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.