The Increment of Noradrenergic Fibers Correlates with the Density of Dedifferentiated ß Cells in Humans

β cells dedifferentiation has been recently introduced as the main mechanism responsible for the functional “disappearance” of β cells from the islands of diabetic subjects. Starting from results obtained from a mouse model of type 2 (T2) diabetes (in whose a significant increase in density of noradrenergic fibers was detected compared to nondiabetic mice), we asked if the result could be replicated in humans and if it could be related to the process of dedifferentiation. Human pancreas of 8 healthy donors and 9 with T2 diabetes were analyzed by immunohistochemistry (M / F 4/4 vs. 5/4 NS; BMI (kg / m2) 24.8 ± 2.8 vs. 25.6 ± 4.1; NS). The dedifferentiation score was calculated as % of cells synaptophysin positive but negative for the four major pancreatic hormones. Tyrosine hydroxylase (TH) was used as a marker for the evaluation of noradrenergic fiber expression. The islands of diabetic subjects were about 3 times more innervated than controls (0.42 ± 0.51 vs. 1.66 ± 2.2 n.fibersTH +/island; p = 0.02); the increase of these fibers correlated positively with the dedifferentiation score (p <0.001; r = 0.69).

In conclusion, our data show an increase in the number of sympathetic nerve fibers potentially able to transmit inhibitory signals on insulin secretion in the islands of diabetic subjects. The important correlation with the dedifferentiation score suggests a significant role of noradrenergic fibers in the pathogenesis of the dedifferentiation process, introducing new strategies for the preservation of cellular mass/secretion and, therefore, for the prevention and treatment of T2 diabetes.