Daily Endocrinology Research Analysis
Analyzed 106 papers and selected 3 impactful papers.
Summary
Analyzed 106 papers and selected 3 impactful articles.
Selected Articles
1. Self-regulating hydrogel for diabetic wound healing: From animal models to a pilot clinical study.
A glucose/oxidative-stress-responsive hydrogel sequentially released therapeutic ions to control infection and promote regeneration, improving angiogenesis, collagen deposition, and wound closure in diabetic mice. Single-cell RNA-seq implicated NF-κB modulation in fibroblasts. In a pilot clinical study, topical application reduced wound area by 94.57% in 4 weeks without adverse events.
Impact: This work delivers a mechanistically rational, self-regulating biomaterial with strong translational promise, bridging robust animal efficacy with a pilot human signal in a high-burden diabetic complication.
Clinical Implications: If validated in controlled trials, this hydrogel could offer a topical, low-toxicity option that simultaneously addresses infection control and tissue regeneration in chronic diabetic wounds, potentially reducing amputations.
Key Findings
- The GPP@ZnBG hydrogel releases Zn2+ early under alkaline conditions for antibacterial activity and later degrades to release Zn2+/Ca2+/silicate ions to promote angiogenesis and repair.
- In diabetic mice, the hydrogel enhanced neovascularization, collagen deposition, and wound closure.
- Single-cell RNA-seq showed hydrogel-mediated fine-tuning of fibroblast NF-κB signaling, and a pilot clinical study achieved a 94.57% wound-area reduction in 4 weeks without adverse events.
Methodological Strengths
- Mechanistic dissection using single-cell RNA sequencing to map immune/stromal responses
- Translational pipeline spanning responsive material design, rigorous murine efficacy, and pilot human feasibility
Limitations
- Pilot clinical study lacked a control arm and reported short-term outcomes (4 weeks)
- Manufacturing scale-up, long-term safety, and comparative effectiveness remain untested
Future Directions: Conduct randomized controlled trials to evaluate efficacy, durability, and safety; optimize dosing/regimen; and assess cost-effectiveness and integration with standard wound care.
Chronic diabetic wounds affect millions and often fail to heal due to infection, inflammation, and poor angiogenesis, leading to high rates of amputation. Current treatments offer limited control over the wound microenvironment. Here, this work develops GPP@ZnBG hydrogels that can respond to elevated glucose and oxidative stress in diabetic wounds to release therapeutic ions in a self-pH-regulated and sequential manner. At an early stage, this hydrogel initiates a release of zinc ions under alkaline conditions, providing antibacterial activity while avoiding toxicity from excessive dosing. During the late stage, the hydrogel degrades, and it steadily releases zinc, calcium, and silicate ions that support angiogenesis, reduce inflammation, and promote tissue repair. In diabetic mice, GPP@ZnBG hydrogels improve neovascularization and enhance collagen deposition, leading to enhanced wound closure. Single-cell RNA sequencing results indicate that the hydrogel modulates fibroblast behavior, specifically fine-tuning NF-κB signaling to reduce detrimental inflammation and promote wound repair. A pilot clinical study demonstrates that topical GPP@ZnBG application showed a 94.57% relative reduction in a wound surface area within 4 weeks, with no adverse events reported. These findings establish a self-pH-driven ion delivery strategy that targets both infection and tissue regeneration, offering a promising therapeutic platform for chronic diabetic wound care.
2. The inhibition of megalin-mediated transcytosis of thyroglobulin as a mechanism for insulin resistance-induced hypothyroidism in male rats.
Insulin resistance suppresses megalin expression and thyroglobulin transcytosis via PI3K signaling, reducing T3 release and producing hypothyroid features. Megalin overexpression or metformin reversed these effects, and megalin knockdown abrogated metformin’s benefit, positioning megalin as a mechanistic link and potential therapeutic target.
Impact: This study provides a first mechanistic link between insulin resistance and hypothyroidism via megalin-dependent thyroglobulin handling, with direct therapeutic implications through metformin-mediated megalin upregulation.
Clinical Implications: The megalin pathway may underlie thyroid dysfunction in insulin-resistant states, suggesting that metformin’s thyroidal benefits and future megalin-targeted therapies could mitigate endocrine comorbidities in diabetes.
Key Findings
- High-fat diet-induced insulin resistance reduced Tg, TPO, and megalin expression in rat thyroid and produced hypothyroid serum markers.
- Hyperinsulinemic FRTL-5 cells recapitulated declines in Tg/TPO/megalin; PI3K signaling mediated suppression of megalin expression and transcytosis, lowering T3 release.
- CRISPR/Cas9 megalin overexpression rescued T3 release; metformin upregulated megalin in vivo, and megalin siRNA abolished metformin’s therapeutic effects.
Methodological Strengths
- Integrated in vivo (diet-induced insulin resistance), in vitro (FRTL-5), genetic (CRISPR/Cas9), and pharmacologic (metformin, siRNA) approaches
- Clear pathway specificity demonstrated by rescue and blockade experiments
Limitations
- Male rat model and rodent thyroid cell line may limit generalizability to humans and females
- Clinical validation of megalin modulation and thyroid outcomes in humans is lacking
Future Directions: Validate megalin–thyroglobulin transcytosis defects in human thyroid tissue and clinical cohorts; test metformin/megalin-targeted strategies on thyroid endpoints in insulin-resistant patients.
To evaluate the impact of insulin resistance on thyroid function and explore megalin-targeting strategies to mitigate hypothyroidism in diabetes. Using a high-fat diet-induced insulin resistance model in male Sprague-Dawley rats, we observed structural thyroid abnormalities and reduced expression of thyroglobulin (Tg), thyroid peroxidase (TPO), and megalin, alongside hypothyroid serum markers. To validate these findings in vitro, hyperinsulinemic FRTL-5 cells exhibited parallel declines in Tg, TPO, and megalin expression. Additionally, the effects of metformin treatment and megalin blockade via siRNA were explored. Mechanistically, insulin resistance inhibited both megalin expression and transcytosis via phosphatidylinositol-3-kinase (PI3K) pathway, thereby reducing triiodothyronine (T3) release. CRISPR/Cas9-mediated megalin overexpression reversed this inhibition, confirming its essential role in T3 regulation. Building on these mechanistic insights, we explored therapeutic interventions. Megalin overexpression rescued T3 release, while metformin upregulated megalin expression in vivo. Crucially, siRNA-mediated megalin blockade abolished metformin's therapeutic effects, demonstrating pathway specificity. Our findings establish megalin inhibition as a critical pathway linking insulin resistance and hypothyroidism in diabetes, with metformin exerting therapeutic effects through megalin upregulation. This highlights megalin as a promising target for managing endocrine comorbidities.
3. Cytokine Dynamics Following Initiation of Gender-Affirming Hormone Therapy in Transgender Subjects.
Over ~6 months of GAHT, trans women receiving estrogen plus antiandrogen therapy showed significant decreases in 10 cytokines/chemokines, while trans men on testosterone exhibited increases in 8 factors; hs-CRP remained unchanged. These opposite shifts indicate sex-steroid-dependent immunomodulation with potential relevance to sex-related disparities in inflammatory diseases.
Impact: Prospective cytokine profiling with LC-MS/MS-steroid quantification demonstrates bidirectional, sex-steroid-dependent immune changes, informing mechanistic understanding and safety monitoring of GAHT.
Clinical Implications: Clinicians should recognize that GAHT can shift inflammatory mediators; while hs-CRP may remain stable, targeted biomarker monitoring could be considered for individuals with (auto)inflammatory comorbidities.
Key Findings
- In trans women after ~6 months of estrogen plus antiandrogen therapy, 10 cytokines/chemokines (e.g., CCL2, CXCL9–11, IL15, TNFSF10) decreased; IL7 increased.
- In trans men on testosterone, 8 factors (e.g., CCL2, CCL7, CCL11, CCL19, IL17C, MMP1, TNFSF10) increased.
- hs-CRP showed no clinically relevant change over time, supporting a specific sex-steroid-associated cytokine response rather than generalized inflammation.
Methodological Strengths
- Prospective pre–post design with cisgender controls
- LC-MS/MS for precise steroid quantification and multiplex cytokine profiling (Olink)
Limitations
- Modest sample size and 6-month follow-up limit power and long-term inference
- Observational design cannot attribute changes to individual GAHT components with certainty
Future Directions: Longer-term studies linking cytokine trajectories to clinical events (e.g., autoimmune flares) and mechanistic work dissecting cell-type-specific responses to sex steroids.
BACKGROUND: Sex is an important determinant for various immune system-related pathologies and sex steroids might possess immunomodulatory properties. OBJECTIVE: To study the effects of sex steroid exposure on the serum levels of immune-related biomarkers (irBMS), using a model of transgender individuals receiving gender-affirming hormone therapy (GAHT). MATERIAL AND METHODS: Serum samples were collected from hormone-naïve trans women (TW) (n=30) and trans men (TM) (n=30) who initiated GAHT at baseline and after ±6 months of treatment. Cisgender men (n=10) and cisgender women (n=10) were included as controls. High-sensitivity C-reactive protein (hs-CRP) was measured using immunoassay. Serum levels of several irBMs, including cytokines and chemokines were determined using a commercial multiplex assay (Olink®). Serum estradiol and testosterone were determined using liquid-chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: After ±6 months of GAHT in TW, serum levels of ten cytokines (CCL2, CCL7, CCL11, CCL13, CCL19, CXCL9, CXCL10, CXCL11, IL15 and TNFSF10) significantly decreased, whereas IL7 increased. In TM, eight factors significantly increased (CCL2, CCL7, CCL11, CCL13, CCL19, IL17C, MMP1 and TNFSF10). Other immune-related biomarkers were not significantly affected, and levels of hs-CRP did not show a clinically relevant change over time. CONCLUSION: Six months of estrogen with antiandrogen treatment resulted in decreased serum levels of several cytokines and chemokines in TW, whereas cytokine and chemokine levels often increased in TM upon treatment with testosterone. These distinct and generally opposite changes suggest a sex steroid-dependent impact, which could contribute to sex-related disparities in (auto)inflammatory diseases. However, additional research should explore potential clinical consequences, as well as the mechanisms involved.