Daily Endocrinology Research Analysis
Three studies advance endocrine-metabolic science and care: a large NHANES cohort shows that achieving moderate-to-high cardiovascular health (Life’s Essential 8) can offset excess mortality risk from insulin resistance; a Diabetologia genetics study finds rare MTNR1B variants with diminished MT2 signaling associate with higher HbA1c but not type 2 diabetes prevalence; and mechanistic work reveals a soluble DPP4–SOX2–SCD1 axis driving hepatic lipid accumulation and blunting DPP4 inhibitor effect
Summary
Three studies advance endocrine-metabolic science and care: a large NHANES cohort shows that achieving moderate-to-high cardiovascular health (Life’s Essential 8) can offset excess mortality risk from insulin resistance; a Diabetologia genetics study finds rare MTNR1B variants with diminished MT2 signaling associate with higher HbA1c but not type 2 diabetes prevalence; and mechanistic work reveals a soluble DPP4–SOX2–SCD1 axis driving hepatic lipid accumulation and blunting DPP4 inhibitor effects.
Research Themes
- Cardiovascular health metrics can mitigate insulin resistance–related mortality
- Circadian genetics (MTNR1B/MT2) influences glycemic traits over disease prevalence
- Soluble DPP4–SOX2–SCD1 signaling as a driver of hepatic steatosis and drug response
Selected Articles
1. Can cardiovascular health and its modifiable healthy lifestyle offset the increased risk of all-cause and cardiovascular deaths associated with insulin resistance?
In 14,172 NHANES participants over 7.6 years, higher insulin resistance (TyG-WC, TyG-WHtR) predicted greater all-cause and cardiovascular mortality, while higher cardiovascular health (LE8) was inversely associated with risk. Notably, individuals with high insulin resistance but moderate/high LE8 did not have significantly elevated mortality compared with those with low insulin resistance, indicating LE8 can offset IR-related risk.
Impact: Provides actionable evidence that improving cardiovascular health metrics can mitigate mortality risk associated with insulin resistance, reframing prevention strategies.
Clinical Implications: Incorporate LE8-based counseling and interventions (diet, activity, sleep, nicotine exposure, BP, lipids, glucose, BMI) for patients with insulin resistance to reduce mortality risk; assess TyG-WC/WHtR to stratify risk.
Key Findings
- Elevated TyG-WC and TyG-WHtR were associated with higher all-cause and cardiovascular mortality.
- Higher cardiovascular health (LE8) was inversely associated with mortality risk.
- Participants with high insulin resistance but moderate or high LE8 did not have significantly increased mortality compared with low insulin resistance.
Methodological Strengths
- Large nationally representative cohort (NHANES) with 14,172 participants and 7.6-year mean follow-up
- Multiple IR metrics (TyG, TyG-WC, TyG-WHtR) and robust weighted Cox models with dose–response analyses
Limitations
- Observational design limits causal inference and residual confounding is possible
- Lifestyle behaviors and cause-of-death classifications may be subject to misclassification
Future Directions: Test whether structured LE8 interventions causally reduce mortality in insulin-resistant populations; evaluate implementation strategies and cost-effectiveness across diverse settings.
2. Rare MTNR1B variants causing diminished MT2 signalling associate with elevated HbA
Across UK Biobank and Danish cohorts, rare MTNR1B missense variants that diminish MT2 signaling were associated with higher HbA1c among individuals without diabetes but were not associated with increased type 2 diabetes prevalence. A recall-by-genotype study further probed melatonin-induced glucose regulation in variant carriers, supporting a functional link between MT2 signaling and glycemic control.
Impact: Clarifies that rare MTNR1B coding variants predominantly affect glycemic traits rather than diabetes prevalence, refining the role of circadian signaling in metabolic regulation.
Clinical Implications: Routine screening for rare MTNR1B coding variants to predict diabetes risk is not supported; however, carriers may show higher HbA1c. Circadian-aware counseling (e.g., light exposure, sleep timing, melatonin use) may be relevant for glycemic optimization in susceptible individuals.
Key Findings
- In UK Biobank, rare MTNR1B variants impairing MT2 signaling were associated with higher HbA1c among individuals without diabetes.
- These variants were not associated with increased type 2 diabetes prevalence in UK Biobank, contrary to prior reports.
- A recall-by-genotype study evaluated melatonin-induced glucose regulation responses, supporting a functional role for MT2 signaling in glycemic control.
Methodological Strengths
- Very large population-scale datasets with replication across independent cohorts
- Integration of genetic burden testing with recall-by-genotype functional assessment
Limitations
- Predominantly cross-sectional analyses limit causal inference
- Rare variant carrier numbers can constrain power for some endpoints; biobank participation bias possible
Future Directions: Mechanistic studies of MT2 signaling in human islets and controlled trials testing circadian/light or melatonin interventions stratified by MTNR1B genotype.
3. Soluble DPP4 promotes hepatocyte lipid accumulation via SOX2-SCD1 signaling and counteracts DPP4 inhibition.
Soluble DPP4 upregulates SOX2 to induce SCD1-driven lipogenesis and hepatocyte lipid accumulation; SOX2 knockdown abrogates these effects. Exogenous sDPP4 reverses the lipid-lowering effects of DPP4 inhibition, and HFD-fed mice show elevated plasma sDPP4 with increased hepatic SOX2, implicating an sDPP4–SOX2 axis in steatotic liver disease.
Impact: Reveals a previously unrecognized sDPP4–SOX2–SCD1 pathway driving hepatic steatosis and suggests why DPP4 inhibition may be less effective when sDPP4 is elevated.
Clinical Implications: Patients with steatotic liver disease and elevated sDPP4 may respond suboptimally to DPP4 inhibitors; measuring sDPP4 and targeting the sDPP4–SOX2 axis could refine therapy.
Key Findings
- sDPP4 upregulated SOX2 and increased hepatocyte triglyceride synthesis and lipid accumulation; SOX2 knockdown abolished these effects.
- SOX2 induction elevated SCD1 expression, establishing an SOX2–SCD1 lipogenic pathway.
- Exogenous sDPP4 counteracted the lipid-lowering effects of pharmacologic DPP4 inhibition.
- HFD-fed mice showed increased plasma sDPP4 with unchanged hepatic mbDPP4 and increased hepatic SOX2.
Methodological Strengths
- Combined in vitro hepatocyte and in vivo HFD mouse models to establish mechanism
- Loss-of-function (SOX2 silencing) and pharmacologic perturbation to test pathway necessity and drug interactions
Limitations
- Preclinical models; human causal relevance and clinical biomarker thresholds for sDPP4 remain to be defined
- Potential off-target effects and pathway specificity require further validation
Future Directions: Prospective human studies correlating circulating sDPP4 with hepatic fat and DPP4 inhibitor response; development of agents targeting sDPP4–SOX2 signaling.