Daily Endocrinology Research Analysis
Three studies advance endocrine science across mechanisms and clinical prediction: a Science Advances study identifies a lysosomal LRRC8 anion channel program that controls lysosomal pH, mTOR signaling, and whole-body insulin sensitivity; an Angewandte Chemie study reveals impaired fusion pore expansion as a mechanistic bottleneck limiting insulin exocytosis in human type 2 diabetes; and a 107,889-woman JCEM cohort shows that the number and type of abnormal pregnancy OGTT values strongly predict
Summary
Three studies advance endocrine science across mechanisms and clinical prediction: a Science Advances study identifies a lysosomal LRRC8 anion channel program that controls lysosomal pH, mTOR signaling, and whole-body insulin sensitivity; an Angewandte Chemie study reveals impaired fusion pore expansion as a mechanistic bottleneck limiting insulin exocytosis in human type 2 diabetes; and a 107,889-woman JCEM cohort shows that the number and type of abnormal pregnancy OGTT values strongly predict future type 2 diabetes.
Research Themes
- Lysosomal nutrient sensing and systemic glucose homeostasis
- Fusion pore dynamics as a determinant of insulin secretion in T2D
- Pregnancy OGTT abnormalities as predictors of future type 2 diabetes
Selected Articles
1. Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
This mechanistic study identifies a lysosomal LRRC8 anion channel program that sets lysosomal pH and morphology, tunes PI3K–AKT–mTOR signaling, and governs systemic insulin sensitivity. Muscle-targeted LRRC8A motif mutation in knock-in mice led to adiposity, glucose intolerance, and insulin resistance with reduced muscle glucose uptake and glycogen incorporation.
Impact: It uncovers a lysosome-based ion channel mechanism linking nutrient sensing to insulin resistance, revealing LRRC8 as a potential metabolic target. This bridges organelle biophysics with whole-body glucose homeostasis.
Clinical Implications: Targeting LRRC8-dependent lysosomal function or its trafficking motif could modulate mTOR tone and insulin sensitivity, motivating drug discovery around lysosomal ion channels and biomarkers of lysosomal pH in metabolic disease.
Key Findings
- Endogenous LRRC8 subunits localize to a lysosomal subset in differentiated myotubes and regulate lysosomal pH, size, and number.
- LRRC8A controls leucine-stimulated mTOR signaling and lysosomal protein expression (LAMP2, P62, LC3B).
- LRRC8A L706A;L707A motif mutation recapitulates AKT signaling defects and altered lysosomal morphology/pH seen in LRRC8A knockout.
- Knock-in mice with LRRC8A motif mutation exhibit increased adiposity, impaired glucose tolerance, and insulin resistance with reduced skeletal muscle PI3K–AKT–mTOR signaling, glucose uptake, and glycogen incorporation.
Methodological Strengths
- Convergent in vitro (myotubes) and in vivo (knock-in mice) evidence with genetic perturbation of a lysosomal targeting motif.
- Comprehensive phenotyping spanning lysosomal biophysics, signaling pathways, and whole-body metabolic outcomes.
Limitations
- Translational relevance to humans remains to be demonstrated; no pharmacologic LRRC8 modulation tested.
- Tissue-specific contributions beyond skeletal muscle were not fully dissected.
Future Directions: Develop selective LRRC8 modulators; define tissue-specific roles in liver/adipose; validate biomarkers of lysosomal pH and signaling in humans with insulin resistance.
2. Single Fusion Pore Analysis via Single Cell Amperometry Uncovers Impaired Pore Expansion That Restricts Insulin Exocytosis in Human Type 2 Diabetes.
Using single-cell amperometry and TIRF microscopy on human donor beta cells, the study shows that in type 2 diabetes, fusion pore opening is prematurely aborted, restricting granule cargo release and insulin secretion. Differences in docked vesicle number further support a secretory machinery defect at the fusion pore level.
Impact: It pinpoints a previously underappreciated bottleneck—fusion pore expansion—linking beta-cell exocytosis biophysics to human T2D. This mechanistic insight opens avenues for therapeutically restoring pore dynamics to improve secretion.
Clinical Implications: Screening for modulators of fusion pore expansion and stabilization could become a strategy to enhance residual insulin secretion in T2D; analytic approaches (SCA/TIRF) may inform functional diagnostics of beta-cell secretory defects.
Key Findings
- In human T2D beta cells, fusion pore opening was prematurely aborted, reducing granule cargo release.
- Single-cell amperometry quantified altered opening, duration, and closing times of fusion pores during individual exocytosis events.
- TIRF microscopy revealed differences in the number of docked vesicles per beta cell between T2D donors and controls.
Methodological Strengths
- High temporal resolution combination of electrochemical (SCA) and optical (TIRF) readouts in human donor cells.
- Event-level quantification of fusion pore kinetics directly linked to secretion phenotype.
Limitations
- Serotonin used as a proxy for insulin may not capture all cargo-specific dynamics.
- Ex vivo human cell studies with limited sample sizes; causal molecular determinants of pore failure remain to be identified.
Future Directions: Identify molecular regulators of fusion pore expansion in human beta cells; develop small-molecule modulators; integrate functional pore metrics into beta-cell phenotyping of T2D subtypes.
3. An oral glucose tolerance test in pregnancy can serve as a valuable predictor for future diabetes.
In 107,889 pregnancies, each additional abnormal value on a 100-g OGTT increased the hazard of future T2D, with fasting hyperglycemia conferring the greatest risk. Prior GDM independently predicted later T2D even when the current OGTT was normal, enabling refined postpartum risk stratification.
Impact: This very large real-world cohort quantifies postpartum diabetes risk by OGTT abnormality count and type, providing actionable thresholds for targeted prevention.
Clinical Implications: Measure OGTT at pregnancy and use both number and fasting status of abnormalities to triage postpartum surveillance intensity (eg, earlier testing, lifestyle/pharmacologic prevention) for high-risk women.
Key Findings
- Among 107,889 women followed a median 6.7 years, T2D risk rose with each additional abnormal OGTT value: HR 3.45 (one), 4.03 (two), 7.15 (three), 10.60 (four).
- Abnormal fasting glucose predicted higher T2D risk (HR 5.28) than abnormal non-fasting values (HR 3.03).
- Prior GDM remained associated with future T2D even when current pregnancy OGTT values were normal.
Methodological Strengths
- Very large population-based cohort with ~900,000 person-years and time-to-event modeling.
- Granular analysis by count and type of abnormal OGTT values; robust HR estimates with narrow CIs.
Limitations
- Retrospective observational design with potential residual confounding and misclassification of diabetes onset.
- Generalizability outside a single national healthcare system may vary; intervention effects were not tested.
Future Directions: Prospectively validate an OGTT-based postpartum risk score across diverse populations and test targeted prevention strategies triggered by fasting-value abnormalities and cumulative abnormal values.