Weekly Endocrinology Research Analysis
This week’s endocrinology literature highlights mechanistic discoveries that nominate druggable targets and near-term translational candidates, alongside a promising new osteoporosis biologic. A preclinical/translational triad (PGK1 in DKD, LONP1 in β-cell mitochondrial proteostasis) provides both biomarker candidates and small-molecule or pathway-based intervention strategies. A phase II randomized anti‑RANKL antibody (narlumosbart) demonstrates meaningful BMD gains, advancing the antiresorptiv
Summary
This week’s endocrinology literature highlights mechanistic discoveries that nominate druggable targets and near-term translational candidates, alongside a promising new osteoporosis biologic. A preclinical/translational triad (PGK1 in DKD, LONP1 in β-cell mitochondrial proteostasis) provides both biomarker candidates and small-molecule or pathway-based intervention strategies. A phase II randomized anti‑RANKL antibody (narlumosbart) demonstrates meaningful BMD gains, advancing the antiresorptive therapeutic pipeline. Overall trends emphasize integrated multi-omics, drug repurposing/screening, and biomarker-driven patient stratification.
Selected Articles
1. Phosphoglycerate kinase 1 contributes to diabetic kidney disease through enzyme-dependent and independent manners.
This integrated translational study identifies PGK1 as a central driver of diabetic kidney disease via enzymatic 3‑PG–GPX1–NLRP3 inflammasome activation and a non‑enzymatic Aldh1l1–UNC5CL inflammatory axis. Tubule‑specific PGK1 knockout mitigated DKD and overexpression worsened it, while several small‑molecule PGK1 antagonists (including an FDA‑approved agent) prevented DKD in models.
Impact: Nomination of PGK1 as a druggable metabolic–inflammatory hub with immediate translational leads (three antagonists, including an FDA‑approved drug) represents a potential paradigm shift in DKD therapeutics.
Clinical Implications: PGK1 inhibition could complement existing DKD therapies by targeting tubular metabolic‑inflammasome pathways; repurposing of identified antagonists (e.g., oxantel pamoate) merits early‑phase clinical trials with 3‑PG and inflammasome biomarkers.
Key Findings
- PGK1 is upregulated in DKD patients and mice; tubule‑specific PGK1 knockout reduced DKD while overexpression exacerbated it.
- Enzymatic production of 3‑PG by PGK1 inhibits GPX1, activating NLRP3 inflammasome; non‑enzymatic PGK1 binds Aldh1l1 to drive UNC5CL-mediated inflammation.
- High-throughput screening identified C‑16, lirinidine, and oxantel pamoate as PGK1 antagonists that prevented DKD in vivo.
2. LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
Using human donor islets and mechanistic models, the study demonstrates mitochondrial (not ER) protein misfolding as a key driver of β‑cell loss in T2D. Reduced LONP1 in β cells leads to mitochondrial proteotoxicity, respiratory dysfunction, apoptosis and hyperglycemia, while LONP1 gain‑of‑function (via chaperone activity with mtHSP70) rescues β‑cell survival after glucolipotoxic insult.
Impact: First comprehensive evidence positioning mitochondrial proteostasis (LONP1–mtHSP70) as a central therapeutic node for β‑cell preservation in T2D, reframing targets away from exclusively ER‑focused approaches.
Clinical Implications: Therapeutic strategies that enhance mitochondrial protein folding (small molecules or biologics augmenting LONP1/HSP70 function) could preserve β‑cell mass and delay T2D progression; motivates biomarker development for mitochondrial proteotoxic stress in clinical cohorts.
Key Findings
- Human T2D islets accumulate misfolded mitochondrial proteins distinct from ER stress signatures.
- LONP1 expression is reduced in β cells from T2D donors; loss of LONP1 causes mitochondrial dysfunction and β‑cell apoptosis.
- LONP1 gain‑of‑function protects β cells via a protease‑independent, mtHSP70‑dependent chaperone mechanism.
3. Efficacy and safety of narlumosbart, an anti-RANKL monoclonal antibody, in postmenopausal women with osteoporosis: a multi-center, randomized, double-blind, placebo- and active-controlled, phased II study.
In a multicenter, randomized, double‑blind phase II trial (n=207), narlumosbart administered every 6 months produced dose‑responsive lumbar spine BMD increases of ~4.8–6.5% at 12 months versus 0.6% with placebo, with a short‑term safety profile comparable to denosumab.
Impact: Demonstrates a new anti‑RANKL biologic with robust BMD gains and an acceptable short‑term safety profile, supporting progression to fracture‑endpoint phase III trials and expanding antiresorptive options.
Clinical Implications: If phase III trials confirm fracture reduction and long‑term safety, narlumosbart could become an alternative to existing antiresorptives (e.g., denosumab), useful in cases of intolerance, supply constraints, or specific regulatory contexts.
Key Findings
- Narlumosbart increased lumbar spine BMD at 12 months by 4.83%, 6.52%, and 5.74% for 45/60/90 mg doses vs 0.63% with placebo (all P<0.001).
- Safety profile over 12 months was comparable to placebo and denosumab; common TEAEs included decreased vitamin D and increased PTH.