Deconstructing the origins of sexual dimorphism in sensory modulation of pancreatic β cells

The regulation of glucose-stimulated insulin secretion and glucose excursion has a sensory component that operates in a sex-dependent manner. Objective: Here, we aim to dissect the basis of the sexually dimorphic interaction between sensory neurons and pancreatic β cells and its overall impact on insulin release and glucose homeostasis. Methods: We used viral retrograde tracing techniques, surgical and chemodenervation models, and primary cell-based co-culture systems to uncover the biology underlying sex differences in sensory modulation of pancreatic β-cell activity. Results: Retrograde transsynaptic labeling revealed a sex difference in the density of sensory innervation in the pancreas. The number of sensory neurons emanating from the dorsal root and nodose ganglia that project in the pancreas is higher in male than in female mice. Immunostaining and confocal laser scanning microscopy confirmed the higher abundance of peri-islet sensory axonal tracts in the male pancreas. Capsaicin-induced sensory chemodenervation concomitantly enhanced glucose-stimulated insulin secretion and glucose clearance in male mice. These metabolic benefits were blunted when mice were orchidectomized prior to the ablation of sensory nerves. Interestingly, orchidectomy also lowered the density of peri-islet sensory neurons. In female mice, capsaicin treatment did not affect glucose-induced insulin secretion nor glucose excursion and ovariectomy did not modify these outcomes. Interestingly, same- and opposite-sex sensory-islet co-culture paradigms unmasked the existence of potential gonadal hormone-independent mechanisms mediating the male-female difference in sensory modulation of islet β-cell activity. Conclusion: Taken together, these data suggest that the sex-biased nature of the sensory control of islet β-cell activity is a result of a combination of neurodevelopmental inputs, sex hormone-dependent mechanisms and the potential action of somatic molecules encoded by the sex chromosome complement.