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

Table 1 Innervation of key metabolic organs and their roles in blood glucose regulation

Organ	Nerve type	Innervation description	Role in glucose regulation	Key neurotransmitters/pathways
Liver	SNS	Predominantly innervated by the greater splanchnic nerve	Activation stimulates hepatic glycogenolysis and gluconeogenesis, thereby increasing hepatic glucose output	Primarily releases norepinephrine, which acts on α- and β-adrenergic receptors
	PSNS	Innervated by the hepatic branch of the vagus nerve	Activation promotes glycogen synthesis and suppresses gluconeogenesis, leading to reduced hepatic glucose output	Releases acetylcholine, acting primarily on M3 muscarinic receptors
	Sensory nerves	Express various metabosensors	Detect intrahepatic signals such as glucose levels, ATP/AMP ratio, and inflammatory cytokines, and relay this information to the brainstem and hypothalamus	/
Pancreas	SNS	Originates from the celiac ganglion	Activation inhibits insulin secretion from β-cells while stimulating glucagon release from α-cells	Releases norepinephrine, which acts on α2-adrenergic receptors to suppress insulin secretion
	PSNS	Derived from the pancreatic branch of the vagus nerve	Activation (particularly postprandially) strongly stimulates the secretion of both insulin and glucagon, exhibiting a biphasic effect	Primarily releases acetylcholine acting on M3 receptors, promoting insulin secretion via the IP3/PKC signaling pathway. Additionally, neuropeptides such as VIP and PACAP are involved in enhancing secretory responses
	Sensory nerves	Densely distributed throughout the islets of Langerhans and surrounding pancreatic tissue	Detect local insulin and glucose levels, and participate in the feedback regulation of pancreatic islet function	/
Adipose tissue	SNS	Heavily innervates both white and brown adipose tissue	Activation stimulates lipolysis, increasing the release of FFAs, which may indirectly affect hepatic glucose output and muscle glucose utilization via lipotoxicity	Releases norepinephrine, which primarily acts on β3-adrenergic receptors to promote lipolysis
	Sensory nerves	Provide feedback on adipose tissue metabolic status	Detect levels of adipokines such as leptin and adiponectin, and relay energy storage signals to the central nervous system	Express receptors such as LepR and TrkB, the latter being a high-affinity receptor for BDNF
Skeletal muscle	SNS	Innervates blood vessels and muscle fibers	Moderate activation induces vasoconstriction, thereby limiting glucose delivery; excessive activation indirectly suppresses glucose uptake via β-AR-mediated mechanisms	Releases norepinephrine, which acts on α1-adrenergic receptors (causing vasoconstriction) and β2-adrenergic receptors (promoting vasodilation and enhancing glucose uptake). Key mechanisms in contraction-induced
	Somatic motor nerves	Regulate voluntary muscle contraction	Muscle contraction per se serves as the most potent stimulus for glucose uptake and utilization, primarily through AMPK activation and enhanced GLUT4 translocation	/
Gastrointestinal tract	PSNS	Vagus nerve (afferent/efferent) SNS	Enhances intestinal motility, stimulates secretion, and increases nutrient absorption surface area, thereby indirectly modulating the rate of blood glucose elevation	/
	Sensory nerves	Extremely abundant	Play an essential role. They detect nutrients such as glucose, fatty acids, and amino acids, as well as hormones (e.g., GLP-1, PYY, CCK), and transmit these signals via vagal afferents to the NTS. This triggers gut-brain axis reflexes that preemptively regulate insulin secretion (cephalic phase insulin release) and promote satiety	Express a wide range of nutrient-sensing receptors, including but not limited to GLP-1R, CCKAR, SGLT1, and GPR40

SNS: Sympathetic nervous system; PSNS: Parasympathetic nervous system; VIP: Vasoactive intestinal peptide; PACAP: Pituitary adenylate cyclase-activating polypeptide; FFA: Free fatty acid; BDNF: Brain-derived neurotrophic factor; NTS: Nucleus tractus solitarius.

Table 2 Overview of the neural regulation of glucose metabolism

Component	Description	Key structures/examples	Primary function	Ref.
Sensors	Sensory nerve endings acting as chemoreceptors and mechanoreceptors	Portal vein, liver, intestine, pancreas	Monitor blood glucose, nutrients, hormones, and metabolites	Joly-Amado et al[15], 2022
Afferent pathway	Nerves transmitting sensory signals to the central nervous system	Vagal afferent nerves (via nodose ganglion), spinal afferent nerves	Encode and relay peripheral signals to the brainstem (NTS)	Li et al[16], 2023
Central integration	Brain regions that process sensory information and generate commands	NTS, hypothalamus (ARC, PVN, VMH), parabrachial nucleus, cortex	Integrate signals to regulate energy balance and generate sensations like hunger	Vohra et al[17], 2022
Efferent pathway	Nerves conveying commands from the brain to peripheral organs	Sympathetic pathways, Parasympathetic pathways (dorsal vagal complex)	Regulate insulin secretion, glucose production/uptake, and gastrointestinal function to restore homeostasis	Papazoglou et al[18], 2022

NTS: Nucleus tractus solitarius; ARC: Arcuate nucleus; PVN: Paraventricular nucleus; VMH: Ventromedial hypothalamus.

Table 3 Typical patents for precise regulation of blood glucose based on the peripheral nervous system

Number	Name	First inventor	Core mechanism	Function	Ref.
US10722714B2	Methods and systems for glucose regulation	Arnold W Thornton	Modulating peripheral nerves affects insulin/GLP-1 secretion to regulate glycemia	Improve blood sugar control in diabetic patients	Yu et al[42], 2022
US8579891B2	Devices for thermally-induced hepatic neuromodulation	Jonathan Allen Coe	Destroying hepatic sympathetic nerves reduces hepatic glucose production via thermal ablation	Thermal ablation lowers blood sugar levels	Zhang et al[43], 2025
US20200046968A1	Transdermal optogenetic peripheral nerve stimulation	Hugh M Herr	Optogenetic activation of peripheral nerves via percutaneous light delivery from wearables regulates physiological functions	Optogenetic stimulation assists in blood glucose regulation	Kaushik et al[44], 2025
US8538542B2	Nerve stimulation and blocking for treatment of gastrointestinal disorders	Mark B Knudson	Vagus nerve electrical stimulation improves pancreatic exocrine, thereby modulating glucose metabolism	Improves digestion and assists in blood sugar regulation	Zhang et al[45], 2023
US9872985B2	Glucose regulation via electrical stimulation of nerves innervating the liver or pancreas	Robert Butera	Hepatic vagus/visceral nerve stimulation directly regulates hepatic glucose flux	No medication for blood sugar control	Dirr et al[46], 2023
US6885888B2	Electrical stimulation of the sympathetic nerve chain	Ali R Rezai	Sympathetic chain stimulation modulates ganglia, altering metabolic responses	It is widely used for treatment and does not directly target blood sugar	Payne et al[47], 2022

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.

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.