Daily Endocrinology Research Analysis
Three papers stand out today in endocrinology and metabolism: a phase 3 Lancet trial shows robust weight loss with once-daily oral GLP-1 receptor agonist orforglipron in adults with type 2 diabetes; a Nature Communications study challenges the prevailing paradigm by demonstrating that fructose (and follistatin) can acutely drive MASLD even with complete hepatic insulin resistance; and a PNAS mechanistic study identifies Neuroplastin-55 as a receptor for MANF that promotes adipose browning and pr
Summary
Three papers stand out today in endocrinology and metabolism: a phase 3 Lancet trial shows robust weight loss with once-daily oral GLP-1 receptor agonist orforglipron in adults with type 2 diabetes; a Nature Communications study challenges the prevailing paradigm by demonstrating that fructose (and follistatin) can acutely drive MASLD even with complete hepatic insulin resistance; and a PNAS mechanistic study identifies Neuroplastin-55 as a receptor for MANF that promotes adipose browning and protects against diet-induced obesity.
Research Themes
- Oral incretin pharmacotherapy for obesity in type 2 diabetes
- Fructose-driven pathogenesis of MASLD independent of insulin signaling
- Adipose browning via receptor-ligand biology (Np55–MANF axis)
Selected Articles
1. Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial.
In a 72-week, multicenter, double-blind phase 3 trial (n=1613), once-daily oral orforglipron (6–36 mg) produced statistically superior bodyweight reduction versus placebo as an adjunct to lifestyle modification in adults with type 2 diabetes and overweight/obesity. Completion was high (89.5%), and adverse events were consistent with the GLP-1RA class profile.
Impact: This is the first large, late-phase RCT to demonstrate robust weight loss with a non-peptide, once-daily oral GLP-1RA in type 2 diabetes, addressing adherence and access barriers to injectable incretins.
Clinical Implications: Orforglipron could expand incretin-based obesity management for type 2 diabetes to an oral option, potentially improving adherence and facilitating earlier combination strategies; safety monitoring should follow class-consistent GI AEs.
Key Findings
- Adults with T2D and BMI ≥27 kg/m2 randomized to orforglipron (6, 12, or 36 mg) had statistically greater bodyweight reduction versus placebo at 72 weeks.
- High study completion (89.5%) across 136 sites in 10 countries supports feasibility and tolerability.
- Adverse events were consistent with GLP-1RA class effects, with no unexpected safety signals reported.
Methodological Strengths
- Phase 3, double-blind, randomized, multicenter design with large sample size (n=1613)
- Dose-ranging evaluation with lifestyle counseling standardization
Limitations
- Industry-sponsored trial; detailed glycemic and cardiometabolic secondary outcomes not fully described in abstract
- Generalizability may vary across populations and comorbidities; long-term cardiovascular outcomes not reported
Future Directions: Head-to-head comparisons with injectable GLP-1RAs, durability beyond 72 weeks, cardiometabolic outcomes, and combination with SGLT2 inhibitors or tirzepatide-like agents.
2. Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance.
Using a genetic mouse model lacking hepatic insulin signaling (LDKO), the authors show that fructose-enriched diets rapidly induce MASLD despite complete hepatic insulin resistance. Mechanistically, fructose enhanced hepatic re-esterification of circulating fatty acids, overturning the assumption that insulin-driven de novo lipogenesis is required for steatosis initiation.
Impact: This study challenges a core paradigm in MASLD pathogenesis and provides a mechanistic basis linking dietary fructose and hepatic steatosis independent of insulin signaling.
Clinical Implications: Supports prioritizing fructose restriction in MASLD prevention and management, even in insulin-resistant states; suggests new therapeutic targets (e.g., pathways governing hepatic re-esterification and follistatin signaling).
Key Findings
- LDKO mice with complete hepatic insulin resistance acutely developed MASLD on fructose-enriched diets (GAN or high-fructose).
- Fructose potentiated hepatic re-esterification of circulating fatty acids in LDKO mice, mechanistically driving steatosis.
- Findings overturn the assumption that insulin-stimulated de novo lipogenesis is essential for MASLD initiation.
Methodological Strengths
- Use of a genetic model (LDKO) ensuring complete loss of hepatic insulin signaling
- Dietary interventions (GAN, high-fructose) enabling causal inference on fructose effects
Limitations
- Preclinical mouse study; human translation and dose–response to dietary fructose require validation
- Abstract does not detail chronic outcomes or fibrosis progression
Future Directions: Human metabolic studies testing fructose restriction in insulin-resistant MASLD; investigation of follistatin and re-esterification enzymes as therapeutic targets; long-term outcomes.
3. Neuroplastin-55 is a receptor of Manf and protects against diet-induced obesity by promoting adipose browning.
The study identifies Neuroplastin-55 (Np55) as a receptor for MANF in adipose tissue. Np55 is upregulated in obese human and mouse adipose tissue, and adipocyte-specific Np55 loss impairs WAT browning/thermogenesis and protection against diet-induced obesity, positioning the MANF–Np55 axis as a therapeutic target.
Impact: Receptor identification for a browning factor (MANF) provides a concrete target to pharmacologically enhance adipose thermogenesis, with translational relevance for obesity.
Clinical Implications: Therapeutics that agonize MANF–Np55 signaling could promote adipose browning and energy expenditure; biomarker-driven stratification using Np55 expression may be explored.
Key Findings
- Np55 expression is markedly upregulated in adipose tissue from obese humans and mice.
- Adipocyte-specific Np55 knockout impairs WAT browning/thermogenesis and protection against diet-induced obesity.
- Np55 functions as a receptor for MANF, defining a ligand–receptor axis that regulates adipose browning.
Methodological Strengths
- Cross-species validation (human and mouse adipose) with adipocyte-specific knockout
- Receptor–ligand mechanistic elucidation supporting causality
Limitations
- Preclinical; absence of pharmacologic agonists/antagonists tested in vivo in the abstract
- Translational dose–response and safety in humans remain unknown
Future Directions: Develop small molecules or biologics targeting MANF–Np55; assess metabolic efficacy and safety in large animals and early-phase clinical trials; explore Np55 expression as a patient-selection biomarker.