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.
Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: "non-diabetogenic hyperinsulinemia," where clusters are not associated with increased T2D risk, and "diabetogenic hyperinsulinemia," where T2D associations are driven by body fat distribution, liver function, circulating lipids, or inflammation. In over 1.1 million multi-ancestry individuals, we demonstrated that diabetogenic hyperinsulinemia cluster-specific polygenic scores exhibit varying risks for cardiovascular conditions, including coronary artery disease, myocardial infarction (MI), and stroke. Notably, the visceral adiposity cluster shows sex-specific effects for MI risk in males without T2D. This study underscores processes that decouple elevated FI levels from T2D and cardiovascular risk, offering new avenues for investigating process-specific pathways of disease.
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.
Ageing-induced skeletal muscle deterioration contributes to sarcopenia and frailty, adversely impacting the quality of life in the elderly. However, the molecular mechanisms behind primate skeletal muscle ageing remain largely unexplored. Here, we show that SIRT5 expression is reduced in aged primate skeletal muscles from both genders. SIRT5 deficiency in human myotubes hastens cellular senescence and intensifies inflammation. Mechanistically, we demonstrate that TBK1 is a natural substrate for SIRT5. SIRT5 desuccinylates TBK1 at lysine 137, which leads to TBK1 dephosphorylation and the suppression of the downstream inflammatory pathway. Using SIRT5 lentiviral vectors for skeletal muscle gene therapy in male mice enhances physical performance and alleviates age-related muscle dysfunction. This study sheds light on the molecular underpinnings of skeletal muscle ageing and presents the SIRT5-TBK1 pathway as a promising target for combating age-related skeletal muscle degeneration.
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.
BACKGROUND: Patients with mutations in the monocarboxylate transporter 8 (MCT8, SLC16A2) suffer from X-linked recessive Allan-Herndon-Dudley syndrome (AHDS), which is characterized by developmental delay and a severe movement disorder. Current trials using thyroid hormone derivatives to overcome the transporter defect have failed to achieve patient-oriented therapeutic goals. OBJECTIVES: Our aim was to define the type of movement disorder in AHDS in an observational cohort study and to investigate the causative role of the dopaminergic system. METHODS: We present longitudinal clinical data from the DEEPTYPE registry of 11 patients with video documentation, standardized phenotyping, cerebrospinal fluid (CSF) analysis, neuroimaging data, and the treatment response to levodopa/carbidopa supplementation. RESULTS: Children presented with signs of childhood parkinsonism, including hypokinesia, hypomimia, inability to sit or stand, rigidity, dystonia, and autonomic dysfunction. CSF homovanillic acid concentrations were decreased (n = 12), suggesting an isolated dopamine pathway impairment. Seven out of 8 patients responded favorably to l-dopa/carbidopa supplementation and we did not observe any adverse drug reactions. CONCLUSIONS: AHDS is associated with childhood parkinsonism, which is linked with biochemical abnormalities of dopamine metabolism. It can be treated with l-dopa/carbidopa supplementation. However, further research is needed to elucidate the exact effect of MCT8 deficiency on dopamine metabolism. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.