Daily Endocrinology Research Analysis
Three impactful endocrinology papers span genetics-to-therapy, brain–pancreas glucose control, and decades-long cardiometabolic outcomes. A JCI GWAS-MR study identifies common variants (DGKD, SLC34A1, CYP24A1) and CaSR pathway biology predisposing to kidney stones, with drug-target MR and in vitro rescue by cinacalcet. A JCI mechanistic study shows that selective AgRP neuron inactivation normalizes hyperglycemia without affecting obesity in ob/ob mice, while a 34-year Diabetes Care cohort links
Summary
Three impactful endocrinology papers span genetics-to-therapy, brain–pancreas glucose control, and decades-long cardiometabolic outcomes. A JCI GWAS-MR study identifies common variants (DGKD, SLC34A1, CYP24A1) and CaSR pathway biology predisposing to kidney stones, with drug-target MR and in vitro rescue by cinacalcet. A JCI mechanistic study shows that selective AgRP neuron inactivation normalizes hyperglycemia without affecting obesity in ob/ob mice, while a 34-year Diabetes Care cohort links newly diagnosed diabetes and IGT to high stroke incidence and benefits of lifestyle intervention.
Research Themes
- Genetic architecture and mechanistic pathways of nephrolithiasis with translational drug targeting
- Central neuroendocrine control of hyperglycemia independent of obesity
- Long-term cerebrovascular risk across the dysglycemia spectrum and effect of lifestyle intervention
Selected Articles
1. Genetic variants predisposing to an increased risk of kidney stone disease.
This multi-method human genetics study mapped 79 signals at 71 loci for kidney stone disease and used Mendelian randomization and colocalization to implicate DGKD, SLC34A1, and CYP24A1 in causal calcium/phosphate pathways. Drug-target MR suggested large relative risk reductions by modulating CASR/DGKD/CYP24A1/SLC34A1, and in vitro experiments showed cinacalcet rescues DGKD-variant CaSR signaling.
Impact: Integrates population genetics, causal inference, and mechanistic validation to reveal common genetic causes and actionable pathways for nephrolithiasis.
Clinical Implications: Genotyping could stratify kidney stone risk and guide pathway-specific interventions (e.g., calcimimetics for impaired CaSR/DGKD signaling or modulation of phosphate handling via SLC34A1). Prospective trials should test genotype-informed prevention.
Key Findings
- Identified 79 independent KSD-associated signals at 71 loci.
- MR implicated increased serum calcium and decreased serum phosphate as causal risk factors from three genomic regions.
- Colocalization pinpointed putative causal noncoding variants near DGKD, SLC34A1, and CYP24A1 explaining 11%–19% of KSD cases.
- Drug-target MR suggested up to ~90% relative risk reduction by reducing calcium via CASR/DGKD/CYP24A1 or increasing phosphate via SLC34A1.
- DGKD missense variants impaired CaSR signaling in vitro, rescued by the calcimimetic cinacalcet.
Methodological Strengths
- Integration of GWAS with region-specific Mendelian randomization and genetic colocalization to infer causality.
- Drug-target MR and in vitro functional assays validating pathway predictions (cinacalcet rescue).
Limitations
- Ancestry composition and cohort-specific details are not provided in the abstract, limiting assessment of generalizability.
- MR relies on instrumental variable assumptions; clinical efficacy of pathway modulation remains to be proven in prospective trials.
Future Directions: Conduct ancestry-diverse validations, pragmatic genotype-guided prevention trials (e.g., calcimimetic use in high-risk genotypes), and mechanistic studies in human tissues to refine targets.
2. AgRP neuron hyperactivity drives hyperglycemia in a mouse model of type 2 diabetes.
Selective, chronic inactivation of AgRP neurons in the hypothalamic arcuate nucleus normalized hyperglycemia for 10 weeks in male ob/ob mice without altering food intake, energy expenditure, body weight, or fat mass. This dissociates central control of glucose homeostasis from energy balance and supports AgRP neuron hyperactivity as a key driver of diabetic hyperglycemia.
Impact: Provides compelling mechanistic evidence that a discrete hypothalamic circuit is necessary for hyperglycemia in T2D models, reframing CNS contributions to diabetes pathogenesis.
Clinical Implications: Suggests the potential for CNS-targeted therapies (e.g., modulators of AgRP neuron excitability or downstream circuits) to restore euglycemia independent of weight loss; translation requires safety and human circuit validation.
Key Findings
- AgRP neuron inactivation via cre-inducible TeTx-GFP normalized hyperglycemia over 10 weeks in ob/ob AgRP-Cre mice.
- No significant changes in food intake, energy expenditure, body weight, or fat mass despite glycemic normalization.
- Findings align with prior icv FGF1 studies implicating AgRP neuron inhibition in sustained glucose lowering.
Methodological Strengths
- Cell-type specific manipulation using cre-inducible tetanus toxin in AgRP neurons with appropriate viral controls.
- Longitudinal metabolic phenotyping dissociating glycemia from energy balance end points.
Limitations
- Male ob/ob mice model only; generalizability to other T2D models and sexes is unknown.
- Mechanistic endpoints (e.g., hepatic glucose production, autonomic outputs) were not directly measured.
Future Directions: Map downstream AgRP circuits controlling glycemia, test pharmacologic neuromodulation, and validate CNS–glucose pathways in diverse T2D models and humans.
3. Stroke Incidence Evolution in People With Newly Diagnosed Diabetes and Impaired Glucose Tolerance: A 34-Year Follow-up of the Da Qing Diabetes Study.
In the Da Qing cohort with 34-year follow-up, both newly diagnosed diabetes and IGT showed high cumulative stroke incidence, while lifestyle intervention reduced stroke risk versus NDD, particularly among women. Findings underscore sustained cerebrovascular risk across dysglycemia and benefits of early lifestyle management.
Impact: Provides rare 3-decade cerebrovascular outcomes linking dysglycemia status and lifestyle intervention to stroke risk, informing prevention strategies.
Clinical Implications: Supports early identification and intensive lifestyle intervention for IGT to mitigate long-term stroke risk, with attention to sex-specific benefits.
Key Findings
- Over 34 years, cumulative stroke incidence was 65.4% (NDD), 62.8% (IGT no intervention), and 49.8% (IGT intervention).
- Adjusted stroke risk was higher vs NGT: NDD HR 1.80; IGT no intervention HR 1.52; IGT intervention HR 1.33.
- Lifestyle intervention in IGT reduced stroke risk compared with NDD (HR 0.77), especially in women (HR 0.64).
Methodological Strengths
- Exceptionally long (34-year) follow-up with randomized lifestyle intervention among IGT participants.
- Age/sex and multivariable risk-adjusted analyses across glucose tolerance strata.
Limitations
- Cohort enrolled in 1986 in China; secular changes in care may limit generalizability to modern settings.
- Potential residual confounding and details of stroke subtypes or competing risks are not provided in the abstract.
Future Directions: Replicate in contemporary multi-ethnic cohorts, evaluate cost-effective screening/implementation of lifestyle programs, and delineate sex-specific mechanisms.