Daily Endocrinology Research Analysis
Three impactful endocrinology papers span mechanism, diagnostics, and comparative effectiveness. A mechanistic study reveals a reno-adipose autonomic neurocircuit whereby SGLT2 inhibitors raise renal adenosine to drive lipolysis and weight loss. Clinically, mass spectrometry–based aldosterone cut-offs strengthen saline infusion testing for primary aldosteronism, and target trial emulation shows higher 5-year cardiovascular risk with glipizide versus DPP4 inhibitors.
Summary
Three impactful endocrinology papers span mechanism, diagnostics, and comparative effectiveness. A mechanistic study reveals a reno-adipose autonomic neurocircuit whereby SGLT2 inhibitors raise renal adenosine to drive lipolysis and weight loss. Clinically, mass spectrometry–based aldosterone cut-offs strengthen saline infusion testing for primary aldosteronism, and target trial emulation shows higher 5-year cardiovascular risk with glipizide versus DPP4 inhibitors.
Research Themes
- Kidney-adipose neuroendocrine crosstalk in metabolic regulation
- Diagnostic standardization in hormonal hypertension
- Cardiovascular safety of antihyperglycemic therapies
Selected Articles
1. Sodium-glucose co-transporter 2 inhibitor-induced increase in adenosine promotes lipolysis and weight reduction by activating reno-adipose autonomic neurocircuitry.
Using renal denervation, β3-adrenergic blockade, and metabolomics in high-fat–fed mice, tofogliflozin increased renal adenosine, activated adipose sympathetic outflow (higher adipose norepinephrine), and drove lipolysis and weight loss. Disrupting renal sympathetic input or β3 signaling blunted these effects, revealing a reno-adipose autonomic neurocircuit.
Impact: This work uncovers a previously unrecognized neuroendocrine circuit linking renal energy sensing to adipose lipolysis, offering a mechanistic basis for the weight-reducing effects of SGLT2 inhibitors.
Clinical Implications: While preclinical, the findings suggest variability in SGLT2 inhibitor–induced weight loss may depend on renal sympathetic integrity and β3-adrenergic signaling. They highlight adenosine pathways and reno-adipose circuitry as potential therapeutic targets or biomarkers.
Key Findings
- Renal denervation attenuated tofogliflozin-induced lipolysis and weight loss in high-fat–fed mice.
- β3-adrenergic blockade reduced the lipolytic and weight-reducing effects of tofogliflozin.
- Metabolomics showed elevated renal adenosine after tofogliflozin; adipose tissue norepinephrine increased, indicating sympathetic activation.
- A reno-adipose autonomic neurocircuit was proposed linking renal energy depletion to systemic fatty acid oxidation.
Methodological Strengths
- Causal manipulations with renal denervation and β3-adrenergic blockade strengthen mechanistic inference.
- Untargeted metabolomics pinpointed adenosine as a mediator; tissue norepinephrine measurements confirmed sympathetic activation.
Limitations
- Findings are in mice; human validation is lacking.
- Specificity of denervation and systemic off-target effects of pharmacologic blockers may confound interpretation.
Future Directions: Validate the reno-adipose circuit and adenosine signaling in humans; test whether renal denervation, autonomic dysfunction, or β3 blockade modulate SGLT2 inhibitor weight effects; develop biomarkers of circuit engagement.
2. Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors.
In a 48,165-person target trial emulation of second-line therapy after metformin, glipizide was associated with the highest 5-year MACE-4 risk compared with DPP4 inhibitors (risk ratio 1.13). Glimepiride and glyburide showed smaller or nonsignificant differences.
Impact: Large-scale, methodologically rigorous comparative effectiveness evidence informs agent selection when adding to metformin, highlighting differential cardiovascular risk within sulfonylureas.
Clinical Implications: When choosing a second-line agent for patients at moderate cardiovascular risk, prefer options with lower MACE risk; avoid or closely monitor glipizide if sulfonylureas are used. Individualize based on comorbidity and hypoglycemia risk.
Key Findings
- Target trial emulation including 48,165 metformin-treated adults initiating sulfonylureas or DPP4 inhibitors.
- 5-year MACE-4 risk was 9.1% for glipizide vs 8.1% for DPP4 inhibitors (risk ratio 1.13; 95% CI, 1.03-1.23).
- Glimepiride (RR 1.07; 95% CI, 0.96-1.16) and glyburide (RR 1.04; 95% CI, 0.83-1.24) showed smaller or nonsignificant differences vs DPP4 inhibitors.
Methodological Strengths
- Target trial emulation across multiple US health systems and insurers with large sample size and multiyear follow-up.
- Clinically meaningful composite outcome (MACE-4) with agent-specific comparisons.
Limitations
- Observational design susceptible to residual confounding and treatment selection bias despite emulation.
- Findings apply to moderate cardiovascular risk populations; generalizability to high-risk or diverse care settings may vary.
Future Directions: Assess subgroup heterogeneity (age, ASCVD, CKD), evaluate hypoglycemia-mediated pathways, and extend comparisons to newer agents (SGLT2i, GLP-1 RA) in similar emulations.
3. The saline infusion test with mass spectrometric measurements of aldosterone to confirm primary aldosteronism.
In a prospective multicenter cohort, mass spectrometry–based aldosterone after seated saline infusion achieved AUC 0.964. A 169 pmol/L cut-off yielded 97% sensitivity and 89% specificity, while 255 pmol/L increased specificity to 95% at 75% sensitivity. Adherence to standard procedures (minimizing ambulation) markedly improved reproducibility.
Impact: Provides actionable, assay-specific cut-offs for a widely used confirmatory test in primary aldosteronism and emphasizes SOPs to ensure reproducibility.
Clinical Implications: Implement seated saline infusion testing with LC-MS/MS aldosterone using 169 pmol/L as a high-sensitivity cut-off and 255 pmol/L for high specificity, ensuring minimized ambulation during infusion. Consider repeat testing if results conflict with clinical probability.
Key Findings
- AUC 0.964 for post-saline aldosterone measured by mass spectrometry; 169 pmol/L cut-off yielded 97% sensitivity and 89% specificity.
- A 255 pmol/L cut-off improved specificity to 95% at 75% sensitivity.
- Intra-patient discordance (26%) was largely center-related; adherence to minimized ambulation improved AUC to 0.985 with 96% sensitivity/specificity.
Methodological Strengths
- Prospective, multicenter design with LC-MS/MS measurement and ROC-derived cut-offs.
- Assessment of intra-patient variability and identification of procedural sources of discordance.
Limitations
- Non-randomized diagnostic cohort; reliance on alternative confirmatory criteria as reference.
- Procedural heterogeneity across centers affected reproducibility before SOP enforcement.
Future Directions: Standardize and validate protocol across diverse centers and populations; integrate cut-offs with pretest probability models; assess cost-effectiveness of LC-MS/MS-based confirmation.