Weekly Endocrinology Research Analysis
This week’s endocrinology literature emphasized translational mechanistic discoveries and high-impact therapeutic/diagnostic advances. Top findings include a microbiota-derived peptide (corisin) as a targetable driver of diabetic kidney fibrosis, branched-chain amino acid–PKM2 pathways linking amino acid dysmetabolism to podocyte failure in DKD, and human GCGR loss-of-function variants mechanistically tied to early hepatic steatosis. Complementary clinical and imaging advances—inclisiran improvi
Summary
This week’s endocrinology literature emphasized translational mechanistic discoveries and high-impact therapeutic/diagnostic advances. Top findings include a microbiota-derived peptide (corisin) as a targetable driver of diabetic kidney fibrosis, branched-chain amino acid–PKM2 pathways linking amino acid dysmetabolism to podocyte failure in DKD, and human GCGR loss-of-function variants mechanistically tied to early hepatic steatosis. Complementary clinical and imaging advances—inclisiran improving LDL-C goal attainment and dual-modal photoacoustic+ultrasound reducing unnecessary thyroid biopsies—signal rapidly actionable changes in practice and target development.
Selected Articles
1. Microbiota-derived corisin accelerates kidney fibrosis by promoting cellular aging.
Translational human–mouse work identifies corisin, a microbiota-derived peptide, as elevated in diabetic CKD and mechanistically driving inflammation, cellular senescence, EMT and apoptosis in kidney cells; anti-corisin monoclonal antibody reduced nephropathy severity in diabetic mice and corisin–albumin binding may enhance renal accumulation.
Impact: Provides a novel, targetable microbiome-derived mediator of diabetic kidney fibrosis with therapeutic proof-of-concept (monoclonal antibody) and mechanistic plausibility linking microbial peptide pharmacokinetics to renal pathology.
Clinical Implications: Corisin merits rapid validation as a prognostic biomarker in prospective diabetic CKD cohorts and prioritized early-phase development of anti-corisin biologics, with close safety and PK assessment given albumin binding and renal accumulation concerns.
Key Findings
- Serum corisin is markedly elevated in diabetic CKD and correlates with disease stage and renal decline.
- Monoclonal anti-corisin antibody significantly attenuates nephropathy severity and fibrosis in diabetic mice.
- Corisin binds human serum albumin and promotes cellular senescence, EMT, and apoptosis in kidney cells.
2. Branched-chain amino acids contribute to diabetic kidney disease progression via PKM2-mediated podocyte metabolic reprogramming and apoptosis.
This cross-species mechanistic study shows podocyte-specific defects in BCAA catabolism in human DKD and mouse models; BCAA excess or podocyte PP2Cm knockout induces PKM2 depolymerization, shifts metabolism away from OXPHOS to serine/folate pathways, activates DDIT3–Chac1/Trib3 pro-apoptotic signaling, and produces DKD phenotypes—nominating BCAA catabolism and PKM2 activation as intervention targets.
Impact: Mechanistically links amino-acid dysmetabolism to podocyte failure and DKD initiation, revealing actionable molecular nodes (PKM2, PP2Cm) with direct implications for dietary guidance and drug discovery.
Clinical Implications: Suggests caution with high-dose BCAA supplementation in diabetes and prioritizes development of PKM2 activators or strategies restoring BCAA catabolism to prevent or slow DKD progression.
Key Findings
- Podocytes from human DKD and db/db mice show specific defects in BCAA catabolism.
- Podocyte PP2Cm knockout or exogenous BCAA supplementation induces DKD phenotypes (dysfunction, apoptosis, proteinuria) in mice.
- BCAAs promote PKM2 depolymerization, shift glucose metabolism to serine/folate pathways, and engage DDIT3-driven apoptotic transcriptional programs.
3. Glucagon Receptor Deficiency Causes Early-Onset Hepatic Steatosis.
A family-based genetic and mechanistic study identified homozygous GCGR missense variants that abolish receptor function, associate with hyperglucagonemia, aminoacidemia, adiposity and early hepatic steatosis/cirrhosis, and when introduced into human iPSC-hepatocytes increase lipid accumulation—providing human genetic evidence that impaired glucagon signaling drives steatosis and informing GCGR-targeted therapy risk–benefit.
Impact: Provides rare human genetic and functional confirmation that impaired GCGR signaling causally contributes to hepatic steatosis—directly relevant to safety and therapeutic design of GCGR antagonists and agonists in development.
Clinical Implications: Clinicians and drug developers should monitor liver fat in patients receiving GCGR antagonists; GCGR agonists may improve steatosis in obesity—genetic screening and careful hepatic monitoring are warranted in trials.
Key Findings
- Two rare homozygous GCGR missense variants cosegregated with early-onset hepatic steatosis/cirrhosis in a consanguineous family.
- Double GCGR mutations caused marked loss-of-function with elevated circulating glucagon and amino acids and increased adiposity.
- CRISPR/Cas9 introduction of the variants into human iPSC-hepatocytes increased lipid accumulation, mechanistically linking GCGR loss to steatosis.