Weekly Endocrinology Research Analysis
This week’s endocrinology literature emphasized mechanistic immunometabolism, targetable immune pathways for therapy-related autoimmune diabetes, and metabolic resilience mechanisms relevant to obesity therapeutics. High-impact translational work identified T follicular helper cell–driven checkpoint-inhibitor diabetes that is preventable with JAK inhibition, and adipose-resident immune circuits (IFNα–IFNAR–CD8+ T cells) that sustain obesity-linked inflammation. Complementary metabolic studies re
Summary
This week’s endocrinology literature emphasized mechanistic immunometabolism, targetable immune pathways for therapy-related autoimmune diabetes, and metabolic resilience mechanisms relevant to obesity therapeutics. High-impact translational work identified T follicular helper cell–driven checkpoint-inhibitor diabetes that is preventable with JAK inhibition, and adipose-resident immune circuits (IFNα–IFNAR–CD8+ T cells) that sustain obesity-linked inflammation. Complementary metabolic studies revealed a concrete β‑cell mediator of imeglimin (adenylosuccinate) and reinforced the clinical value of simple prognostic tools (TyG‑BMI, MASLD‑HCC) and technology-enabled care (CGM/isCGM) for risk stratification and complication reduction.
Selected Articles
1. Polyfunctional T follicular helper cells drive checkpoint-inhibitor diabetes and are targeted by JAK inhibitor therapy.
This translational study identifies expansion of IL‑21/IFN‑γ–producing T follicular helper (Tfh) cells as a mechanistic hallmark of checkpoint inhibitor–induced autoimmune diabetes (ICI‑T1DM). Both cytokines were required for disease in models, and JAK inhibitor treatment prevented ICI‑T1DM in vivo and impaired Tfh differentiation in patient samples.
Impact: Uncovers a targetable immune mechanism for a severe, therapy‑related autoimmune complication and provides preclinical evidence supporting JAK inhibition as a preventive strategy.
Clinical Implications: Supports prioritizing clinical trials of JAK inhibitor prophylaxis or early intervention in high‑risk ICI recipients and suggests monitoring Tfh/IL‑21/IFN‑γ signatures as potential biomarkers to stratify risk.
Key Findings
- Expansion of IL‑21 and IFN‑γ–producing CD4+ Tfh cells characterizes ICI‑T1DM.
- Both IL‑21 and IFN‑γ are necessary for autoimmune β‑cell attack in preclinical models.
- JAK inhibition prevents ICI‑T1DM in mice and impairs Tfh differentiation in patient samples.
2. Adipose tissue harbors pathogenic T cells in obesity that exacerbate inflammatory arthritis.
Using antigen‑induced arthritis models and VAT transplantation, this study shows that obesity drives homing and expansion of pathogenic CD8+ T cells in visceral adipose tissue via IFNα signaling. These adipose‑resident T cells worsen arthritis; genetic ablation of Ifnar1 in T cells attenuated VAT CD8 expansion and disease severity, linking adipose immune niches to systemic autoimmunity.
Impact: Provides mechanistic evidence that adipose tissue is an active immunologic niche driving obesity‑related exacerbation of autoimmune disease and identifies the IFNα/IFNAR axis as a candidate therapeutic target.
Clinical Implications: Suggests novel therapeutic strategies for obesity‑associated autoimmunity (target IFNα/IFNAR or adipose CD8+ populations) and provides mechanistic support for prioritizing weight loss plus targeted immunomodulation in obese patients with inflammatory arthritis.
Key Findings
- Obesity promotes homing/expansion of antigen‑specific CD8+ T cells in visceral adipose tissue.
- VAT from arthritic mice transfers disease severity to recipients; CD8 depletion mitigates this effect.
- IFNα (via IFNAR) drives VAT CD8 expansion; T cell–specific Ifnar1 deletion reduces arthritis severity.
3. Adenylosuccinate Mediates Imeglimin-Induced Proliferative and Antiapoptotic Effects in β-Cells.
This mechanistic study demonstrates that imeglimin increases adenylosuccinate (S‑AMP) and aspartate in β‑cells, and that inhibition of adenylosuccinate synthase (ADSS) blunts imeglimin’s proliferative and anti‑apoptotic effects across mouse, human, porcine islets and hPSC‑derived β‑cells, positioning S‑AMP/ADSS as a mediator and potential translational biomarker/target for β‑cell preservation.
Impact: Identifies a concrete metabolic mediator (S‑AMP) linking imeglimin to β‑cell survival and proliferation with cross‑species validation, informing biomarker development and combination strategies to preserve β‑cell mass.
Clinical Implications: Although preclinical, the S‑AMP/ADSS axis suggests avenues for developing biomarkers to monitor β‑cell response to imeglimin and for combination therapies that potentiate β‑cell preservation in T2D or islet transplantation settings.
Key Findings
- Imeglimin increases adenylosuccinate (S‑AMP) and aspartate content in β‑cells/islets.
- Pharmacologic ADSS inhibition attenuates imeglimin‑induced β‑cell proliferation and antiapoptotic effects.
- Effects were consistent across mouse, human, porcine islets and hPSC‑derived β‑cells, indicating broad biological relevance.