Adrenaline: insights into its metabolic roles in hypoglycaemia and diabetes

Abstract

Adrenaline is a hormone that has profound actions on the cardiovascular system and is also a mediator of the fight-or-flight response. Adrenaline is now increasingly recognized as an important metabolic hormone that helps mobilize energy stores in the form of glucose and free fatty acids in preparation for physical activity or for recovery from hypoglycaemia. Recovery from hypoglycaemia is termed counter-regulation and involves the suppression of endogenous insulin secretion, activation of glucagon secretion from pancreatic α-cells and activation of adrenaline secretion. Secretion of adrenaline is controlled by presympathetic neurons in the rostroventrolateral medulla, which are, in turn, under the control of central and/or peripheral glucose-sensing neurons. Adrenaline is particularly important for counter-regulation in individuals with type 1 (insulin-dependent) diabetes because these patients do not produce endogenous insulin and also lose their ability to secrete glucagon soon after diagnosis. Type 1 diabetic patients are therefore critically dependent on adrenaline for restoration of normoglycaemia and attenuation or loss of this response in the hypoglycaemia unawareness condition can have serious, sometimes fatal, consequences. Understanding the neural control of hypoglycaemia-induced adrenaline secretion is likely to identify new therapeutic targets for treating this potentially life-threatening condition.

Figure 1

Biosynthesis and catabolism of adrenaline. Adrenaline biosynthesis begins with the hydroxylation of phenylalanine to tyrosine. Tyrosine hydroxylase catalyses the conversion of tyrosine to DOPA (dihydroxyphenylalanine), the rate‐limiting step in catecholamine biosynthesis. The final step in adrenaline biosynthesis is the methylation of noradrenaline by PNMT.

Figure 2

Innervation of the adrenal gland. The adrenal gland is innervated by preganglionic cholinergic neurons that target the adrenal chromaffin cells exclusively. Postganglionic noradrenergic neurons target only the vasculature of the entire gland. ‘Adrenaline’ chromaffin cells receive input from preganglionic neurons that receive premotor input from the rostral ventrolateral medulla (RVLM) that, in turn, receive input from glucose‐sensing neurons located elsewhere in the brain and the periphery. ‘Noradrenaline’ chromaffin cells receive input from preganglionic neurons that receive premotor input from barosensitive neurons in the RVLM.

Figure 3

Neuroglucoprivation activates a sympathetic preganglionic neuron (SPN) with PNMT inputs. This choline acetyltransferase‐immunoreactive (grey cytoplasmic staining) SPN from a rat that had received 2‐DG (400 mg·kg⁻¹. i.p.) has a black Fos‐immunoreactive nucleus and receives close appositions from varicosities of black PNMT‐immunoreactive axons. The presence of Fos‐immunoreactivity indicates neuronal activation.

Figure 4

Central neurocircuitry that controls hypoglycaemia‐induced adrenaline release from the adrenal gland. Perifornical hypothalamic (PeH) orexin neurons are activated by falling brain concentrations of glucose (Glu) that are probably detected by GABAergic ventromedial hypothalamic (VMH) neurons. VMH glucose‐sensitive neurons are ‘glucose excited’, and so, the declining brain glucose concentration results in disinhibition of the orexin neurons. Orexin (Ox) release onto ‘adrenal’ sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) activates sympathetic drive to adrenal chromaffin cells, which release adrenaline thereby raising blood levels of this metabolic hormone.