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

F Cinti,T Mezza,I Severi,M Suleiman,C.M.A Cefalo,G.P Sorice,S Moffa,F Impronta,G Quero,S Alfieri,A Mari,A Pontecorvi,L Marselli,S Cinti,P Marchetti,A Giaccari

doi:10.1016/j.metabol.2020.154414

Abstract

Aims/hypothesisType 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. MethodsUsing 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. ResultsThe 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). Conclusions/interpretationNoradrenergic 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.

Highlights

Type 2 diabetes is characterized by insulin resistance and a progressive loss of beta-cell function [1,2]
In a genetically obese mouse model of type 2 diabetes, we found a significant increase in the density of noradrenergic fibers in diabetic mice compared to non-diabetic ones
Despite wide consensus on the role played by insulin resistance and beta-cell dysfunctions in the natural history of type 2 diabetes, many other aspects of its pathogenesis are still unclear [1,38]

Summary

Introduction

Type 2 diabetes is characterized by insulin resistance and a progressive loss of beta-cell function [1,2]. The exhausted beta-cell, challenged by persistent glucotoxicity, seems to undergo dedifferentiation to escape cell death, exploiting this process to rest, while awaiting improved metabolic conditions to re-differentiate [6,7,8,9,10]. The fact that this process has been described in human type 2 diabetes and that its reversibility has been confirmed in mouse models, has shifted the spotlight onto the still unclear molecular mechanisms underlying it [8,9,11]. Noradrenergic fibers exert a well-known inhibitory effect on insulin secretion [18,22,23,24], most of the literature is focused on pancreatic noradrenergic innervation

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Results

Conclusion