Daily Endocrinology Research Analysis
Meal timing reshapes endocrine physiology: meal-feeding amplifies ghrelin-driven growth hormone pulsatility and supports skeletal growth, challenging grazing/snacking habits. A simple oral urea challenge enables the first copeptin-based outpatient test to distinguish primary polydipsia from AVP deficiency with 93% sensitivity and specificity. A phase 2 randomized trial of an ANGPTL-3 monoclonal antibody (SHR-1918) produced up to 30% additional LDL-C lowering on top of standard therapy, advancing
Summary
Meal timing reshapes endocrine physiology: meal-feeding amplifies ghrelin-driven growth hormone pulsatility and supports skeletal growth, challenging grazing/snacking habits. A simple oral urea challenge enables the first copeptin-based outpatient test to distinguish primary polydipsia from AVP deficiency with 93% sensitivity and specificity. A phase 2 randomized trial of an ANGPTL-3 monoclonal antibody (SHR-1918) produced up to 30% additional LDL-C lowering on top of standard therapy, advancing cardiometabolic risk reduction.
Research Themes
- Hormone rhythmicity and nutrition timing
- Simplified diagnostics in water-balance disorders
- Novel lipid-lowering biologics for ASCVD risk
Selected Articles
1. Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity.
Across rodents and humans, structured meal-feeding induced preprandial ghrelin surges and tripled GH secretion by increasing burst height and frequency, sustaining skeletal growth despite reduced intake. Continuous enteral feeding sustained ghrelin and flattened GH rhythmicity, while bolus feeding enhanced ultradian GH rhythms. Findings challenge grazing/snacking behavior as optimal for growth, implicating ghrelin-GHS-R–dependent GH pulsatility as a key mediator.
Impact: This study links feeding pattern to endocrine pulsatility and growth with cross-species mechanistic evidence, reframing how nutrition timing influences the GH axis and skeletal outcomes.
Clinical Implications: Structured meal timing may optimize GH pulsatility and growth, informing dietary counseling in pediatrics and potentially augmenting GH therapies; however, interventional trials on growth outcomes are needed before guideline changes.
Key Findings
- Meal-feeding induced preprandial ghrelin surges and tripled GH secretion via increased burst height with two additional daily GH bursts.
- Rodent skeletal growth (body length and tibial epiphyseal plate width) was maintained in meal-fed animals through ghrelin/GHS-R signaling despite reduced caloric intake.
- In humans, continuous enteral feeding sustained ghrelin and minimized GH rhythmicity, whereas bolus enteral feeding restored ultradian GH rhythms with postprandial ghrelin troughs.
Methodological Strengths
- Cross-species design integrating automated feeding in rodents and controlled nasogastric feeding in humans
- Mechanistic linkage through ghrelin and GHS-R dependency with detailed hormone pulsatility analyses
Limitations
- Human experiments were short-term physiological studies without growth outcomes
- Rodent studies used males; generalizability to females, children, and clinical populations remains to be tested
Future Directions: Randomized trials testing meal timing interventions on longitudinal growth and GH therapy response; mechanistic dissection of downstream targets of GH pulses on growth plates in humans.
The physiological effect of ultradian temporal feeding patterns remains a major unanswered question in nutritional science. We have used automated and nasogastric feeding to address this question in male rodents and human volunteers. While grazing and meal-feeding reduced food intake in parallel (compared with ad libitum-fed rodents), body length and tibial epiphysial plate width were maintained in meal-fed rodents via the action of ghrelin and its receptor, GHS-R. Grazing and meal-feeding initially suppre
2. Urea-stimulated copeptin: a novel diagnostic approach in polyuria polydipsia syndrome.
An oral urea challenge robustly increases copeptin in healthy adults and those with primary polydipsia but not in AVP deficiency. A 120-minute copeptin cut-off of 3.5 pmol/L yielded 93% sensitivity and specificity, establishing the first simple oral copeptin-based test to differentiate AVP deficiency from primary polydipsia.
Impact: Provides a widely accessible, low-complexity diagnostic alternative to hypertonic saline for polyuria–polydipsia syndrome, with high accuracy.
Clinical Implications: Clinicians could adopt an oral urea copeptin test to triage suspected diabetes insipidus vs primary polydipsia in outpatient settings, reducing need for specialized hypertonic saline testing; external validation and safety protocols are required.
Key Findings
- In healthy adults, oral urea increased copeptin from 4.6 to 10.1 pmol/L at 120 minutes, while placebo showed no change (P < .001).
- In AVP deficiency, copeptin remained below detection throughout; in primary polydipsia, copeptin peaked at 150 minutes (~7.4 pmol/L).
- A 120-minute copeptin cut-off of 3.5 pmol/L provided 93% sensitivity and 93% specificity in differentiating AVP deficiency from primary polydipsia.
Methodological Strengths
- Randomized, double-blind, placebo-controlled cross-over design in healthy volunteers
- Prospective diagnostic cut-off derivation with patient pilot cohort including AVP deficiency and primary polydipsia
Limitations
- Small sample sizes in both healthy volunteers and patient cohorts
- Open-label design in the patient pilot without external validation
Future Directions: Multicenter validation with standardized protocols, assessment in partial AVP deficiency and nephrogenic DI, and evaluation of safety/tolerability across comorbidities.
BACKGROUND: Distinguishing arginine vasopressin (AVP) deficiency from primary polydipsia remains challenging. While hypertonic saline-stimulated copeptin testing offers high diagnostic accuracy, it is complex and limited to specialized centers. Intravenous urea is known to stimulate AVP secretion, but the effect of oral urea on copeptin levels is unknown. METHODS: Twenty-two healthy adults were included in a randomized, double-blind, placebo-controlled cross-over trial receiving a single dose of urea (0.5 g/kg; minimum 30 g, maximum 45 g) and placebo. Serum copeptin was measured at 30-min intervals for 2.5 h. In a second step, 13 patients with AVP-deficiency and 13 patients with primary polydipsia were included in an open-label pilot study, receiving urea only. The primary endpoint was maximum copeptin within 150 min. RESULTS: In healthy adults, median [IQR] copeptin significantly increased from 4.6 [3.0-5.7] pmol/L at baseline to a maximum of 10.1 [7.2-11.6] pmol/L at 120 min after ingestion of urea, while it remained stable at 3.8 [2.9-6.6] pmol/L after placebo intake (P < .001). In patients with AVP-deficiency, copeptin remained below detection limit throughout the test, while in patients with primary polydipsia the peak was seen 150 min after ingestion of urea at 7.4 pmol/L [4.3, 10.3]. The best copeptin cut-off for differentiating AVP-deficiency from primary polydipsia was 3.5 pmol/L after 120 min, with 93% sensitivity and specificity. CONCLUSION: Oral urea stimulates copeptin in healthy adults and patients with primary polydipsia, but not in patients with AVP-deficiency, establishing the first oral copeptin-based test in differentiating primary polydipsia from AVP-deficiency.
3. Angiopoietin-Like 3 Antibody Therapy in Patients With Suboptimally Controlled Hyperlipidemia: A Phase 2 Study.
In a phase 2 randomized, double-blind trial of 333 patients with inadequately controlled hyperlipidemia on standard therapy, the ANGPTL-3 antibody SHR-1918 reduced LDL-C by 21.7–29.9% vs placebo with substantial triglyceride and apoB lowering and acceptable tolerability. Effects were dose- and interval-dependent (Q4W and Q8W).
Impact: Demonstrates clinically meaningful, additive LDL-C and TG lowering via ANGPTL-3 inhibition beyond standard therapy, supporting a new class for high residual ASCVD risk.
Clinical Implications: ANGPTL-3 antibodies may offer an option for patients not at LDL-C goal or with mixed dyslipidemia despite statins/ezetimibe/PCSK9i; long-term outcome trials, safety, and positioning vs evinacumab are needed.
Key Findings
- LDL-C reductions vs placebo: 21.7%, 27.3%, 29.9% with 150, 300, 600 mg Q4W; 22.5% with 600 mg Q8W.
- Marked decreases in triglycerides, non-HDL-C, apolipoprotein B, and apolipoprotein A1, with improved LDL-C target attainment.
- Generally well tolerated over 16 weeks with dose-dependent effects.
Methodological Strengths
- Multicenter randomized double-blind placebo-controlled dose-ranging design
- Prespecified lipid endpoints with clear dose-response across Q4W and Q8W regimens
Limitations
- Phase 2 duration; not powered for cardiovascular outcomes
- Population at moderate-to-high ASCVD risk but heterogenous background therapies
Future Directions: Phase 3 trials assessing hard cardiovascular outcomes, head-to-head comparisons with existing biologics (e.g., evinacumab), and evaluation in severe hypertriglyceridemia and statin-intolerant populations.
BACKGROUND: Angiopoietin-like 3 (ANGPTL-3) inhibits the activity of lipoprotein lipase and endothelial lipase, increasing both serum low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. SHR-1918 is a fully human monoclonal antibody against ANGPTL-3. OBJECTIVES: The aim of this study was to assess the lipid-altering efficacy and safety of SHR-1918 in patients at moderate or higher risk of atherosclerotic cardiovascular disease (ASCVD) with suboptimally controlled hyperlipidemia. METHODS: A multicenter, randomized, double-blind, placebo-controlled, dose-escalation phase 2 study was designed to evaluate the effects of SHR-1918 in hypercholesterolemic patients, who did not achieve optimal LDL-C after 4 to 8 weeks of standard lipid-lowering therapies. A total of 333 patients were enrolled sequentially into 1 of 8 dose cohorts at a 4:1 (active/placebo) ratio. Patients received subcutaneous SHR-1918 at doses of 150, 300, or 600 mg every 4 weeks (Q4W), or SHR-1918 at a dose of 600 mg every 8 weeks (Q8W), alternating with placebo for a total treatment period of 16 weeks. The extension treatment included subcutaneous SHR-1918 at a dose of 150, 300, or 600 mg Q4W over 36 weeks, or SHR-1918 a dose of 600 mg Q8W over 40 weeks and then followed for safety. Prespecified endpoints included percentage change from baseline in LDL-C and TG. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. RESULTS: SHR-1918 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q4W and Q8W administration: 21.7%, 27.3%, and 29.9% with 150, 300, and 600 mg Q4W compared with placebo, respectively, and 22.5% with 600 mg Q8W compared with placebo. SHR-1918 also substantially reduced TG, non-high-density lipoprotein cholesterol, apolipoprotein B, and apolipoprotein A1, with a better achievement of LDL-C targets. SHR-1918 was generally well-tolerated. CONCLUSIONS: Based on standard lipid-lowering therapy, ANGPTL-3 inhibition with SHR-1918 further reduces LDL-C by 21.7% to 29.9% in patients at moderate or higher risk of ASCVD. These additional reductions are both dose and dosing frequency dependent. (Evaluate the Efficacy and Safety of SHR-1918 in Patients With Hyperlipidemic; NCT06109831).