Weekly Endocrinology Research Analysis
This week’s endocrinology literature highlights rapid translation of novel metabolic therapeutics, mechanistic advances in β‑cell and neuroendocrine biology, and large comparative/registry studies that shape clinical practice. First‑in‑class agents (SANA) and tissue‑targeted approaches (adipocyte FGF21) advance new anti‑obesity mechanisms, while BRD4–ATF5 epigenetic control of β‑cell identity suggests a target to prevent dedifferentiation. Large systematic reviews and real‑world cohorts (MEN1 me
Summary
This week’s endocrinology literature highlights rapid translation of novel metabolic therapeutics, mechanistic advances in β‑cell and neuroendocrine biology, and large comparative/registry studies that shape clinical practice. First‑in‑class agents (SANA) and tissue‑targeted approaches (adipocyte FGF21) advance new anti‑obesity mechanisms, while BRD4–ATF5 epigenetic control of β‑cell identity suggests a target to prevent dedifferentiation. Large systematic reviews and real‑world cohorts (MEN1 meta‑analysis, SGLT2 add‑on studies) refine surgical and pharmacologic decision making.
Selected Articles
1. A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss.
SANA, a nitroalkene salicylate derivative, activates creatine‑dependent thermogenesis, improves mitochondrial respiration, reduces hepatic steatosis and insulin resistance in preclinical models, and showed good safety with early weight and glucose signals in a randomized phase 1A/B study.
Impact: First human translational evidence for a novel, non‑UCP1/AMPK thermogenic pathway (creatine cycling) that could complement incretin therapy and broaden anti‑obesity pharmacology.
Clinical Implications: If phase 2/3 efficacy is confirmed, SANA could be integrated as a complementary therapy to incretins for weight reduction and metabolic improvements; monitoring of longer‑term cardiometabolic outcomes and safety will be essential.
Key Findings
- Activates creatine‑dependent thermogenesis and increases mitochondrial respiration in adipose tissue, independent of UCP1 and AMPK.
- Reduces hepatic steatosis and improves insulin resistance in diet‑induced obesity models.
- Phase 1A/B randomized, double‑blind, placebo‑controlled study showed favorable safety/tolerability and early signals of body weight and glucose improvement with short multiple dosing.
2. BRD4 Signaling Maintains the Differentiated State of β Cells.
Across multiple mouse models and human islet organoids, BRD4 expression sustains β‑cell differentiation and insulin synthesis; BRD4 loss leads to dedifferentiation and impaired insulin production, with ATF5 identified as a direct downstream target and a patient variant (p.R749C) perturbing BRD4 signaling.
Impact: Provides convergent mechanistic and human genetic evidence that an epigenetic regulator (BRD4–ATF5) preserves β‑cell identity, opening a new target class to prevent β‑cell failure in diabetes.
Clinical Implications: Preclinical but nominates BRD4/BET pathway modulation as a strategy to preserve β‑cell function; careful translational work is needed to define selective modulators, dosing, and safety in humans.
Key Findings
- BRD4 expression is reduced in human diabetic β cells and increased by calorie restriction in diabetic mice.
- Long‑term and acute Brd4 knockout impairs β‑cell differentiation; BRD4 knockdown in human islet organoids reduces insulin synthesis.
- ATF5 is a direct BRD4 target in β cells; a patient BRD4 variant (p.R749C) affects BRD4 signaling.
3. Treatments for MEN1-associated endocrine tumours: three systematic reviews and a meta-analysis.
Three linked systematic reviews and meta‑analysis synthesize outcomes for MEN1 management: subtotal parathyroidectomy reduces persistence/recurrence in MEN1 hyperparathyroidism, active surveillance may be reasonable for non‑functioning pNETs ≤2 cm in select patients, and MEN1 prolactinomas respond to dopamine agonists similarly to sporadic cases.
Impact: Provides the most comprehensive, guideline‑informing synthesis to date for surgical extent and medical surveillance decisions in MEN1, directly translatable to clinical pathways.
Clinical Implications: Favor subtotal parathyroidectomy for MEN1 hyperparathyroidism to lower persistence/recurrence; consider active surveillance for small (≤2 cm) non‑functioning pNETs in selected patients and treat MEN1 prolactinomas with dopamine agonists as in sporadic disease.
Key Findings
- Subtotal parathyroidectomy significantly lowered persistent primary hyperparathyroidism compared with less‑than‑subtotal procedures in pooled analyses.
- Limited data suggest active surveillance may be comparable to surgery for non‑functioning pNETs ≤2 cm, supporting individualized management.
- Dopamine agonist responsiveness in MEN1 prolactinomas is similar to non‑MEN1 prolactinomas.