Daily Endocrinology Research Analysis
Three impactful endocrinology papers span nutrition, immunometabolism, and lipid genetics. A UK Biobank cohort shows healthier plant-based diets lower all-cause mortality in type 2 diabetes, while an Endocrinology study identifies the S100A9–TLR4 axis as a therapeutic lever improving ketone, lipid, and glucose metabolism in insulin deficiency. A BMC Medicine Mendelian randomization study establishes remnant cholesterol as a causal cardiovascular risk factor in East Asians.
Summary
Three impactful endocrinology papers span nutrition, immunometabolism, and lipid genetics. A UK Biobank cohort shows healthier plant-based diets lower all-cause mortality in type 2 diabetes, while an Endocrinology study identifies the S100A9–TLR4 axis as a therapeutic lever improving ketone, lipid, and glucose metabolism in insulin deficiency. A BMC Medicine Mendelian randomization study establishes remnant cholesterol as a causal cardiovascular risk factor in East Asians.
Research Themes
- Dietary patterns and mortality in type 2 diabetes
- Immunometabolic reprogramming in insulin deficiency
- Genetic causality of remnant cholesterol in cardiovascular disease
Selected Articles
1. Plant-Based Dietary Patterns Associated With Reduced Risk of All-Cause Mortality in Diabetes Subgroups: A Prospective Cohort Study From the UK Biobank.
In 4,829 UK Biobank participants with type 2 diabetes followed for a mean of 11.3 years, higher adherence to an overall plant-based dietary index was associated with lower all-cause mortality (T3 vs T1 HR 0.79), while an unhealthy plant-based index was linked to higher mortality (HR 1.24). Associations were stronger among those with poor glycemic control, larger waist circumference, earlier age at diagnosis, and longer diabetes duration.
Impact: This well-designed prospective cohort links diet quality to mortality in type 2 diabetes and identifies high-risk subgroups who may derive greater benefit, directly informing nutritional counseling.
Clinical Implications: Clinicians should emphasize healthier plant-based dietary patterns (e.g., vegetables, fruits, whole grains, legumes, nuts) while discouraging unhealthy plant-based choices (refined grains, sweets, sugar-sweetened beverages). Patients with poor glycemic control or central obesity may benefit most.
Key Findings
- Highest tertile of overall plant-based dietary index adherence reduced all-cause mortality (HR 0.79, 95% CI 0.63–0.99).
- Unhealthy plant-based dietary index increased mortality risk (HR 1.24, 95% CI 1.00–1.54).
- Stronger associations observed in subgroups with higher HbA1c, larger waist circumference, earlier diagnosis, and longer diabetes duration.
Methodological Strengths
- Prospective design with long follow-up (mean 11.3 years).
- Repeated 24-hour dietary recalls and multivariable Cox regression with subgroup interaction analyses.
Limitations
- Observational design susceptible to residual confounding and measurement error in dietary assessment.
- Generalizability may be limited by UK Biobank volunteer selection.
Future Directions: Randomized dietary interventions in type 2 diabetes targeting plant-forward diets, with stratification by glycemic control and adiposity, and mechanistic studies linking specific plant foods to cardiometabolic pathways.
2. Harnessing Distinct Tissue-Resident Immune Niches via S100A9/TLR4 Improves Ketone, Lipid, and Glucose Metabolism.
In insulin-deficient mice, the liver immune niche is remodeled with reduced T cells and polarized Kupffer cells. S100A9 treatment, acting via TLR4, rescued Kupffer cell polarization and corrected lipid and ketone abnormalities, reducing hypertriglyceridemia and hyperketonemia; it also increased skeletal muscle glucose uptake, improving hyperglycemia.
Impact: This study identifies the S100A9–TLR4 axis as a lever to reprogram tissue-resident immune niches and improve multiple metabolic derangements in insulin deficiency, opening a tractable therapeutic avenue.
Clinical Implications: Suggests immunomodulatory strategies (e.g., S100A9-based approaches or TLR4-targeting) could complement insulin therapy by mitigating hypertriglyceridemia, hyperketonemia, and hyperglycemia in insulin-deficient states; translation will require rigorous safety and dose-ranging studies.
Key Findings
- Insulin deficiency remodels the liver immune landscape, decreasing T cells and altering Kupffer cell polarization.
- S100A9 rescues Kupffer cell polarization and reverses lipid-related changes in a TLR4-dependent manner, lowering hypertriglyceridemia and hyperketonemia.
- S100A9 increases skeletal muscle glucose uptake via effects on immune niches, improving hyperglycemia.
Methodological Strengths
- Integrated multi-tissue mechanistic interrogation with immune and metabolic readouts.
- Causal pathway supported by TLR4 dependency.
Limitations
- Preclinical mouse model; human translatability and safety are unknown.
- Dosing, durability of effects, and off-target immune consequences require clarification.
Future Directions: Define cellular and molecular intermediates linking S100A9–TLR4 signaling to metabolic fluxes; evaluate pharmacology, safety, and efficacy in larger animal models; explore combinatorial strategies with insulin in diabetic ketoacidosis-prone settings.
3. The causal effects of remnant cholesterol on increased risk of cardiovascular diseases in East Asians.
In Chinese cohorts, circulating remnant cholesterol associated with multiple cardiovascular outcomes. A GWAS (n=14,939) identified seven loci for RC. Two-sample Mendelian randomization using Biobank Japan showed genetically higher RC increased cardiovascular risks, notably aortic aneurysm (OR 1.82 per SD). Replication in European datasets supported the findings, establishing RC as a causal CVD risk factor in East Asians.
Impact: By integrating ancestry-specific GWAS with Mendelian randomization and replication, this study provides strong causal evidence that remnant cholesterol drives CVD in East Asians, informing targeted prevention.
Clinical Implications: Risk stratification and prevention in East Asians should prioritize lowering remnant cholesterol (e.g., targeting triglyceride-rich lipoproteins via fibrates, omega-3s, ApoC-III/ANGPTL3 inhibition), complementing LDL-C lowering.
Key Findings
- Circulating remnant cholesterol associated with multiple cardiovascular outcomes in Chinese populations.
- GWAS in 14,939 Chinese identified seven RC-associated loci.
- Mendelian randomization (Biobank Japan) showed higher genetically predicted RC increases CVD risk, notably aortic aneurysm (OR 1.82 per SD), with replication in European datasets.
Methodological Strengths
- Triangulation of evidence: observational analyses, ancestry-specific GWAS, Mendelian randomization, and external replication.
- Large biobank datasets improving power and generalizability.
Limitations
- MR assumptions (e.g., no horizontal pleiotropy) may be violated.
- Potential residual population stratification and assay variability in RC estimation.
Future Directions: Intervention trials targeting remnant cholesterol in East Asians; development of precise RC assays; exploration of gene–environment interactions and ancestry-informed risk algorithms.