Noradrenergic fibers are associated with beta-cell dedifferentiation and impaired beta-cell function in humans

• Published in: Metabolism, clinical and experimental clinical and experimental, 2021-01, Vol.114, p.154414-154414, Article 154414
• Main Authors: Cinti, F., Mezza, T., Severi, I., Suleiman, M., Cefalo, C.M.A., Sorice, G.P., Moffa, S., Impronta, F., Quero, G., Alfieri, S., Mari, A., Pontecorvi, A., Marselli, L., Cinti, S., Marchetti, P., Giaccari, A.
• Format: Article
• Language: English
• Subjects: Adrenergic Neurons - physiology; Aged; Beta cell failure; Blood Glucose - metabolism; Cell Dedifferentiation - physiology; Dedifferentiation; Diabetes Mellitus, Type 2 - metabolism; Female; Glucose Intolerance - metabolism; Glyburide - metabolism; Human type 2 diabetes mellitus; Humans; Innervation; Insulin - metabolism; Insulin Secretion - physiology; Insulin-Secreting Cells - metabolism; Islets of Langerhans - metabolism; Male; Middle Aged; Nerve Fibers - physiology; Personalized medicine
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2020.154414

Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the “disappearance” of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. The islets of diabetic subjects were 3 times more innervated than controls (0.91 ± 0.21 vs 0.32 ± 0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = −0.84; p = 0.01), incremental second-phase insulin secretion (r = −0.84, p = 0.03) and arginine-stimulated insulin secretion (r = −0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process. •The islets of diabetic subjects are 3 times more innervated than controls.•Noradrenergic fibers increase is related to β-cell dedifferentiation and dysfunctions.•Noradrenergic fibers are in direct contact with β-cell.•Noradrenergic fibers: a new target to prevent β-cell dedifferentiation and dysfunctions.