Daily Endocrinology Research Analysis
Three papers stood out today: (1) discovery of a sleep-inducible hypothalamic hormone (Raptin) that suppresses appetite and protects against obesity via GRM3 signaling; (2) evidence that FRAX without BMD underestimates fracture risk in key subgroups of older adults with diabetes; and (3) mechanistic data showing NFAT5 drives β-cell ferroptosis by repressing PRDX2, with in vivo reversal improving glucose control.
Summary
Three papers stood out today: (1) discovery of a sleep-inducible hypothalamic hormone (Raptin) that suppresses appetite and protects against obesity via GRM3 signaling; (2) evidence that FRAX without BMD underestimates fracture risk in key subgroups of older adults with diabetes; and (3) mechanistic data showing NFAT5 drives β-cell ferroptosis by repressing PRDX2, with in vivo reversal improving glucose control.
Research Themes
- Neuroendocrine control of appetite and sleep–metabolism coupling
- Fracture risk prediction bias in diabetes
- β-cell stress pathways and ferroptosis in type 2 diabetes
Selected Articles
1. Raptin, a sleep-induced hypothalamic hormone, suppresses appetite and obesity.
The authors identify Raptin, a peptide hormone cleaved from RCN2, whose secretion peaks during sleep and is controlled by an SCN–PVN circuit. Raptin binds GRM3 in hypothalamic and gastric neurons to suppress appetite and slow gastric emptying via PI3K-AKT, protecting against obesity; human data link sleep deficiency with impaired Raptin and an RCN2 nonsense variant with night eating and obesity.
Impact: This work reveals a previously unknown endocrine axis linking sleep to energy balance via a discrete hormone–receptor pair, offering a potential therapeutic target for obesity and sleep-related metabolic disorders.
Clinical Implications: Emphasizes sleep health as a metabolic intervention and nominates GRM3–Raptin signaling as a potential target for appetite suppression; Raptin or GRM3 agonists might complement lifestyle therapy, pending safety and efficacy studies.
Key Findings
- Identified Raptin, a peptide hormone cleaved from RCN2, with sleep-peaking secretion controlled by an SCN (AVP+) to PVN circuit.
- Raptin binds GRM3 in hypothalamic and gastric neurons to reduce appetite and delay gastric emptying via PI3K–AKT signaling.
- Sleep deficiency blunts Raptin release; humans with an RCN2 nonsense variant exhibit night eating syndrome and obesity.
Methodological Strengths
- Cross-species validation with mechanistic receptor identification (GRM3) and signaling pathway mapping (PI3K–AKT).
- Integration of neural circuit mapping (SCN–PVN), physiology, and human genetic/phenotypic data.
Limitations
- Predominantly preclinical; causal effects and safety in humans remain to be established.
- Long-term metabolic and cardiovascular consequences of modulating GRM3–Raptin signaling are unknown.
Future Directions: Develop pharmacologic agonists/analogs of Raptin or GRM3 agonists; test efficacy and safety in obesity and sleep-disorder populations; evaluate biomarker utility of circulating Raptin.
2. NFAT5 exacerbates β-cell ferroptosis by suppressing the transcription of PRDX2 in obese type 2 diabetes mellitus.
In obese T2D mice and β-cell models, NFAT5 expression and nuclear translocation increase under glucolipotoxicity, driving β-cell ferroptosis by repressing PRDX2 transcription. Genetic inhibition of NFAT5 in β cells reduces ferroptosis, enhances insulin secretion, and improves glucose tolerance in vivo.
Impact: Defines a tractable β-cell death pathway (ferroptosis) driven by NFAT5 repression of PRDX2 and demonstrates in vivo reversibility, nominating NFAT5–PRDX2 as a therapeutic axis.
Clinical Implications: Suggests that inhibiting NFAT5 or boosting PRDX2/antioxidant defenses, or employing ferroptosis modulators, may preserve β-cell function in T2D; supports biomarker development around ferroptosis signatures.
Key Findings
- Glucolipotoxicity increases NFAT5 expression and nuclear translocation in MIN6 cells and obese T2D mouse islets.
- NFAT5 binds the PRDX2 promoter, repressing its transcription and promoting β-cell ferroptosis and insulin secretory failure.
- β-cell–specific NFAT5 knockdown (AAV8-RIP2-miR30-shNFAT5) reduces ferroptosis, increases insulin secretion, and improves glucose tolerance in obese T2D mice.
Methodological Strengths
- Combined in vivo obese T2D mouse model with in vitro β-cell assays and genetic perturbation (AAV8-mediated β-cell–specific knockdown).
- Mechanistic validation via promoter binding (luciferase, ChIP) linking NFAT5 to PRDX2 repression and ferroptosis.
Limitations
- Translation to human β cells and clinical T2D remains to be demonstrated.
- Potential off-target or compensatory effects with AAV-based gene modulation were not fully explored.
Future Directions: Evaluate NFAT5 inhibitors or PRDX2-enhancing approaches in human islets and diabetic models; test ferroptosis-targeted therapies alongside standard T2D treatments.
3. Biases in the performance of FRAX without BMD in predicting fracture risk in a multiethnic population with diabetes: the Diabetes and Aging Study.
In 96,914 older adults with diabetes (mean follow-up 4.3 years), FRAX without BMD showed good discrimination (AUC 0.72 for MOF; 0.77 for hip) but underestimated fracture risk overall (O/P 1.2) and in key subgroups, including Hispanic women, Black men, long diabetes duration (≥20 years), and those aged ≥80.
Impact: Identifies algorithmic bias of a widely used fracture risk tool in diabetes, informing the need for diabetes-specific calibration or new models to improve fracture prevention.
Clinical Implications: Clinicians should interpret FRAX without BMD cautiously in older adults with diabetes—especially in Hispanic women, Black men, long-duration diabetes, and the oldest old—and consider adjuncts (BMD, TBS, diabetes variables) or alternative thresholds pending diabetes-specific tools.
Key Findings
- Among 96,914 diabetic adults (65–89 years), MOF and hip fracture AUCs were 0.72 and 0.77 using FRAX without BMD.
- Overall calibration showed underestimation (O/P 1.2), with substantial underestimation in Hispanic women (O/P up to 1.8) and Black men (O/P up to 1.8).
- Risk underestimation was notable in diabetes duration ≥20 years and in those >80 years; discrimination worsened in age >75 (AUC <0.7).
Methodological Strengths
- Very large, ethnically diverse, real-world cohort with robust assessment of discrimination and calibration.
- Subgroup analyses by race/ethnicity, age, and diabetes duration revealed clinically actionable biases.
Limitations
- FRAX was evaluated without BMD; inclusion of BMD might alter performance.
- Observational design with potential residual confounding; external validation beyond the KPNC system is needed.
Future Directions: Develop and validate diabetes-specific fracture risk models or recalibrations of FRAX incorporating diabetes-related variables (duration, treatments, HbA1c) and skeletal measures (BMD, TBS).