Daily Endocrinology Research Analysis
Top advances span mechanistic, clinical, and causal-inference endocrinology. A JCI study identifies the chromatin remodeler BAF60a as a key regulator of β cell glucose sensing and GLP-1 responsiveness. A meta-analysis in type 1 diabetes shows once-weekly basal insulin matches HbA1c of daily analogues but increases severe hypoglycemia. Mendelian randomization plus RCT synthesis challenges a causal role of liver fat in hyperglycemia.
Summary
Top advances span mechanistic, clinical, and causal-inference endocrinology. A JCI study identifies the chromatin remodeler BAF60a as a key regulator of β cell glucose sensing and GLP-1 responsiveness. A meta-analysis in type 1 diabetes shows once-weekly basal insulin matches HbA1c of daily analogues but increases severe hypoglycemia. Mendelian randomization plus RCT synthesis challenges a causal role of liver fat in hyperglycemia.
Research Themes
- Epigenetic control of β-cell function and incretin responsiveness
- Safety-efficacy balance of once-weekly basal insulin in type 1 diabetes
- Causal role of hepatic steatosis in glycaemic traits re-evaluated
Selected Articles
1. BAF60a-dependent chromatin remodeling preserves β cell function and contributes to the therapeutic benefits of GLP-1R agonists.
Across mouse, nonhuman primate, and human β cells, BAF60a maintains biphasic GSIS and glucose homeostasis by orchestrating chromatin accessibility with Nkx6.1. A human BAF60a V278M variant and a knock-in mouse model corroborate causality. BAF60a deficiency lowers GLP-1R/GIPR expression, blunting GLP-1R agonist insulinotropic effects, linking epigenetics to incretin pharmacodynamics.
Impact: Reveals a previously unappreciated epigenetic regulator of β-cell stimulus-secretion coupling with direct implications for incretin therapy responsiveness. Integrates multi-species models and human genetics, advancing mechanistic understanding and precision endocrinology.
Clinical Implications: BAF60a status may predict or modulate response to GLP-1R agonists; targeting chromatin remodeling could preserve β-cell function under metabolic stress. Genetic or epigenetic profiling might inform incretin therapy selection.
Key Findings
- BAF60a sustains biphasic GSIS and prevents β-cell dysfunction in metabolic stress; loss impairs GSIS and glucose tolerance.
- BAF60a interacts with Nkx6.1 to modulate chromatin accessibility of GSIS-coupling genes.
- A human BAF60a V278M variant reduces GSIS; knock-in mice recapitulate β-cell dysfunction and dysglycaemia.
- BAF60a deficiency reduces GLP-1R/GIPR expression, attenuating GLP-1R agonist insulinotropic effects.
Methodological Strengths
- Multi-species validation (mouse, nonhuman primate, human islets) with convergent evidence.
- Genetic causality supported by human variant identification and knock-in mouse modeling.
Limitations
- Therapeutic modulation of BAF60a was preclinical; no interventional human data.
- Extent to which findings generalize across diverse T2D etiologies and treatments remains to be defined.
Future Directions: Evaluate BAF60a as a predictive biomarker for incretin therapy and explore pharmacologic or epigenetic interventions to upregulate BAF60a/Nkx6.1 axis in β cells.
2. Efficacy and safety of once-weekly basal insulin therapy in people with type 1 diabetes: A systematic review and meta-analysis.
Across five RCTs (n=1629), once-weekly basal insulin achieved HbA1c, weight, and time-in-range outcomes comparable to once-daily analogues but significantly increased level 3 hypoglycaemia. Weekly regimens needed less total bolus insulin, indicating altered basal–bolus dynamics.
Impact: This is the first meta-analysis focused exclusively on type 1 diabetes, directly informing regulatory, guideline, and adoption decisions for weekly basal insulins by quantifying a severe hypoglycaemia safety signal.
Clinical Implications: Weekly basal insulin may not be broadly safer in T1D despite HbA1c equivalence; clinicians should weigh convenience against elevated severe hypoglycaemia risk and consider patient selection, education, and CGM-linked safeguards.
Key Findings
- HbA1c, body weight, time-in-range and time-above-range were similar between weekly and daily basal insulin arms (high to moderate certainty).
- Level 3 hypoglycaemia occurred more frequently with once-weekly basal insulin (IRR 2.532, 95% CI 1.758–3.645).
- Weekly basal insulin reduced weekly bolus insulin dose (ETR 0.837, 95% CI 0.794–0.882).
Methodological Strengths
- Exclusive inclusion of T1D RCTs with predefined outcomes and certainty grading.
- Comprehensive multi-database search and independent triple-reviewer screening.
Limitations
- Heterogeneity in trial designs, algorithms, and adjunct technologies (e.g., CGM use) may influence hypoglycaemia rates.
- Long-term cardiovascular and microvascular outcomes were not assessed.
Future Directions: Define patient phenotypes and care pathways that maximize weekly insulin benefit while mitigating severe hypoglycaemia, including algorithm refinements and closed-loop integration.
3. Reevaluating the causal link between liver fat and hyperglycaemia.
Two-sample Mendelian randomization in 37,358 individuals found no causal effect of liver fat on fasting/postprandial glucose, HbA1c, fasting insulin, or HOMA-IR. Meta-analysis of 13 RCTs of steatosis-targeting drugs (n=2482) similarly showed no glycaemic improvements, challenging a direct causal model.
Impact: Combines genetic causal inference and RCT synthesis to overturn a prevalent assumption about hepatic steatosis driving hyperglycaemia, redirecting mechanistic and therapeutic focus in MASLD/MASH and diabetes.
Clinical Implications: Liver fat reduction alone may not lower glycaemia; treatment strategies should target pathways beyond steatosis (e.g., inflammation, hepatic insulin signaling, adipose-liver crosstalk). Outcome expectations from steatosis-directed drugs should be calibrated.
Key Findings
- MR showed no causal effect of liver fat on fasting glucose, HbA1c, postprandial glucose, fasting insulin, or HOMA-IR.
- Meta-analysis of 13 RCTs targeting hepatic steatosis found no significant improvements in fasting glucose or HbA1c versus controls.
- Meta-regression found no linear relationship between liver fat reduction and change in glycaemic indices.
Methodological Strengths
- Triangulation using MR with large GWAS and independent RCT meta-analysis.
- Consistent null findings across multiple glycaemic endpoints with sensitivity analyses.
Limitations
- MR assumes valid instruments and linearity; residual pleiotropy cannot be entirely excluded.
- RCTs varied in drug classes, duration, and populations; power to detect small glycaemic effects may be limited.
Future Directions: Probe non-steatosis mechanisms (inflammation, mitochondrial function, hepatokines) linking MASLD to dysglycaemia; design trials targeting these pathways with glycaemic endpoints.