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.
Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.
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.
PURPOSE: INSR encodes the insulin receptor, the essential entrainer of growth and metabolism to nutritional cues. INSR variants cause a spectrum of monogenic insulin resistance (IR) syndromes, namely, type A insulin resistance, Rabson-Mendenhall, and Donohue syndromes. However, to our knowledge, no large cohort studies focused on variant classification and its diagnostic value have been described. METHODS: This multicentric cohort study included 73 patients carrying INSR variants, referred for IR by 52 centers from 6 countries. Variants were classified using new bioinformatic tools relying on different prediction mechanisms and the American College of Medical Genetics and Genomics guidelines. RESULTS: Besides expanding the INSR mutational spectrum, this study suggested a semidominant inheritance in several Donohue/Rabson-Mendenhall syndrome families. Questioning strictly Mendelian inheritance, heterozygous loss-of-function (LoF) variants were mostly found in overweight patients, with a higher LoF frequency in IR patients than in the general population (odds ratio 5.77). Diagnostic challenges arose when trying to refine classification criteria for variants of uncertain significance. Among the variant effect predictors assessed, MISTIC and AlphaMissense outperformed REVEL. CONCLUSION: The spectrum of INSR-related disorders extends beyond traditional entities. Heterozygous INSR LoF variants may increase IR susceptibility. International collaboration and functional assays are needed to drive precision medicine forward.
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.
AIMS/HYPOTHESIS: The nPOD-Virus group collaboratively applied innovative technologies to detect and sequence viral RNA in pancreas and other tissues from organ donors with type 1 diabetes. These analyses involved the largest number of pancreas samples collected to date. The aim of the current work was to examine the presence of enterovirus RNA in pancreas and lymphoid tissues of organ donors with and without type 1 diabetes. METHODS: We analysed pancreas, spleen, pancreatic lymph nodes and duodenum samples from the following groups: (1) donors with type 1 diabetes (n=71) with (n=35) or without (n=36) insulin-containing islets; (2) donors with single or double islet autoantibody positivity without diabetes (n=22); and (3) autoantibody-negative donors without diabetes (control donors) (n=74). Five research laboratories participated in this collaborative effort using approaches for unbiased discovery of RNA viruses (two RNA-Seq platforms), targeted detection of Enterovirus A-D species using RT-PCR, and tests for virus growth in cell culture. RESULTS: Direct RNA-Seq did not detect virus signal in pancreas samples, whereas RT-PCR detected enterovirus RNA confirmed by sequencing in low amounts in pancreas samples in three of the five donor groups: donors with type 1 diabetes with insulin-containing islets, 16% (5/32) being positive; donors with single islet autoantibody positivity, 53% (8/15) being positive; and non-diabetic donors, 8% (4/49) being positive. Detection of enterovirus RNA was significantly more frequent in single islet autoantibody-positive donors compared with donors with type 1 diabetes with insulin-deficient islets (p<0.001) and control (non-diabetic) donors (p=0.004). In some donors, pancreatic lymph nodes were also positive. RT-PCR detected enterovirus RNA also in the spleen of a small number of donors and virus enrichment in susceptible cell lines before RT-PCR resulted in much higher rate in spleen positivity, particularly in donors with type 1 diabetes. Interestingly, the enterovirus strains detected did not cause a typical lytic infection, possibly reflecting their persistence-prone nature. CONCLUSIONS/INTERPRETATION: This was the largest coordinated effort to examine the presence of enterovirus RNA in the pancreas of organ donors with type 1 diabetes, using a multitude of assays. These findings are consistent with the notion that donors with type 1 diabetes and donors with islet autoantibodies may carry a low-grade enterovirus infection in the pancreas and lymphoid tissues.