Daily Endocrinology Research Analysis
Analyzed 25 papers and selected 3 impactful papers.
Summary
Three studies advance endocrinology and metabolism: (1) an INS (R6C) variant is reclassified as a recessive cause of monogenic diabetes using integrated population genetics, iPSC-derived β cells, and in vivo validation; (2) new transgenic mouse reporters enable in vivo, single-cell visualization of lysosome damage and lysophagy across organs, including diabetic modeling; (3) brown adipose tissue epigenetic responses to cold are shaped by metabolic state, suggesting targets to restore thermogenesis in obesity.
Research Themes
- Monogenic diabetes reclassification via multi-modal mechanistic evidence
- In vivo tools for organelle quality control (lysophagy) with metabolic disease relevance
- Epigenetic regulation of brown fat thermogenesis shaped by diet-cold interactions
Selected Articles
1. A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data.
Using population data, patient iPSC-derived β cells, and in vivo grafts, the study shows INS R6C causes recessive, not dominant, monogenic diabetes. Homozygotes develop early-onset insulin-requiring diabetes with β-cell ER translocation defects, whereas heterozygotes generally do not show increased diabetes risk.
Impact: This work reclassifies a widely cited INS variant, resolving a long-standing ambiguity and providing a multi-modal framework for variant interpretation in monogenic diabetes.
Clinical Implications: Genetic counseling for R6C carriers should consider recessive inheritance; heterozygotes may not require enhanced diabetes surveillance. Therapeutic expectations may shift given poor GLP-1RA response in homozygous β cells.
Key Findings
- Homozygous INS R6C individuals develop early-onset insulin-treated diabetes; heterozygous carriers show variable or absent glycemic phenotypes with no population-level enrichment of diabetes.
- Homozygous iPSC-derived β cells accumulate preproinsulin, with reduced insulin content and secretion; heterozygous cells show minimal defects.
- In vivo β-cell transplants from homozygous R6C recapitulate insulin deficiency and respond poorly to GLP-1 receptor agonists; transcriptomics reveal attenuated translation/translocation and ER pathway signatures.
- Evidence supports reclassification of R6C as a recessive loss-of-function variant, informing clinical reassessment of carriers.
Methodological Strengths
- Integrated population genetics, patient iPSC-derived β-cell modeling, and in vivo transplantation
- Functional validation across cellular and organismal systems with transcriptomic profiling
Limitations
- Likely small number of homozygous cases limits precision and generalizability
- Clinical endpoints and long-term outcomes were not systematically assessed; applicability to other INS variants remains uncertain
Future Directions: Expand to larger, multi-ethnic cohorts and additional INS variants; test targeted therapeutics addressing ER translocation stress; develop clinical algorithms integrating population and functional evidence.
The INS c.16 C > T (insulin p.Arg6Cys, R6C) variant was reported to cause autosomal dominant monogenic diabetes, yet its pathogenicity has been questioned. R6C preproinsulin exhibits impaired translocation into the endoplasmic reticulum (ER). We explored R6C pathogenicity using integrative clinical, genetic, and functional approaches.Homozygous INS R6C individuals presented early-onset insulin-treated diabetes, whereas heterozygous carriers showed variable or absent glycemic phenotypes. Population-level analysis revealed no significant enrichment of diabetes among heterozygotes. Heterozygous R6C patient's induced pluripotent stem cell (iPSC)-derived pancreatic β cells exhibited minimal defects, while homozygous R6C β cells displayed preproinsulin accumulation and reduced insulin content and secretion. In vivo, homozygous R6C β cell transplants recapitulated insulin deficiency and responded poorly to GLP-1 receptor agonist. Homozygous R6C β cells had a gene signature of attenuated translation, translocation and ER related pathways.Our findings establish R6C as a recessive loss-of-function mutation, prompting a clinical reassessment of heterozygous R6C carriers. This study highlights the power of population genetic databases, patients' iPSC-based modeling and multi-modal variant classification frameworks for dissecting the consequences of genetic variants in monogenic diabetes.
2. Measuring lysosome damage and lysophagy in vivo.
The authors generated constitutive and Cre-inducible tfGAL3 reporter mice that visualize lysosome damage and lysophagy flux at single-cell resolution in vivo. Cross-organ analyses revealed tissue-specific baselines and stress-induced shifts (starvation, acute kidney injury, diabetic modeling), providing a versatile tool for basic and translational studies.
Impact: Provides the first broadly applicable in vivo reporters to quantify lysosome damage and lysophagy dynamics across tissues, enabling mechanistic studies in metabolic and kidney diseases.
Clinical Implications: Facilitates target discovery and preclinical evaluation of lysosomal quality control pathways relevant to diabetic complications and acute kidney injury, potentially informing biomarker development.
Key Findings
- Creation of two tfGAL3 transgenic mouse lines (constitutive and Cre-inducible) to visualize damaged lysosomes and lysophagy in vivo at single-cell resolution.
- Systemic, cross-organ analyses reveal substantial variation in basal lysophagy in vivo and in vitro.
- Under starvation, acute kidney injury, and diabetic modeling, tissues exhibit marked shifts in lysosome integrity and lysophagy flux.
- The reporter models provide a quantifiable platform for studying lysosomal quality control in physiology and disease.
Methodological Strengths
- Genetically encoded reporter enabling spatiotemporal, single-cell in vivo readouts
- Broad organ coverage with both constitutive and conditional expression, including validation in primary cultures
Limitations
- Potential reporter-related artifacts and variable signal thresholds across tissues
- Translational relevance to human disease requires further validation; limited disease contexts tested
Future Directions: Apply reporters to longitudinal disease models (e.g., diabetic nephropathy, neurodegeneration), integrate with quantitative proteomics, and test pharmacologic modulators of lysophagy.
Lysosome homeostasis is vital for cellular fitness due to the essential roles of this organelle in various pathways. Given their extensive workload, lysosomes are prone to damage, which can stimulate lysosomal quality control mechanisms such as biogenesis, repair, or autophagic removal - a process termed lysophagy. Despite recent advances highlighting lysophagy as a critical mechanism for lysosome maintenance, the extent of lysosome integrity perturbation and the magnitude of lysophagy in vivo remain largely unexplored. Additionally, the pathophysiological relevance of lysophagy is poorly understood. To address these gaps, it is necessary to develop quantifiable methods for evaluating lysosome damage and lysophagy flux in vivo. To this end, we created two transgenic mouse lines expressing a tandem fluorescent LGALS3/galectin 3 probe (tfGAL3), either constitutively or conditionally under Cre recombinase control, utilizing the property of LGALS3 to recognize damaged lysosomes. This tool enables spatiotemporal visualization of lysosome damage and lysophagy activity at single-cell resolution in vivo. Systemic analysis across various organs, tissues, and primary cultures from these lysophagy reporter mice revealed significant variations in basal lysophagy, both in vivo and in vitro. Additionally, this study identified substantial changes in lysosome integrity and lysophagy flux in different tissues under stress conditions such as starvation, acute kidney injury and diabetic modeling. In conclusion, these complementary lysophagy reporter models are valuable resources for both basic and translational research.
3. Diet and temperature interactively impact brown adipose tissue gene regulation controlled by DNA methylation.
In lean vs diet-induced obese mice, seven days of cold exposure revealed 1,364 genes whose expression depended on the interaction between metabolic state and temperature, with 65 showing coordinated methylation-expression changes. Epigenetic regulators (Tet2, Dnmt3a, Apobec1) and TF motifs (Ahr::Arnt, Foxn1) were implicated, and in vitro methylation perturbation altered thermogenic gene expression.
Impact: Provides the first demonstration that BAT’s epigenetic cold response is contingent on metabolic state, identifying regulators that could be targeted to restore thermogenesis in obesity.
Clinical Implications: Suggests epigenetic targets and biomarkers to stratify cold responsiveness and to design interventions that re-activate BAT thermogenesis in obesity.
Key Findings
- Identified 1,364 DEGs uniquely affected by the interaction of metabolic state (lean vs DIO) and cold exposure; most were downregulated in DIO.
- Found 65 differentially methylated and expressed genes linking DNA methylation to altered cold responses, enriched for mitochondrial, lipid, neuroendocrine, and stress pathways.
- Epigenetic regulators (Tet2, Dnmt3a, Apobec1) and TF motifs (Ahr::Arnt, Foxn1) were implicated; in vitro methylation modulation altered thermogenic gene expression.
- First evidence that BAT’s epigenetic cold response diverges by metabolic condition.
Methodological Strengths
- Integrated RNA-seq and RRBS to map transcriptome–methylome coupling under environmental perturbations
- Validated epigenetic influence on thermogenic genes via in vitro methylation modulation
Limitations
- Mouse model with unspecified sample size; RRBS captures a subset of CpGs and cold exposure was short (7 days)
- Causality between methylation changes and in vivo thermogenic phenotypes remains to be established
Future Directions: Test causal roles of identified regulators (Tet2, Dnmt3a, Apobec1; Ahr::Arnt, Foxn1) in BAT activation in vivo, extend to human BAT, and evaluate pharmacologic epigenetic modulators.
Controlling brown adipose tissue (BAT) plasticity offers potential for novel obesity therapies. DNA methylation is closely linked to thermogenic and metabolic pathways and thereby influences BAT function. How metabolic state and cold exposure interact to shape methylation-dependent BAT gene regulation was investigated. Five-week-old mice were fed either chow for 11 weeks (lean) or high-fat diet for 22 weeks to induce obesity (DIO), after which cold exposure was applied for seven days. BAT transcriptomes (RNAseq) and methylomes (RRBS) were generated, and differentially methylated and expressed genes (DMEGs) showing metabolic state-dependent cold responses were identified. Pathway enrichment, epigenetic regulator screening, and transcription factor (TF) motif analyses were performed. DNA methylation was experimentally modulated in vitro to validate selected gene expression responses. A total of 1,364 differentially expressed genes (DEGs) were uniquely affected by the interaction of metabolic state and cold, with most downregulated in DIO mice. Sixty-five DMEGs (4% of DEGs) showed metabolic state-specific responses to cold. In DIO mice, DMEGs were enriched in pathways associated with mitochondrial dysfunction, altered lipid metabolism, neuroendocrine signaling, and stress responses. Several epigenetic regulators, including Tet2, Dnmt3a, and Apobec1, exhibited metabolic state- and cold-dependent expression, and TF-motif analyses highlighted roles for Ahr::Arnt and Foxn1. In vitro assays confirmed that DNA methylation influences expression of thermogenic genes. These findings provide the first evidence that the epigenetic cold response of BAT differs by metabolic condition. BAT remodeling is shaped by coordinated transcriptional and epigenetic mechanisms integrating environmental and metabolic cues.