Daily Endocrinology Research Analysis
Three impactful endocrinology studies span translational obesity therapeutics and diabetes technology. A first-in-class nitroalkene (SANA) activates creatine-dependent thermogenesis and showed favorable safety with early weight/glucose benefits in a phase 1 trial. An adipocyte-targeted FGF21 study extended lifespan and improved metabolism in diet-induced obesity, and an open-source tubeless hybrid automated insulin delivery system significantly increased time-in-range in adults with type 1 diabe
Summary
Three impactful endocrinology studies span translational obesity therapeutics and diabetes technology. A first-in-class nitroalkene (SANA) activates creatine-dependent thermogenesis and showed favorable safety with early weight/glucose benefits in a phase 1 trial. An adipocyte-targeted FGF21 study extended lifespan and improved metabolism in diet-induced obesity, and an open-source tubeless hybrid automated insulin delivery system significantly increased time-in-range in adults with type 1 diabetes.
Research Themes
- Creatine-dependent thermogenesis as an anti-obesity target
- Endocrine regulation of longevity via adipose FGF21 signaling
- Open-source automated insulin delivery improving glycemic control
Selected Articles
1. A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss.
SANA activated creatine-dependent thermogenesis, improved mitochondrial respiration, and reduced steatosis/insulin resistance in diet-induced obesity models. In a randomized, double-blind, placebo-controlled phase 1A/B (single ascending doses in lean; multiple doses for 15 days in overweight/obese), SANA showed good safety/tolerability and early benefits on body weight and glucose.
Impact: This is a first-in-class human translational readout for creatine-dependent thermogenesis, a new energy expenditure pathway for obesity treatment. Early clinical signals and a favorable safety profile position SANA as a potential complementary therapy to GLP-1 agents.
Clinical Implications: If efficacy is confirmed in phase 2/3, SANA could offer a non-UCP1, non-AMPK thermogenic mechanism for obesity and metabolic dysfunction, potentially combining with incretin therapies to enhance weight loss and glycemic control.
Key Findings
- SANA increased creatine-dependent energy expenditure and mitochondrial respiration in adipose tissue, effective at thermoneutrality and independent of UCP1 and AMPK.
- In diet-induced obesity models, SANA reduced hepatic steatosis and improved insulin resistance.
- Phase 1A/B randomized, double-blind, placebo-controlled trial showed good safety/tolerability and early improvements in body weight and glucose within 2 weeks of multiple dosing.
- Pharmacokinetics and safety supported dose escalation (single 200–800 mg; multiple 200–400 mg/day for 15 days).
Methodological Strengths
- Randomized, double-blind, placebo-controlled phase 1A/B design spanning single and multiple ascending doses.
- Strong translational bridge with mechanistic validation across preclinical models and human safety signals.
Limitations
- Early-phase trial with short treatment duration and limited sample size; efficacy endpoints exploratory.
- No long-term cardiometabolic outcomes or head-to-head data versus existing anti-obesity agents.
Future Directions: Proceed to phase 2 efficacy trials (weight, HbA1c, NAFLD endpoints), mechanistic biomarker validation (creatine phosphate cycling), and combination studies with GLP-1/GIP agonists.
2. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
Adult-onset adipocyte-specific FGF21 overexpression extended lifespan up to 3.3 years in high-fat-fed mice, with resistance to weight gain, improved insulin sensitivity, and reduced hepatic steatosis. Benefits included reductions in inflammatory immune cells and lipotoxic ceramides in visceral fat and occurred even without adiponectin, implicating adipose tissue as a key site of FGF21 action.
Impact: Provides rigorous mechanistic evidence that adipose FGF21 signaling can extend lifespan and improve metabolic health independent of growth suppression, refining FGF21’s therapeutic positioning.
Clinical Implications: Supports targeting adipose FGF21 pathways to treat obesity-related metabolic dysfunction and potentially promote healthy aging; informs biomarker selection (adipose inflammation, ceramides) and adiponectin-independent mechanisms.
Key Findings
- Adult-onset adipocyte-specific FGF21 overexpression extended lifespan up to 3.3 years under high-fat diet.
- Improved insulin sensitivity and reduced hepatic steatosis; resisted weight gain in diet-induced obesity.
- Lower inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits persisting without adiponectin.
- Suggests adipose tissue as a central site for FGF21’s metabolic and longevity effects.
Methodological Strengths
- Adult-onset, tissue-specific overexpression avoids developmental confounding and isolates adipose effects.
- Multi-dimensional phenotyping (lifespan, insulin sensitivity, steatosis, immune/ceramide profiling) strengthens mechanistic inference.
Limitations
- Preclinical mouse study; translational efficacy and safety in humans remain to be established.
- Specific overexpression models may not capture pharmacologic dosing dynamics.
Future Directions: Evaluate pharmacologic FGF21 or analogs targeting adipose tissue in clinical trials; dissect downstream adipose pathways (ceramide metabolism, immune modulation) as co-targets.
3. Efficacy and safety of a tubeless open-source hybrid automated insulin delivery use at home among adults with type 1 diabetes mellitus: Results from a 26-week, free-living, randomized crossover trial.
In a 26-week, open-label randomized crossover trial of 28 adults with T1D, the tubeless Android APS increased TIR from 60.4% (SAP) to 75.6% (p<0.01), with greater nocturnal improvements (80.9% vs 73.8%, p<0.01) and no increase in time below range or severe hypoglycemia.
Impact: Demonstrates clinically meaningful glycemic benefits of an open-source, tubeless hybrid AID in a setting without commercial AID access, supporting pragmatic pathways to broaden advanced diabetes technology.
Clinical Implications: Supports adoption of open-source hybrid AID with appropriate oversight and education where commercial systems are unavailable, to improve TIR without increasing hypoglycemia risk.
Key Findings
- TIR (70–180 mg/dL) improved to 75.6% with OS-AID vs 60.4% with SAP (p<0.01).
- Nocturnal TIR improved more than daytime (80.9% vs 73.8%, p<0.01).
- No increase in time below range; no severe hypoglycemia or serious adverse events reported.
- Adults were AID-naïve, enhancing generalizability to broader clinical settings lacking commercial AID.
Methodological Strengths
- Randomized crossover design reduces inter-individual variability.
- Free-living, home use over 26 weeks reflects real-world performance.
Limitations
- Open-label design and small sample size (n=28) limit blinding and precision.
- Single-country study; device/algorithm generalizability beyond AAPS requires evaluation.
Future Directions: Larger, multicenter trials comparing open-source and commercial AID systems with patient-reported outcomes and cost-effectiveness; evaluation in diverse healthcare settings.