Peripheral nerve-mediated glucose lowering: Mechanisms, translational strategies, and future perspectives

Glucose homeostasis is crucial for metabolic health, with disruptions leading to hyperglycemia (e.g., diabetes affecting over 589 million adults worldwide in 2025) or hypoglycemia, both associated with severe complications like nephropathy, neuropathy, and cardiovascular disease. The peripheral nervous system (PNS) is a less studied regulator of glucose balance through neural circuits involving the sympathetic, parasympathetic, sensory, and somatic nerves, which interact with organs like the liver, pancreas, and gut. This review aims to synthesize recent advances in PNS-mediated glucose lowering, covering mechanistic foundations, organ-specific pathways, translational interventions (e.g., device-based neuromodulation, pharmacological approaches, closed-loop systems, and regenerative strategies), preclinical/clinical evidence, translational challenges, and future perspectives to provide a roadmap for developing novel, drug-free therapies for dysglycemia.