Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans

Abstract

Acetylcholine is a neurotransmitter that plays a major role in the function of the insulin secreting pancreatic beta cell1,2. Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species1,3,4, but the role of autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to mouse islets, cholinergic innervation of human islets is sparse. Instead, we find that the alpha cells of the human islet provide paracrine cholinergic input to surrounding endocrine cells. Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine when stimulated with kainate or a lowering in glucose concentration. Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration. We anticipate these results to revise models about neural input and cholinergic signaling in the endocrine pancreas. Cholinergic signaling within the islet represents a potential therapeutic target in diabetes5, highlighting the relevance of this advance to future drug development.

Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice

“…The muscarinic receptor is classically described as the terminal effector of the cholinergic signaling in pancreatic β-cells [34][35][36] and the function of nAChRs in the context of pancreatic islets has long been limited to their role in ganglionic autonomic vagal neurotransmission [37][38][39][40]. Nevertheless, paracrine cholinergic signaling sensitizes the glucoseinduced β-cell response in human islets [41] and nicotinic cholinergic stimulation dampens insulin secretion [15,42] whereas antagonism of the α7nAChR increases insulin release [43,44] according to previous studies. We presently report that α7 and β2 are the nAChR subunits most predominantly expressed in pancreatic islets isolated from mice whereas α5 and β2nAChR subunits are prevalent in human islets, highlighting clinical associations between variants in the genes encoding these nAChR subunits with both insulin resistance and type 2 diabetes [45].…”

Tuning to the right signal

“…In this issue of Diabetologia, Carol Yang, Quin Wills and Jim Johnson systematically evaluate the beta cell-protective properties of an extensive panel of over 200 factors on primary mouse beta cells [4]. These factors were selected on the basis of the expression of their cognate receptors in mouse or human islets, derived from prior work by the authors [5] among many others [6][7][8][9][10]. Recognising that beta cell stress in diabetes can occur in many different shapes and forms [3], each factor was systematically evaluated in five distinct islet cell culture conditions, reflective of different type 1 or type 2 diabetes-associated stresses.…”

Nicotinic Cholinergic Signaling in Adipose Tissue and Pancreatic Islets Biology: Revisited Function and Therapeutic Perspectives

“…Few parasympathetic cholinergic axons penetrate the human islet, and the invading sympathetic fibers preferentially innervate smooth muscle cells of blood vessels located within the islet, suggesting a role in the control of local blood flow (Rodriguez-Diaz et al 2011a). Poor cholinergic innervation of human islets appears to be substituted by the a cells which provide paracrine cholinergic input to surrounding endocrine cells (Rodriguez-Diaz et al 2011b). ACh secretion by a cells seems to sensitize the b cell response to increase in glucose concentration (Rodriguez-Diaz et al 2011b), making the paracrine cholinergic signaling within islets a potential therapeutic target in diabetes.…”

“…Poor cholinergic innervation of human islets appears to be substituted by the a cells which provide paracrine cholinergic input to surrounding endocrine cells (Rodriguez-Diaz et al 2011b). ACh secretion by a cells seems to sensitize the b cell response to increase in glucose concentration (Rodriguez-Diaz et al 2011b), making the paracrine cholinergic signaling within islets a potential therapeutic target in diabetes. In rodents, the expression of ChAT, VAChT, CHT-1 and a7 nAChR is identified in the core of islets (b cells), and expression of AChE is stronger in the surrounding exocrine tissue and in the mantle region of the islet (Delbro 2012), suggesting that rat b cells produce ACh which could in an autocrine/paracrine mechanism participate in insulin secretion via a7 nAChR receptors.…”