Weekly Endocrinology Research Analysis
This week’s endocrinology literature features high-impact advances across therapeutics, translational immunometabolism, and cross-ancestry metabolomics. A multicenter randomized trial shows automated insulin delivery (AID) meaningfully improves glycemic control and time-in-range in insulin-treated type 2 diabetes. Translational Hepatology work identifies neutrophil proteases (NE, PR3) under miR‑223/STAT3 control as druggable drivers of MASH fibrosis, while cross-ancestry metabolomics GWAS with M
Summary
This week’s endocrinology literature features high-impact advances across therapeutics, translational immunometabolism, and cross-ancestry metabolomics. A multicenter randomized trial shows automated insulin delivery (AID) meaningfully improves glycemic control and time-in-range in insulin-treated type 2 diabetes. Translational Hepatology work identifies neutrophil proteases (NE, PR3) under miR‑223/STAT3 control as druggable drivers of MASH fibrosis, while cross-ancestry metabolomics GWAS with MR links HDL-triglycerides and glycine to coronary and heart‑failure risk, respectively, enabling biomarker and pathway prioritization.
Selected Articles
1. A Randomized Trial of Automated Insulin Delivery in Type 2 Diabetes.
In a 13‑week multicenter randomized trial (n=319), automated insulin delivery (AID) reduced HbA1c by 0.9% vs 0.3% in control (adjusted difference −0.6%; P<0.001) and increased CGM time‑in‑range by 14 percentage points, with low rates of hypoglycemia. AID improved multiple hyperglycemia metrics compared with continuation of prior insulin delivery.
Impact: Provides high‑level RCT evidence that closed‑loop AID benefits insulin‑treated T2D — a population historically underrepresented in closed‑loop trials — potentially shifting standards for intensification and device access.
Clinical Implications: Clinicians should consider AID for insulin‑treated T2D patients needing intensification to improve HbA1c and time‑in‑range while maintaining low hypoglycemia risk; evaluate access, training, and cost‑effectiveness for implementation.
Key Findings
- AID reduced HbA1c by 0.9% vs 0.3% in control; adjusted difference −0.6% (95% CI −0.8 to −0.4; P<0.001).
- Time‑in‑range (70–180 mg/dL) increased from 48% to 64% with AID vs 51% to 52% with control (mean difference 14 percentage points; P<0.001).
- CGM hyperglycemia metrics favored AID; hypoglycemia frequency was low in both groups (one severe event in AID).
2. Cross-ancestry analyses of Chinese and European populations reveal insights into the genetic architecture and disease implication of metabolites.
Large GWAS of 171 NMR‑measured metabolites in 10,792 Han Chinese (replication n=4,480) plus meta‑analysis with 213,397 Europeans identified hundreds of variant–metabolite associations and improved fine‑mapping. Mendelian randomization linked HDL‑triglycerides to higher coronary artery disease risk and glycine to lower heart failure risk across ancestries.
Impact: Provides cross‑ancestry genetic architecture and MR evidence that prioritize metabolite pathways (HDL‑TG, glycine) with causal links to major cardiovascular outcomes, informing target discovery and biomarker development.
Clinical Implications: Enables metabolite‑informed risk prediction and prioritizes pathways for therapeutic development; cross‑ancestry findings improve generalizability of metabolite biomarkers for cardiovascular risk stratification.
Key Findings
- Discovery GWAS in 10,792 Han Chinese found 15 variant–metabolite associations (8 replicated); cross‑ancestry meta‑analysis with 213,397 Europeans added 228 associations.
- Fine‑mapping improved through large meta‑analysis, enabling prioritization of loci.
- Mendelian randomization implicated HDL‑triglycerides in increased CAD risk and glycine in reduced heart failure risk across ancestries.
3. Neutrophil serine proteases NE and PR3 controlled by the miR-223/STAT3 axis potentiate MASH and liver fibrosis.
Human MASH livers show marked increases in neutrophil proteases NE and PR3 correlated with histologic severity. Genetic deletion or AAV‑mediated inhibition of NE/PR3 reduced steatohepatitis and fibrosis in mice. Mechanistically, miR‑223 suppresses NE/PR3 via STAT3 and bone‑marrow miR‑223 chimerism regulates hepatic NE/PR3 and fibrosis progression.
Impact: Identifies neutrophil proteases NE and PR3 as causal, druggable immunometabolic drivers of MASH fibrosis with convergent human and mouse evidence and mechanistic placement in the miR‑223/STAT3 axis.
Clinical Implications: Supports development of NE/PR3 inhibitors or miR‑223–modulating strategies as candidate anti‑fibrotic therapies in MASH, and suggests NE/PR3 may serve as biomarkers for disease activity and response.
Key Findings
- NE and PR3 are markedly increased in human MASH/fibrotic livers and correlate with histologic severity.
- Genetic ablation or AAV‑mediated inhibition of NE/PR3 reduced steatohepatitis and fibrosis in murine models.
- miR‑223 suppresses NE/PR3 via STAT3; miR‑223 deficiency increases inflammation and fibrosis; bone marrow chimerism modulates hepatic NE/PR3 content.