Pancreatic nerves across species: Anatomical and functional disparities and their metabolic ramifications

Table 1 Summary of rodent pancreatic innervation features

Feature	Mouse	Rat
Nerve distribution	Clustered around vessels/lymphoid structures	Diffuse, regional heterogeneity
Key structural feature	Peri-islet nerve sheath	Absent
Nerve density (head/tail)	0.15%/0.02% tissue area	Head > tail (no exact values)
Sympathetic targets	Islet alpha/delta cells, vasculature	Islet alpha cells, vasculature

Table 2 Differences in the innervation of the pancreas among humans, mice, cats and dogs

Species category	Origin and pattern of pancreatic innervation	Islet architecture	Innervation of individual cells within the pancreatic islets	Disease-associated regulatory pathways or mechanisms of action
Humans	Derived from celiac and superior mesenteric plexuses; sympathetic (T6-L2) and parasympathetic (vagus) postganglionic fibers form networks, with sensory fibers and intrinsic neurons; denser innervation in pancreatic head/body and endocrine region, forming intrapancreatic neural network	Mixed distribution of α/β/δ cells	Sympathetic fibers contact α/δ cells; parasympathetic directly innervates a small number of β cells (signal transmission via electrocoupling). Sympathetic causes pancreatic vasoconstriction and inhibits exocrine secretion under stress; parasympathetic induces indirect vasodilation and promotes exocrine secretion	Parasympathetic: Preprandial glucagon secretion promotion, postprandial digestive enzyme and insulin secretion promotion; Sympathetic (stress): Insulin secretion inhibition and glucagon release promotion. Neural dysfunction + hypothalamic microinflammation → obesity and diabetes; sustained hyperglycemia/dyslipidemia aggravates nerve injury, forming a vicious cycle
Mice	Pancreatic nerves aggregate along blood vessels/Lymphatics, denser in pancreatic head/body; nerve sheaths around islets. Sympathetic/parasympathetic innervate islets; CGRP+ nociceptive fibers enriched in pancreatic tail	Pancreatic islets: Α/δ cells at periphery, β cells in core; nerves distribute as aggregated trunks with perislet nerve sheaths	Sympathetic innervates islet α/δ cells and blood vessels; parasympathetic innervates islets	Parasympathetic promotes postprandial insulin secretion; weak α-cell inhibition on β-cells. Reduced VIPergic fibers cause glucose metabolism disorders in CF mice; CGRP inhibits glucose-induced insulin release
Rats	Nerves diffusely distributed with regional heterogeneity (pancreatic head > body > tail); no perislet nerve sheaths. Sympathetic innervates islet blood vessels and α-cells; parasympathetic contacts β-cells	Islet β-cells in core, surrounded by α/δ/PP cells; nerves diffusely distributed	Sympathetic innervates islet blood vessels and α-cells; parasympathetic contacts β-cells	SP inhibits glucagon secretion in rats; TRPM3/PAK2. Excessive vagal nerve activity enhances glucose-stimulated insulin secretion by directly acting on pancreatic β-cells through the release of acetylcholine from its nerve terminals, leading to pathological hyperinsulinemia. The vagus nerve regulates the local immune environment of the pancreas via the spleen-dependent cholinergic anti-inflammatory pathway. Spleen deficiency impairs this pathway, thereby reducing the responsiveness of pancreatic islets to cholinergic stimulation and exacerbating pancreatic fat infiltration and inflammatory states[7]. Activation induces acute pancreatitis in rats, NRI/aTx model causes abnormal pancreatic load test responses in rats
Cat	Vagal afferent fibers originate from its dorsal motor nucleus; sympathetic postganglionic neurons in thoracolumbar DRG (T3-L5); VAChT+ parasympathetic fibers contact islet β-cells	Regional specificity: Α-cell enrichment in splenic region, PP-cell enrichment in duodenal region[8]	VAChT+ parasympathetic fibers contact islet β-cells; sympathetic postganglionic and sensory neurons innervate the more cranial duodenal segments densely, and the splenic segments sparsely and centrally[8]	Pancreatitis is often complicated with inflammatory bowel disease, cholangitis (triad); obesity induces insulin resistance, increasing the β-cell load; chronic hyperglycemia generates toxicity, impairing β-cell function and reducing their quantity, thereby forming a vicious cycle of “resistance-secretion imbalance”[9]. NRI + SDR regimen restores pancreatic nerve conduction function in cat models
Dog	Derived from celiac and superior mesenteric plexuses; vagal activation increases insulin secretion, visceral sympathetic stimulation enhances glucagon release	Mixed distribution of α/β/δ cells (similar to humans)	Vagal activation promotes insulin secretion in β-cells; sympathetic stimulation enhances glucagon release in α-cells	Sympathetic-parasympathetic fiber ratio affects pancreatic tone & stress metabolism; SP regulates insulin/glucagon secretion depending on concentration; pancreatitis is mostly associated with high fat, diet and drugs

CGRP: Calcitonin gene-related peptide; VAChT: Vesicular acetylcholine transporter; SP: Substance P; VIP: Vasoactive intestinal peptide; NK-1R: Neurokinin-1 receptor; TRPM3: Transient receptor potential melastatin type 3 channel; PAK2: P21-activated kinase 2; CF: Cystic fibrosis; CFRD: Cystic fibrosis-related diabetes; AP: Acute pancreatitis; NRI: Nerve reconstruction and implantation; aTx: Axotomy; SDR: Selective dorsal root rhizotomy; PP cells: Pancreatic polypeptide cells; DRG: Dorsal root ganglion.