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.
BACKGROUND: Insulin resistance(IR) is associated with an increased risk of all-cause and cardiovascular death, and modifiable healthy lifestyles play an active role in the improvement of IR and the reduction of all-cause and cardiovascular death. Whether cardiovascular health (CVH) and modifiable healthy lifestyles within it can attenuate or even offset the heightened perils of both all-cause and cardiovascular deaths associated with insulin resistance remains unclear. METHODS: The study encompassed 14,172 healthy participants from the 2005-2018 NHANES programme. Insulin resistance was evaluated using the TyG index, TyG-WC, and TyG-WHtR, while CVH was assessed employing the LE8 score, in addition to the LE4 index redefined according to four health behaviours. Weighted multifactor Cox regression models were used to assess the association of IR and CVH with all-cause and cardiovascular mortality, and dose-response relationships were assessed using restricted cubic spline. Furthermore, subjects were grouped according to IR and CVH scores, and generalised linear models were used to estimate the weighted mortality and risk of death for each group and to calculate the absolute risk difference. Finally, the predicted probability of all-cause and cardiovascular mortality risk as a function of IR was computed, and the complex relationship between the three was visualised using two-dimensional grouped scatter plots and three-dimensional surface plots. RESULTS: Among the 14,172 healthy participants included in the study, 1534 deaths occurred over a mean follow-up period of 7.6 years (382 of these deaths were due to cardiovascular causes). The weighted Cox regression analysis indicated that elevated TyG-WC and TyG-WHtR correlated with a greater likelihood of mortality from all causes and cardiovascular events, whereas cardiovascular health was inversely associated with these risks. Additional stratification revealed a notable reduction in the likelihood of mortality from all causes and cardiovascular events as cardiovascular health improved, irrespective of the presence of insulin resistance. Additionally, participants with high insulin resistance but moderate or high cardiovascular health did not have significantly increased risks compared with those with low insulin resistance. Stratified scatter plots and 3D surface plots revealed that cardiovascular health and modifiable healthy lifestyles significantly reduced the risk of insulin resistance-related death, with greater reductions observed at higher insulin resistance levels. CONCLUSIONS: In this cohort study, improving cardiovascular health and modifiable health behaviors significantly reduced the risk of insulin resistance-related all-cause and cardiovascular deaths. Maintaining cardiovascular health at moderate or high levels (LE8 ≥ 50) could offset the increased risks caused by insulin resistance.
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.
AIMS/HYPOTHESIS: An intronic variant (rs10830963) in MTNR1B (encoding the melatonin receptor type 2 [MT2]) has been shown to strongly associate with impaired glucose regulation and elevated type 2 diabetes prevalence. However, MTNR1B missense variants have shown conflicting results on type 2 diabetes. Thus, we aimed to gain further insights into the impact of MTNR1B coding variants on type 2 diabetes prevalence and related phenotypes. METHODS: We conducted a cross-sectional study, performing MTNR1B variant burden testing of glycaemic phenotypes (N=248,454, without diabetes), other cardiometabolic phenotypes (N=330,453) and type 2 diabetes prevalence (case-control study; N=263,739) in the UK Biobank. Similar burden testing with glycaemic phenotypes was performed in Danish Inter99 participants without diabetes (N=5711), and type 2 diabetes prevalence (DD2 cohort serving as cases [N=2930] and Inter99 serving as controls [N=4243]). Finally, we evaluated the effects of MTNR1B variants on the melatonin-induced glucose regulation response in a recall-by-genotype study of individuals without diabetes. RESULTS: In the UK Biobank, MTNR1B variants were not associated with cardiometabolic phenotypes, including type 2 diabetes prevalence, except that carriers of missense MTNR1B variants causing impaired MT2 signalling exhibited higher HbA CONCLUSIONS/INTERPRETATION: The higher type 2 diabetes prevalence previously observed in carriers of missense MTNR1B variants causing impairment in MT2 signalling was not replicated in the UK Biobank, yet carriers had elevated HbA DATA AVAILABILITY: Data (Inter99 cohort and recall-by-genotype study) are available on reasonable request from the corresponding author. Requests for DD2 data are through the application form at https://dd2.dk/forskning/ansoeg-om-data . Access to UK Biobank data can be requested through the UK Biobank website ( https://www.ukbiobank.ac.uk/enable-your-research ).
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.
Dipeptidyl peptidase-4 (DPP4), a well-known target of antidiabetic therapy, is implicated in steatotic liver disease. However, its role in hepatic lipid metabolism, particularly the distinct functions of soluble DPP4 (sDPP4) and membrane-bound DPP4 (mbDPP4), remains unclear. Here, we identify SOX2 as a key mediator linking sDPP4 to hepatocyte lipid accumulation, uncovering a previously unreported regulatory mechanism. sDPP4 promotes free fatty acid (FFA)-induced lipid accumulation and triglyceride (TG) synthesis in hepatocytes by upregulating SOX2, a stemness-associated transcription factor. SOX2 induction increased the expression of stearoyl-coenzyme A desaturase 1 (SCD1), a key lipogenic enzyme, supporting the role of SOX2-SCD1 signaling in sDPP4-mediated hepatic steatosis. SOX2 silencing abolished these effects, confirming its requirement for sDPP4-induced lipid accumulation. Similarly, mbDPP4 overexpression increased FFA-induced lipid synthesis and SOX2 expression, while its knockdown suppressed these responses. Pharmacological inhibition of mbDPP4 activity reduced lipid accumulation and downregulated SOX2, SCD1, and fatty acid synthase expression. However, exogenous sDPP4 reversed these effects, counteracting the lipid-suppressing effect of DPP4 inhibition. In vivo, high-fat diet (HFD)-fed mice exhibited increased plasma sDPP4 levels, whereas hepatic mbDPP4 expression remained unchanged. This correlated with enhanced hepatic SOX2 expression, suggesting that elevated sDPP4 may contribute to hepatic lipid accumulation independent of mbDPP4 activity. Collectively, our findings highlight the role of sDPP4-SOX2 signaling in hepatic lipid accumulation and underscore the need to distinguish sDPP4 from mbDPP4 in steatotic liver disease. Targeting the sDPP4-SOX2 axis could be explored as a potential therapeutic approach for steatotic liver disease.