Daily Endocrinology Research Analysis
Three papers reshape current thinking across metabolic and endocrine science: lysosomal acid lipase-driven lipolysis is indispensable for fasting/cold responses in adipocytes; coordinated multi-lab analyses support low-grade enteroviral RNA in pancreas/lymphoid tissues in type 1 diabetes; and a multicenter genetics cohort redefines the inheritance and diagnostic spectrum of INSR-related insulin resistance.
Summary
Three papers reshape current thinking across metabolic and endocrine science: lysosomal acid lipase-driven lipolysis is indispensable for fasting/cold responses in adipocytes; coordinated multi-lab analyses support low-grade enteroviral RNA in pancreas/lymphoid tissues in type 1 diabetes; and a multicenter genetics cohort redefines the inheritance and diagnostic spectrum of INSR-related insulin resistance.
Research Themes
- Lysosomal lipolysis in energy homeostasis
- Viral persistence and autoimmunity in type 1 diabetes
- Precision genomics of insulin receptor variants and insulin resistance
Selected Articles
1. Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
This mechanistic study shows that lysosomal acid lipase-driven lipolysis is upregulated during fasting, cold exposure, and β-adrenergic stimulation, and is essential for maintaining circulating FFAs, thermogenesis, and energy expenditure. Adipocyte LIPA deficiency impairs cold tolerance and increases susceptibility to diet-induced obesity, acting independently of cytosolic ATGL.
Impact: It revises the canonical view that cytosolic lipases dominate physiologic lipolysis, revealing a required lysosomal pathway for whole-body fuel supply and thermogenesis.
Clinical Implications: Targeting lysosomal lipolysis (e.g., modulating LIPA) could open new avenues for treating obesity, cold intolerance, and metabolic disorders, but safety must be carefully evaluated given its role in thermogenesis.
Key Findings
- Adipocyte LIPA expression increases during fasting, cold exposure, and β-adrenergic stimulation.
- Genetic or pharmacologic inhibition of LIPA lowers plasma FFAs under lipolytic conditions and impairs thermogenesis and oxygen consumption.
- Lysosomal lipolysis operates independently of ATGL and its deficiency predisposes mice to diet-induced obesity.
Methodological Strengths
- Convergent genetic and pharmacologic manipulation with in vivo physiological readouts (thermogenesis, oxygen consumption).
- Demonstration of pathway independence from ATGL, clarifying mechanistic specificity.
Limitations
- Preclinical mouse and cellular models; human translatability remains to be established.
- Molecular trafficking and regulation of lysosomal lipolysis across adipocyte subtypes not fully resolved.
Future Directions: Define LIPA regulation in human adipose depots, assess pharmacologic modulation in large animals/humans, and map interplay with cytosolic lipases under diverse metabolic states.
2. Insulin receptor variants: Extending the traditional Mendelian spectrum.
In a 73-patient multicenter cohort, the authors expand the INSR mutational spectrum and suggest semidominant inheritance in severe insulin resistance syndromes. Heterozygous INSR loss-of-function variants were enriched in insulin-resistant individuals (OR 5.77), indicating they may confer susceptibility beyond classic monogenic patterns.
Impact: It challenges strictly Mendelian views of INSR disorders and provides practical guidance for variant classification and risk interpretation in precision endocrinology.
Clinical Implications: Genetic counseling and clinical risk assessment for insulin resistance should consider heterozygous INSR LoF variants as susceptibility factors, and laboratories may prioritize MISTIC/AlphaMissense for classification triage while pursuing functional assays.
Key Findings
- Semidominant inheritance suggested in several Donohue/Rabson-Mendenhall families carrying INSR variants.
- Heterozygous INSR loss-of-function variants enriched in insulin-resistant patients vs general population (OR 5.77).
- Variant prediction tools MISTIC and AlphaMissense outperformed REVEL for classification support.
Methodological Strengths
- Multicenter international cohort with standardized variant classification aligned to ACMG.
- Comparative evaluation of state-of-the-art variant effect predictors.
Limitations
- Limited functional validation for all variants; potential referral/selection bias.
- Phenotypic heterogeneity and confounding by adiposity in heterozygous carriers.
Future Directions: Prospective registries with systematic metabolic phenotyping and high-throughput functional assays to refine penetrance, inheritance models, and treatment stratification.
3. Detection of enterovirus RNA in pancreas and lymphoid tissues of organ donors with type 1 diabetes.
Across 167 organ donors, RT-PCR (but not direct RNA-Seq) detected low-level enterovirus RNA in pancreas more often in single autoantibody-positive donors (53%) and in T1D donors with insulin-containing islets (16%) than in controls (8%). Positivity in lymphoid tissues and non-lytic behavior suggests persistence-prone infection.
Impact: This coordinated, largest-to-date multi-assay analysis substantively informs the longstanding viral hypothesis of T1D pathogenesis and refines expectations for detection methods.
Clinical Implications: Findings support continued surveillance for enteroviral footprints in at-risk individuals and may guide sampling and assay choice (RT-PCR over unbiased RNA-Seq) in biobank studies; therapeutic strategies against persistent enteroviral infection warrant exploration.
Key Findings
- RT-PCR detected enterovirus RNA in pancreas in 16% of T1D donors with insulin-containing islets, 53% of single autoantibody-positive donors, and 8% of controls; direct RNA-Seq was negative.
- Enterovirus RNA was occasionally detected in pancreatic lymph nodes and spleen; enrichment in cell culture increased spleen detection, particularly in T1D donors.
- Detected strains lacked typical lytic infection patterns, suggesting persistence-prone infection.
Methodological Strengths
- Largest coordinated multi-lab effort with multiple tissues and orthogonal assays (RNA-Seq, RT-PCR, culture enrichment).
- Group stratification by autoantibody status and islet insulin content strengthens biological interpretation.
Limitations
- Low viral loads and cross-sectional design limit causal inference.
- RNA-Seq sensitivity insufficient for low-grade infection; donor heterogeneity may confound detection rates.
Future Directions: Longitudinal sampling in at-risk cohorts with matched pancreas/lymphoid tissues, improved targeted sequencing sensitivity, and intervention studies targeting persistent enteroviral infection.