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

Table 4 Summary of representative neuromodulation and biophysical stimulation interventions for glycemic regulation in experimental and clinical models

Intervention methods	Experimental subject	Intervention duration	Stimulus parameter	Main results	Ref.
taVNS	ZDF rats with T2D	4 weeks, 30 minutes daily	2 mA, 15 Hz	The blood glucose level in the taVNS group decreased from the second week and remained below the baseline level throughout the observation period	Payne et al[48], 2020
taVNS	Male Balb/C mice with HFD	1 week	1.0 mA, 10 Hz	The elevated fasting blood glucose levels in the HFD mice were ameliorated by taVNS	Kufaishi et al[49], 2025
taVNS	Male albino Wistar rats	2 weeks	6 Hz, 1 ms, 6 V	The fasting glucose level was significantly supressed by VNS therapy	Cotero et al[50], 2022
taVNS	Male ZDF rats with T2D	6 weeks	2 mA, 2 Hz/15 Hz	The fasting blood glucose was decreased (P < 0.05, P < 0.01) and the insulin receptor expression level in the liver, the skeletal muscle and the pancreas was increased (P < 0.05, P < 0.01, P < 0.001)	Wang et al[51], 2025
pVNS	Male Lewis rats with T1D	30 minutes	0-3 mA, 10 Hz	After 30 minutes of stimulation, insulin levels rose significantly (+279 pg/mL)	Chang et al[52], 2023
eVNS	Male Sprague-Dawley rats with T2D	1 hour	15 Hz distal pulses with 26 kHz/4 mA proximal HF block	During 1 hour of eVNS, glycemia decreased in 90% of subjects (-1.25 ± 1.25 mM/hour, P = 0.017)	Ashe et al[53], 2023
aVNS	Male Sprague-Dawley rats	60 minutes	4 mA, 40 kHz	High-frequency stimulation at 40 kHz did not affect blood glucose levels but led to a significant reduction in glucagon levels	Li et al[54], 2021
taVNS	Individuals with T1D or T2D and DAN	8 weeks	60 mA, 25 Hz	No significant changes were observed in CGM metrics between treatment arms, while individuals with T1D and DAN decreased their CV after 8 weeks of tVNS treatment	Yu et al[55], 2021
pFUS	ZDF rats with T2D, HFD or db/db mice, swine	40 days, 3 minutes daily	1.1 MHz, 5 Hz, 125.7 W/cm2	Daily application of pFUS for 3 minutes can maintain the circulating blood glucose of T2D animals to normal levels, increase glucose uptake and glycogen accumulation in peripheral tissues, especially skeletal muscles, and comprehensively improve glucose tolerance and insulin sensitivity	Mansouri et al[56], 2021
LIPUS	C57BL/6J mice with T2D	4 weeks	1 MHz, 1.0 kHz	The mice in the T2D-LIPUS group displayed significantly lower area under the curve of glucose tolerance tests and insulin tolerance tests and fasting serum insulin levels compared to the T2D-sham group	Petersen et al[57], 2025
US	Sprague-Dawley rats with T2D	30 minutes	1 MHz, 15 Hz, 7.21 W/cm2	The blood glucose level decreased within 5 minutes of US and the insulin concentration showed an upward trend	Huang et al[72], 2014
pFUS	Individuals with T2D	3 days	2.28 MHz, 3.7 Hz, 200 µs, 489 mW/cm2	Fasting insulin was lowered, resulting in a reduction of HOMA-IR scores	Nicolai et al[73], 2023
OS	Mice with T1D	Not mentioned	460 nm, 1.4 W/m2	Blue light regulates insulin expression and reduces blood glucose levels in T1D mice	Browning et al[58], 2014
OS	Mice with T1D	40 days, 2 hours daily	730 nm, 10 mW/cm2	Far-red light exposure raised insulin levels, reduced blood glucose levels and glycated hemoglobin concentrations	EAS FHSC[59], 2024
OS	Mice with T1D	15 minutes	2-5 mW/cm2	After 15 minutes of white light irradiation, insulin levels increased and glucose concentration decreased	Lincoff et al[60], 2023

taVNS: Transcutaneous auricular vagus nerve stimulation; ZDF: Zucker diabetic fatty rat; T2D: Type 2 diabetes; HFD: High fat diet; VNS: Vagus nerve stimulation; eVNS: Electrical vagus nerve stimulation; pVNS: Peripheral vagus nerve stimulation; aVNS: Auricular vagus nerve stimulation; T1D: Type 1 diabetes; DAN: Diabetic autonomic neuropathy; CGM: Continuous glucose monitoring; CV: Coefficient of variation; tVNS: Transcutaneous vagus nerve stimulation; pFUS: Peripheral focused ultrasound stimulation; LIPUS: Low-intensity pulsed ultrasound stimulation; US: Ultrasound stimulation; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; OS: Optical stimulation; EAS FHSC: European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration.