRT5 expression is reduced in aged primate skeletal muscle from both sexes.
- TBK1 is a SIRT5 substrate; desuccinylation at K137 reduces TBK1 phosphorylation and downstream inflammatory signaling.
- SIRT5 deficiency accelerates senescence and inflammation in human myotubes.
- Skeletal muscle-directed SIRT5 gene therapy improves physical performance and alleviates age-related dysfunction in mice.
Methodological Strengths
- Cross-species validation including primate tissue, human myotubes, and mouse models
- Mechanistic mapping of a specific post-translational modification (desuccinylation site K137) with functional readouts
Limitations
- Preclinical models; human interventional data are lacking
- Gene therapy experiments reported in male mice; sex-specific efficacy requires further study
Future Directions: Evaluate pharmacologic SIRT5 modulation, test translational biomarkers of TBK1 succinylation/dephosphorylation, and conduct early-phase trials targeting sarcopenia.
3. Patients with Allan-Herndon-Dudley Syndrome (MCT8 Deficiency) Display Symptoms of Parkinsonism in Childhood and Respond to Levodopa/Carbidopa Treatment.
In an 11-patient registry, AHDS manifested as childhood parkinsonism with reduced CSF homovanillic acid, indicating dopaminergic pathway impairment. Seven of eight treated patients showed clinical improvement with levodopa/carbidopa without adverse reactions.
Impact: Reclassifies MCT8 deficiency as a treatable childhood parkinsonism and provides immediate, low-risk therapeutic guidance.
Clinical Implications: Consider levodopa/carbidopa trials in AHDS with parkinsonian features; CSF HVA may help identify dopaminergic involvement.
Key Findings
- AHDS patients exhibited childhood parkinsonism (hypokinesia, hypomimia, rigidity, dystonia, autonomic dysfunction).
- CSF homovanillic acid levels were decreased, indicating dopaminergic pathway impairment.
- Seven of eight treated patients responded to levodopa/carbidopa without adverse drug reactions.
- Standardized phenotyping with videos, CSF, and imaging supports diagnostic clarity.
Methodological Strengths
- Prospective registry with standardized phenotyping and multi-modal assessments
- Objective CSF biomarker (HVA) corroborating dopaminergic dysfunction with treatment response data
Limitations
- Small sample size and lack of control group
- Duration of follow-up and long-term efficacy/safety not fully characterized
Future Directions: Conduct controlled trials to validate levodopa efficacy, define dosing strategies, and explore mechanisms linking MCT8 deficiency to dopaminergic metabolism.