Weekly Endocrinology Research Analysis
This week’s endocrinology literature highlights paradigm-shifting mechanistic work, high-quality translational evidence, and clinically actionable genomic diagnostics. Key advances include identification of endogenous cyanide as a regulatory gasotransmitter affecting mitochondrial bioenergetics, convergent human-and-animal evidence that GLP-1 receptor agonists reduce alcohol intake (supporting rapid repurposing trials), and large-scale genetic screening establishing non-coding HK1 regulatory var
Summary
This week’s endocrinology literature highlights paradigm-shifting mechanistic work, high-quality translational evidence, and clinically actionable genomic diagnostics. Key advances include identification of endogenous cyanide as a regulatory gasotransmitter affecting mitochondrial bioenergetics, convergent human-and-animal evidence that GLP-1 receptor agonists reduce alcohol intake (supporting rapid repurposing trials), and large-scale genetic screening establishing non-coding HK1 regulatory variants as a major cause of congenital hyperinsulinism. Together these studies push basic discovery toward new therapeutic and diagnostic directions.
Selected Articles
1. Regulation of mammalian cellular metabolism by endogenous cyanide production.
This mechanistic study demonstrates that mammalian cells produce low levels of cyanide endogenously, which at defined rates enhances mitochondrial bioenergetics, metabolism, and proliferation via protein S-cyanylation, while higher concentrations are bioenergetically harmful. Glycine-stimulated, lysosome-associated production and peroxidase dependence were shown, with low-dose cyanide protective in hypoxia/reoxygenation models and pathological excess harmful in disease models.
Impact: Identifies cyanide as a previously unrecognized endogenous gasotransmitter with broad implications across metabolism, ischemia–reperfusion biology, and potential therapeutic/biomarker development.
Clinical Implications: Though preclinical, the work suggests new biomarker and therapeutic strategies (modulating cyanide production/signaling or S-cyanylation) for ischemia-reperfusion and metabolic diseases, but careful dose-safety profiling is essential due to potential toxicity.
Key Findings
- Endogenous cyanide detected in human cells (multiple compartments) and mouse tissues/blood; production stimulated by glycine and dependent on lysosomal low pH and peroxidase activity.
- Low-rate cyanide production enhanced mitochondrial bioenergetics, cellular metabolism and proliferation; high concentrations impaired bioenergetics.
- Cyanide mediates protein S-cyanylation detectable basally and inducible by glycine; low-dose cyanide provided cytoprotection in hypoxia/reoxygenation models, while pathological excess (e.g., nonketotic hyperglycinemia) was detrimental.
2. Glucagon-like peptide-1 receptor agonists, but not dipeptidyl peptidase-4 inhibitors, reduce alcohol intake.
Using a large VA electronic health record cohort (2008–2023) with propensity-score matching and difference-in-difference analysis, plus reverse-translational rodent models, GLP-1 receptor agonist recipients showed greater reductions in AUDIT-C drinking scores versus both unexposed controls and DPP-4 inhibitor recipients. Rodent experiments confirmed that DPP-4 inhibitors lower glucose but do not reduce alcohol intake. Findings support GLP-1RA repurposing for alcohol use disorder and prioritize randomized trials.
Impact: Provides convergent human and animal evidence for GLP-1RA efficacy in reducing alcohol intake—directly informing clinical trial prioritization and potential rapid repurposing for AUD.
Clinical Implications: Clinicians and trialists should prioritize RCTs of GLP-1RAs for alcohol use disorder, and consider potential dual benefits in patients with comorbid obesity/diabetes; do not expect DPP-4 inhibitors to reduce alcohol consumption.
Key Findings
- GLP-1RA recipients had greater reductions in AUDIT-C scores than unexposed individuals (DiD 0.09) and than DPP-4I recipients (DiD 0.11); larger effects in baseline AUD/hazardous drinkers.
- DPP-4 inhibitors showed no effect on alcohol intake in humans and failed to reduce drinking in mice and alcohol-dependent rats despite lowering blood glucose.
- Reverse-translational rodent models provided mechanistic specificity linking GLP-1 pathways to alcohol intake reduction.
3. Non-coding cis-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity.
Screening 1,761 probands with unexplained hyperinsulinism identified HK1 cis-regulatory non-coding variants in 5% (89 probands) plus 63 relatives, establishing HK1 regulatory mutations as a major, variably penetrant cause. Phenotypes ranged from neonatal treatment-resistant disease to asymptomatic adulthood, and the minimal regulatory element was refined—supporting inclusion of non-coding regions in diagnostic panels and counseling on variable penetrance.
Impact: Quantifies and characterizes the burden of non-coding regulatory HK1 variants in congenital hyperinsulinism, moving non-coding diagnostics into clinical relevance and affecting testing algorithms and counseling.
Clinical Implications: Diagnostic panels for congenital hyperinsulinism should include HK1 regulatory regions; clinicians must counsel families about variable penetrance and anticipate a spectrum of management approaches from medical therapy to surgery.
Key Findings
- HK1 cis-regulatory non-coding variants found in 89/1761 probands (5%) plus 63 relatives, establishing HK1 as a frequent cause of unexplained hyperinsulinism.
- Clinical presentations varied from neonatal onset with treatment resistance to adults without symptoms; inherited variants from asymptomatic parents confirm variable penetrance.
- Two novel variants extended the minimal regulatory element definition (42 → 46 bp), emphasizing diagnostic sequencing of non-coding regions.