Daily Endocrinology Research Analysis
Analyzed 71 papers and selected 3 impactful papers.
Summary
Three impactful endocrinology studies span mechanisms and populations: endothelial IRE1α safeguards islet vascular adaptation under metabolic stress, hepatic stellate cell autocrine Netrin-1 drives fibrosis in MASH with therapeutic knockdown benefits, and delayed puberty predicts early-adult type 2 diabetes independent of BMI in a 964,108-person cohort. Together they link stress signaling, fibrogenic circuitry, and developmental timing to metabolic disease risk and targets.
Research Themes
- Endothelial ER-stress signaling and islet adaptation in metabolic disease
- Autocrine fibrogenic signaling in MASH and therapeutic targeting
- Pubertal timing as a predictor of early-adult type 2 diabetes
Selected Articles
1. Endothelial IRE1α promotes thrombospondin-1 mRNA decay and supports metabolic stress adaptation of pancreatic islets.
Endothelial-specific IRE1α loss in high-fat diet-fed male mice caused glucose intolerance due to impaired insulin secretion, with blunted intra-islet angiogenesis and growth. IRE1α RNase activity degrades THBS1 mRNA in islet endothelium, relieving anti-angiogenic pressure and enabling adaptive islet vascularization.
Impact: This study reveals a previously unrecognized endothelial ER-stress checkpoint that controls islet vascular support via THBS1 mRNA decay, linking vascular stress signaling to endocrine adaptation under obesity.
Clinical Implications: Targeting the endothelial IRE1α–THBS1 axis could enhance islet revascularization and beta-cell functional adaptation in obesity and type 2 diabetes, suggesting a vascular-centric adjunct to metabolic therapies.
Key Findings
- Endothelial IRE1α deletion in high-fat diet-fed male mice caused glucose intolerance with impaired insulin secretion.
- Loss of endothelial IRE1α blunted intra-islet angiogenesis and compensatory islet growth without affecting adiposity.
- IRE1α RNase activity decayed THBS1 mRNA in islet ECs, relieving anti-angiogenic signaling to support islet adaptation.
Methodological Strengths
- Endothelial cell-specific genetic manipulation with in vivo metabolic phenotyping (glucose tolerance, insulin secretion).
- Mechanistic linkage via RNase-mediated mRNA decay of THBS1 demonstrated in relevant endothelial context.
Limitations
- Preclinical mouse study; translatability to humans remains to be established.
- Experiments focused on male mice; potential sex differences were not addressed.
Future Directions: Test pharmacologic modulation of IRE1α–THBS1 signaling in vivo, assess sex-specific effects, and evaluate relevance in human islet endothelium and obesity-related diabetes.
Vascular endothelial cells (ECs) play pivotal roles in maintaining metabolic tissue homeostasis, and EC dysfunction is associated with obesity and metabolic disorders. The mammalian ER stress sensor IRE1α kinase/RNase responds to metabolic cues, but it remains unclear whether endothelial IRE1α is implicated in controlling systemic metabolism. Here we show that genetic depletion of IRE1α in ECs leads to maladaptation of pancreatic islets under obesity-associated metabolic stress. We find that in high-fat diet-fed male mice, loss of IRE1α in ECs has no significant impact upon adiposity, but unexpectedly results in glucose intolerance with impaired insulin secretion, accompanied by blunted intra-islet angiogenesis and compensatory islet growth. Mechanistically, IRE1α RNase decays the mRNA encoding the endogenous anti-angiogenic factor thrombospondin-1 (THBS1/TSP1) in islet ECs. These findings thus uncover a critical role of the endothelial IRE1α suppression of THBS1 in governing the vascular support that enables the functional adaptation of islets to metabolic stress.
2. Autocrine Netrin-1 Signaling in Hepatic Stellate Cells Drives Liver Fibrosis and Diet-Induced Metabolic Dysfunction-Associated Steatohepatitis in Mice.
Netrin-1 functions as an autocrine activator of hepatic stellate cells: overexpression worsened fibrosis, HSC-specific deletion mitigated diet- and toxin-induced fibrosis, and LNP-delivered siRNA therapeutically reduced fibrotic burden. Signaling proceeds via UNC5B and rapid intracellular calcium.
Impact: Identifies a tractable, cell-autonomous fibrogenic driver with convergent genetic and RNAi evidence, opening a therapeutic avenue for MASH where anti-fibrotic options are limited.
Clinical Implications: Therapeutically targeting Netrin-1 (e.g., siRNA or receptor antagonism) may attenuate fibrosis progression in MASH, supporting development of anti-fibrotic interventions alongside metabolic therapies.
Key Findings
- Hepatic Netrin-1 expression is elevated in MASH and across multiple liver fibrosis models.
- AAV-mediated Netrin-1 overexpression exacerbates fibrosis, while HSC-specific Netrin-1 ablation attenuates diet-induced MASH and CCl4 fibrosis.
- Lipid nanoparticle-delivered siRNA against Netrin-1 ameliorates liver fibrosis; signaling involves UNC5B and rapid intracellular Ca2+.
Methodological Strengths
- Convergent evidence from gain- and loss-of-function models (AAV overexpression, HSC-specific knockout).
- Therapeutic validation using lipid nanoparticle-mediated siRNA in vivo.
Limitations
- Preclinical mouse models; human safety/efficacy of Netrin-1 targeting remains unknown.
- Mechanistic pathway beyond initial UNC5B–Ca2+ events requires deeper delineation.
Future Directions: Evaluate long-term efficacy and safety of Netrin-1 inhibition, define downstream signaling networks, and validate target engagement and biomarkers in human MASH.
Liver fibrosis is a central feature of progressive liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH). The profibrotic liver microenvironment drives hepatic stellate cell (HSC) activation and collagen deposition. However, the nature of HSC-mediated autocrine signaling during the fibrotic response has not been completely characterized. Here, we identify Netrin-1 as an autocrine factor that drives HSC activation and liver fibrosis in patients with MASH. Hepatic Netrin-1 expression was consistently elevated across multiple experimental models of liver fibrosis. Functional studies showed that adenovirus-associated virus (AAV)-mediated hepatic Netrin-1 overexpression exacerbated fibrosis, whereas HSC-specific conditional ablation of Netrin-1 markedly attenuated diet-induced MASH and CCl4-induced liver fibrosis. Notably, lipid nanoparticle-mediated siRNA knockdown of Netrin-1 ameliorated liver fibrosis in mice. Mechanistic investigations revealed that Netrin-1 promotes HSC activation through autocrine signaling mediated by the UNC5B receptor, which triggers rapid intracellular Ca
3. Delayed puberty and early-onset type 2 diabetes risk: a nationwide cohort study of male adolescents in Israel.
Among 964,108 Israeli male adolescents, delayed puberty (n=4,307) was associated with higher early-adult type 2 diabetes incidence (2.6% vs 0.7%) and earlier diagnosis age, independent of BMI. This positions delayed puberty as an early-life marker for later dysglycemia risk.
Impact: The sheer scale and rigorous case ascertainment provide strong epidemiologic evidence that pubertal timing carries long-term metabolic consequences beyond adiposity.
Clinical Implications: Adolescents with delayed puberty warrant targeted metabolic screening and preventive lifestyle or pharmacologic strategies to mitigate future diabetes risk.
Key Findings
- In 964,108 male adolescents, delayed puberty was diagnosed in 4,307 and linked to higher early-adult type 2 diabetes incidence (2.6% vs 0.7%).
- Delayed puberty was associated with earlier age at diabetes diagnosis (35.5 vs 36.8 years) and increased risk independent of BMI.
- Diabetes case identification used registry-linked HbA1c/glucose criteria and medication purchase records with quality checks.
Methodological Strengths
- Nationwide cohort with over 15 million person-years of follow-up and registry linkage for outcomes.
- Specialist-diagnosed delayed puberty and validated case definitions for type 2 diabetes.
Limitations
- Male-only cohort from a single country; generalizability to females or other populations is uncertain.
- Retrospective observational design with potential residual confounding despite adjustments.
Future Directions: Extend analyses to females, dissect biological mediators linking delayed puberty to dysglycemia, and test targeted prevention strategies in at-risk youths.
BACKGROUND: Delayed puberty has been associated with adverse metabolic outcomes, yet longitudinal evidence on its relation to type 2 diabetes risk is scarce. We aimed to investigate the association between delayed puberty during adolescence and early-adult-onset type 2 diabetes in male adolescents. METHODS: This nationwide, population-based, retrospective cohort study included Israeli male adolescents aged 16-19 years who were examined before military recruitment during 1992-2015 and followed up until Dec 31, 2019. Exclusion criteria were diabetes at the baseline medical assessment, hypogonadotropic hypogonadism, missing height or weight data, and death before the establishment of the Israeli National Diabetes Registry (INDR) in 2012. Delayed puberty was diagnosed by board-certified paediatric endocrinologists, based on physical examinations and laboratory evaluations. By linking data to the INDR, diabetes was identified by: glycated haemoglobin concentrations of more than 6·5%, serum glucose concentrations of more than 200 mg/dL in two tests at least 1 month apart, or repeated purchases of glucose-lowering medications. Type 2 diabetes was classified according to medication records, which underwent quality assessment to ensure accuracy. Cox proportional hazards models were applied. FINDINGS: The study included 964 108 Israeli male adolescents (mean age at evaluation 17·3 years [SD 0·5]). Delayed puberty was diagnosed in 4307 males, whereas 959 801 did not have delayed puberty. During a cumulative follow-up of 15 242 068 person-years, type 2 diabetes was diagnosed in 111 (2·6%) individuals with delayed puberty (mean age at diagnosis 35·5 years [SD 5·2]) and 6259 (0·7%) individuals without delayed puberty (36·8 years [4·7]). The respective incidence rates of type 2 diabetes were 140·3 cases per 10 INTERPRETATION: Male adolescents with delayed puberty are at increased risk of developing type 2 diabetes in early adulthood, independent of BMI. Our findings suggest that delayed puberty is not a benign developmental variant, but might serve as an early marker of increased risk for later abnormal glucose metabolism. FUNDING: Sheba Medical Center.