Weekly Endocrinology Research Analysis
This week’s endocrinology literature emphasized translational advances spanning practice-changing clinical trials and mechanistic discoveries with therapeutic potential. A multicenter double-blind RCT shows dapagliflozin added to calorie restriction substantially increases 12‑month remission of type 2 diabetes. Mechanistic studies identify targetable liver and hepatic‑metabolic axes (a liver→brain vagal sensory pathway and a USP25→PPARα deubiquitination axis) that modulate steatosis and metaboli
Summary
This week’s endocrinology literature emphasized translational advances spanning practice-changing clinical trials and mechanistic discoveries with therapeutic potential. A multicenter double-blind RCT shows dapagliflozin added to calorie restriction substantially increases 12‑month remission of type 2 diabetes. Mechanistic studies identify targetable liver and hepatic‑metabolic axes (a liver→brain vagal sensory pathway and a USP25→PPARα deubiquitination axis) that modulate steatosis and metabolic disease. Large syntheses and cohorts reinforced implementation-ready diagnostics and treatment strategies for obesity, MASLD, and survivorship screening.
Selected Articles
1. Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial.
In a multicenter, double‑blind RCT (n=328) of overweight/obese people with early type 2 diabetes, dapagliflozin 10 mg daily plus structured calorie restriction produced a 44% remission rate at 12 months versus 28% with calorie restriction plus placebo (RR 1.56). The dapagliflozin arm also achieved greater reductions in weight, HOMA‑IR, body fat, systolic blood pressure and other metabolic risk factors without an increase in adverse events.
Impact: A high‑quality randomized trial demonstrating a practical pharmacologic augmentation (SGLT2 inhibitor) of dietary remission strategies advances remission‑oriented care and provides actionable guidance for clinicians aiming for disease modification rather than glucose control alone.
Clinical Implications: Consider SGLT2 inhibitor (dapagliflozin) added to structured calorie restriction for overweight/obese patients with early T2D who are candidates for remission protocols, with individualized monitoring for renal function and volume status.
Key Findings
- Diabetes remission at 12 months: 44% (dapagliflozin + diet) vs 28% (placebo + diet); RR 1.56.
- Greater reductions in body weight (−1.3 kg difference) and HOMA‑IR in the dapagliflozin group.
- No significant difference in overall adverse events between groups during 12 months.
2. Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice.
In mice, selective ablation of a small population of liver‑projecting vagal sensory neurons increased energy expenditure, prevented diet‑induced obesity, attenuated hepatic steatosis, and reduced anxiety‑like behavior. Glucose homeostasis improved in both sexes (male‑specific increase in insulin sensitivity), indicating a causal liver→brain neural pathway linking metabolic and behavioral phenotypes.
Impact: Identifies a discrete, tractable neural afferent pathway causally linking liver metabolic state to systemic energy balance and behavior, opening neuromodulation and peripheral afferent modulation as novel therapeutic strategies for MASLD and obesity‑related neuropsychiatric comorbidity.
Clinical Implications: Although preclinical, the data motivate translational work on neuromodulatory therapies (targeted afferent modulation, neuromodulation devices) and biomarker studies to assess liver→brain signaling in human obesity and MAFLD with behavioral comorbidity.
Key Findings
- Ablation of liver‑projecting vagal sensory neurons prevented diet‑induced obesity by increasing energy expenditure.
- Loss of these neurons limited hepatic steatosis and improved glucose homeostasis; males showed increased insulin sensitivity.
- Neuronal loss reduced anxiety‑like behavior, implicating the liver–brain axis in metabolic and behavioral regulation.
3. USP25 directly interacts with and deubiquitinates PPARα to increase PPARα stability in hepatocytes and attenuate high-fat diet-induced MASLD in mice.
This mechanistic study shows hepatic USP25 expression is reduced in MASLD and that USP25 directly deubiquitinates PPARα (removing K48 ubiquitin at Lys429 via His608), stabilizing PPARα, enhancing fatty acid handling, and protecting against HFD‑induced steatosis. Genetic USP25 loss worsened steatosis while hepatocyte‑specific induction rescued it in mice; protection was PPARα‑dependent.
Impact: Uncovers a druggable deubiquitinase–nuclear receptor axis (USP25→PPARα) with clear biochemical mapping and in vivo rescue data, offering a novel therapeutic direction for MASLD beyond classical metabolic interventions.
Clinical Implications: Preclinical evidence supports development of USP25 modulators or strategies to enhance PPARα stability in MASLD; hepatic USP25 expression could evolve as a stratification biomarker for targeted approaches.
Key Findings
- Hepatic USP25 expression is reduced in human and mouse MASLD.
- USP25 directly binds PPARα and removes K48 ubiquitin at Lys429 (His608‑dependent), stabilizing PPARα.
- Usp25 deficiency worsens HFD‑induced steatosis; hepatocyte USP25 induction protects, and protection is lost in Ppara‑deficient mice.