Lactate-activated GPR81/FARP1 signaling drives insulin-independent glucose uptake and metabolic control.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and molecular mechanistic study with secondary human genetic association data
PubMed 41530347 · doi:10.1038/s41422-025-01207-3
What was done
Investigated how L-lactate regulates glucose homeostasis using mouse models with muscle-specific knockout of lactate dehydrogenase A (LDHA) or the lactate receptor GPR81, alongside lactate administration, genetic upregulation, and pharmacological activation of GPR81. Evaluated the downstream molecular mechanism involving FARP1, RAC1, and GLUT4 translocation, tested pathway expression after exercise, and assessed human genetic correlations between GPR81 variants and fasting insulin levels.
What was found
The abstract reports no numerical values, effect sizes, or confidence intervals. Directionally, muscle LDHA loss or GPR81 knockout impaired glucose tolerance in mice, while lactate administration or GPR81 activation improved carbohydrate metabolism. GPR81 signaling recruited FARP1 to activate RAC1 and promote GLUT4 translocation without requiring insulin signaling. Expression of LDHA, GPR81, and FARP1 was upregulated following exercise, and GPR81 genetic variants correlated with fasting insulin levels in humans.
Why it matters
Reveals an insulin-independent pathway for muscle glucose uptake mediated by lactate signaling through GPR81 and FARP1. This identifies potential molecular targets to help clear glucose in insulin-resistant states or hyperglycemia.
Limits
The abstract reports no quantitative data, sample sizes, effect magnitudes, or statistical measures. The primary findings are derived from rodent and in vitro models, and human evidence is limited to correlational genetic associations without interventional clinical validation.
Cited by
- partial Lactate produced during high-intensity vigorous exercise acts as a signaling molecule that prompts glucose transporters to translocate to the muscle cell surface.
- supports Lactate produced during vigorous exercise signals the increase in GLUT4 glucose transporters and their translocation to the muscle cell surface.