Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet

Abstract

Acetylcholine regulates hormone secretion from the pancreatic islet and is thus crucial for glucose homeostasis. Little is known, however, about acetylcholine (cholinergic) signaling in the human islet. We recently reported that in the human islet, acetylcholine is primarily a paracrine signal released from α-cells rather than primarily a neural signal as in rodent islets. In this study, we demonstrate that the effects acetylcholine produces in the human islet are different and more complex than expected from studies conducted on cell lines and rodent islets. We found that endogenous acetylcholine not only stimulates the insulin-secreting β-cell via the muscarinic acetylcholine receptors M3 and M5, but also the somatostatin-secreting δ-cell via M1 receptors. Because somatostatin is a strong inhibitor of insulin secretion, we hypothesized that cholinergic input to the δ-cell indirectly regulates β-cell function. Indeed, when all muscarinic signaling was blocked, somatostatin secretion decreased and insulin secretion unexpectedly increased, suggesting a reduced inhibitory input to β-cells. Endogenous cholinergic signaling therefore provides direct stimulatory and indirect inhibitory input to β-cells to regulate insulin secretion from the human islet.

Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

“…Elevated FEV, TPH1, and SLC6A4 expression suggests PP/ gamma cells share a suite of characteristic genes with serotonergic neurons that, in the pancreas, integrate central and peripheral hunger and satiety cues. We also observed high PP/gamma expression of muscarinic acetylcholine receptor M3, CHRM3, which stimulates exocrine pancreatic amylase (Gautam et al 2005), insulin secretion (Kong and Tobin 2011;Molina et al 2014), and smooth muscle contraction and gastric emptying (Eglen et al 1994). These data implicate the less abundant delta and PP/gamma cell types as critical for islet function via the integration of systemic cues and warrant further studies to elucidate the function and health of these cells in normal and diabetogenic conditions.…”

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

“…2). Moreover, other nutrients (such as free fatty acids (Gravena et al 2002, Itoh et al 2003), hormones (such as GLP1 (Campbell & Drucker 2013)) and neurotransmitters (such as acetylcholine (Gautam et al 2007, Molina et al 2014) can also augment the action of Ca 2+ on exocytosis (Fig. 2).…”

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

“…We analyzed the enrichment of the DNA template by conventional PCR using primers specific for Cav1. 1,Cav1.2,Cav1.3,Cav1.4 …”

“…The functions of different cell types within Langerhans islets are precisely regulated by paracrine interactions, and these coordinate the rate and level of reciprocal insulin and glucagon secretion, thereby maintaining glucose homeostasis in response to changes in nutrient levels in different physiological contexts (1)(2)(3)(4). The disruption of this fine-tuned islet circuit by the aberrant regulation of paracrine islet interactions plays an important role in the development of diabetes (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

“…The disruption of this fine-tuned islet circuit by the aberrant regulation of paracrine islet interactions plays an important role in the development of diabetes (1)(2)(3)(4)(5)(6)(7)(8)(9). For example, the loss of the important paracrine factor urocortin 3 (UCN3) in pancreatic β cells caused dysregulation of a somatostatin-mediated negative feedback loop between islet δ and β cells, resulting in aberrant glucoseinduced insulin secretion and contributing to the pathophysiology of diabetes (5,10,11).…”