Activation of Nicotinic Acetylcholine Receptors Decreases Apoptosis in Human and Female Murine Pancreatic Islets

Abstract

Type 1 diabetes (T1DM) results from destruction of most insulin-secreting pancreatic ␤-cells. The persistence of ␤-cells decades after the onset of the disease indicates that the resistance of individual cells to the autoimmune insult is heterogeneous and might depend on the metabolic status of a cell at a given moment. The aim of this study is to investigate whether activation of nicotinic acetylcholine receptors (nACh-Rs) could increase ␤-cell resistance against the adverse environment prevailing at the onset of T1DM. Here, we show that nACh-R activation by nicotine and choline, 2 agonists of the receptor, decreases murine and human ␤-cell apoptosis induced by proinflammatory cytokines known to be present in the islet environment at the onset of T1DM. The protective mechanism activated by nicotine and choline involves attenuation of mitochondrial outer membrane permeabilization via modulation of endoplasmic reticulum stress, of the activity of B-cell lymphoma 2 family proteins and cytoplasmic calcium levels. Local inflammation and endoplasmic reticulum stress being key determinants of ␤-cell death in T1DM, we conclude that pharmacological activation of nACh-R could represent a valuable therapeutic option in the modulation of ␤-cell death in T1DM. (Endocrinology 157: 3800 -3808, 2016) N icotinic acetylcholine receptors (nACh-Rs) belong to a family of ligand-gated channels that form a cationselective pathway across the plasma membrane of a given cell (1) and consist of hetero-or homopentamers of 17 different ␣-, ␤-, ␥-, ␦-, and ⑀-subunits that determine the properties of the channel (2, 3). They are implicated in neuronal processes such as synaptic transmission but also in the regulation of neuronal cell death in response to injuries such as hypoxia and glutamate excitotoxicity (4) and, outside the central nervous system, in the modulation of peripheral inflammation (5, 6). Their presence has been demonstrated on human and murine ␤-cells (7, 8). The ␣7-and ␤2-subunits are the most abundantly expressed subunits in murine islets, followed by the ␣3-and ␣5-subunits (7).Type 1 diabetes (T1DM) results from autoimmune destruction of most insulin-producing ␤-cells (9). The remaining ␤-cells, although not sufficient to properly regulate blood glucose, persist several decades after the onset of the disease (10). Thus, identifying strategies to modulate the resistance of ␤-cells to the adverse environment prevailing at the onset of T1DM could be of value to prevent the massive cell death observed at the onset of the disease or even to restore a sufficient cell mass from residual cells. ␤-cells, due to their high secretory activity, are susceptible to endoplasmic reticulum (ER) stress, a mech- Abbreviations: Bcl, B-cell lymphoma; BH3, Bcl-2 homology; CHOP, CCAAT/enhancer binding protein homologous protein; Cx36, connexin36; DP5, cell death-promoting gene 5; ER, endoplasmic reticulum; IFN, interferon; MOMP, mitochondrial outer membrane permeabilization; nACh-R, nicotinic acetylcholine receptor; NO, nitric oxide; PUMA, p53 u...

β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation

“…These data support the hypothesis that ␣7R agonist treatment, in the context of MLDS-induced islet inflammation, preserves BCM by reducing proinflammatory drive and enhancing survival. Our results are also in accord with a recent study demonstrating that nonspecific nAChR activation attenuates inflammatory cytokine-mediated ␤-cell apoptosis in mouse and human islets by reducing endoplasmic reticulum stress and alleviating the mitochondrial/Bcl2 protein-driven apoptotic cascade (41).…”

Vagotomy and Splenectomy Reduce Insulin Secretion and Interleukin-1β

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Nicotinic acetylcholine receptor signaling regulates inositol‐requiring enzyme 1α activation to protect β‐cells against terminal unfolded protein response under irremediable endoplasmic reticulum stress

“…To investigate nAChR signaling in detail, we focused on signaling through the α7 subunit for the following reasons. First, it is the most commonly expressed subunit among the nAChR subunits in rodent β‐cells. Second, the mechanisms underlying the recently revealed anti‐apoptotic effects of a complete and highly specific nAChR α7 agonist, PNU, in β‐cells are still unknown.…”