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

Table 5 Comparison of peripheral neuromodulation techniques for glucose regulation

Category	Techniques	Primary targets/ depth	Mechanistic modality	Advantages& limitations	Potential population/stage
Non-invasive electrical stimulation[48-52,54,55,62]	taVNS; pVNS; aVNS	Auricular or cervical vagal branches (superficial/subcutaneous)	Transcutaneous or percutaneous electrical activation of vagal afferent fibers	Safe, inexpensive, easily repeatable; limited depth and targeting precision	Mild hyperglycemia, impaired glucose tolerance, metabolic syndrome
Invasive electrical stimulation[53,61,63]	eVNS; SCS	Cervical vagus trunk or thoracic dorsal column (deep)	Implantable electrodes deliver direct neural modulation via electrical pulses	High precision and sustained effects; invasive surgery, infection risk	Advanced or refractory diabetes with neuropathic complications
Acoustic/mechanical neuromodulation[56-59]	pFUS; LIPUS; US	Hepatic hilum, portal vein region, or peripheral nerve plexus (deep tissue)	Mechanical stress on glucose-sensing afferents by focused ultrasound	Non-invasive, spatially selective, real-time image guidance; limited mechanistic resolution	Obese or insulin-resistant individuals, early T2DM
Optogenetic neuromodulation[58-60]	OS	Pancreatic parasympathetic fibers, hepatic vagal branches (experimental)	Optical activation of genetically targeted neurons controlling endocrine output	High cellular specificity; requires genetic modification, currently preclinical	Conceptual or experimental models of neural and metabolic coupling

taVNS: Transcutaneous auricular vagus nerve stimulation; pVNS: Peripheral vagus nerve stimulation; aVNS: Auricular vagus nerve stimulation; eVNS: Electrical vagus nerve stimulation; SCS: Spinal Cord Stimulation; pFUS: Peripheral focused ultrasound stimulation; LIPUS: Low-intensity pulsed ultrasound stimulation; US: Ultrasound stimulation; OS: Optical stimulation; T2DM: Type 2 diabetes mellitus.