CNS control of the endocrine pancreas

Abstract

Increasing evidence suggests that, although pancreatic islets can function autonomously to detect and respond to changes in the circulating glucose level, the brain cooperates with the islet to maintain glycaemic control. Here, we review the role of the central and autonomic nervous systems in the control of the endocrine pancreas, including mechanisms whereby the brain senses circulating blood glucose levels. We also examine whether dysfunction in these systems might contribute to complications of type 1 diabetes and the pathogenesis of type 2 diabetes. Graphical abstract.

Keywords: Autonomic nervous system; Brain; Diabetes; Glucagon; Glucose; Insulin; Islet; Pancreas; Review.

Fig. 1

Sensory and autonomic innervation of the endocrine pancreas. The islet receives efferent innervation (solid lines) from both sympathetic (orange) and parasympathetic (teal) branches of the ANS, as well as sensory afferent fibres (dashed lines). Projecting from the lateral horn of the spinal cord, the cell bodies of sympathetic efferent fibres are positioned within the celiac ganglia (CG) and superior mesenteric ganglia (SMG). These fibres enter the islet along blood vessels (inset) and release noradrenaline from their terminals, stimulating glucagon secretion through binding to β-adrenergic receptors on alpha cells and inhibiting insulin secretion through activation of beta cell α2-adrenergic receptors. Afferent sympathetic fibres have their cell bodies in the dorsal root ganglia (DRG) and project to the laminae I and IV of the spinal cord. Efferent parasympathetic fibres originate in the DMNX and innervate intrapancreatic ganglia (IPG), which, in turn, sends cholinergic input to the islet to stimulate increased glucagon secretion from alpha cells and to potentiate insulin secretion through local release of acetylcholine via muscarinic receptors on beta cells (inset). Pseudounipolar afferent parasympathetic neurons have their cell bodies within the nodose ganglion (NG), and terminals in the islet and NTS. In response to hypoglycaemia, increased sympathetic activity inhibits insulin secretion, while both increased sympathetic and parasympathetic activity stimulates glucagon secretion. This figure is available as part of a downloadable slideset.

Fig. 2

Central neurocircuits implicated in efferent outflow to the islet. Motor neurons of the SNS and PNS receive input from extensively overlapping brain nuclei, including both hypothalamic and hindbrain regions. Motor neurons of the SNS lie within the IML of the spinal cord and receive synaptic input directly from premotor neurons within the NTS. These sympathetic premotor neurons receive input from hypothalamic regions, including the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA), which, in turn, receive input from the VMN and ARC, amongst other brain areas. In contrast, efferent PNS pathways consist of preganglionic neurons in the DMNX, intrapancreatic ganglia and postganglionic neurons in the pancreas. The DMNX, in turn, receives input from hypothalamic areas, including the PVN, LHA, and VMN, via the periaqueductal grey (PAG) and/or raphe pallidus (Ra) and noradrenergic cell group 5 (A5). AP, area postrema. This figure is available as part of a downloadable slideset.

Fig. 3

Model for central glucose sensing. Circulating blood glucose levels are detected in both the periphery, by sensory afferent fibres (e.g., that innervate the hepatic portal vein), and central CVOs, including the ARC-ME and the area postrema (AP). This afferent information is relayed to neural centres located behind the BBB that comprise the efferent limb of the brain’s glucoregulatory system. These neurons also have the capacity to detect concentrations of glucose in brain ISF and, when activated, regulate both neuroendocrine and autonomic mechanisms through peripheral tissues, via both direct and indirect mechanisms, to regulate circulating blood glucose levels. This figure is available as part of a downloadable slideset.