Glucose is an essential metabolic substrate for all bodily tissues. The brain depends particularly on a constant supply of glucose to satisfy its energy demands. Fortunately, a complex physiological system has evolved to keep blood glucose at a constant level. The consequences of poor glucose homeostasis are well-known: hyperglycemia associated with uncontrolled diabetes can lead to cardiovascular disease, neuropathy and nephropathy, while hypoglycemia can lead to convulsions, loss of consciousness, coma, and even death. The glucose counterregulatory response involves detection of declining plasma glucose levels and secretion of several hormones including glucagon, adrenaline, cortisol, and growth hormone (GH) to orchestrate the recovery from hypoglycemia. Low blood glucose leads to a low brain glucose level that is detected by glucose-sensing neurons located in several brain regions such as the ventromedial hypothalamus, the perifornical region of the lateral hypothalamus, the arcuate nucleus (ARC), and in several hindbrain regions. This review will describe the importance of the glucose counterregulatory system and what is known of the neurocircuitry that underpins it.
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. AbbreviationsASNA, adrenal sympathetic nerve activity; CART, cocaine-and amphetamine-regulated transcript; CVLM, caudal ventrolateral medulla; IML, intermediolateral cell column; PeH, perifornical hypothalamic; RVLM, rostroventrolateral medulla; SPNs, sympathetic preganglionic neurons IntroductionThe path to the discovery of adrenaline began when Oliver and Schafer described the pressor effect of extracts of the adrenal gland (Oliver and Schafer, 1895). Although they neither isolated the active principle nor gave it a name, they concluded that it was confined to the adrenal medulla and not the cortex. At the turn of the 20th century, purification of a similar extract was achieved by Abel in Baltimore and independently by Takamine in New York working under the auspices of the Parke-Davis Company: Takamine referred to the new compound as 'adrenalin ' (Takamine, 1902), while Abel preferred 'epinephrin' (Abel, 1898). As pointed out by Davenport, the Merck Index lists as many as 35 names for adrenaline including 'adrenine' (Merck, 1968;Davenport, 1982). In 1849, Addison noted that the adrenal glands were necessary for life; and, for a short time, some thought that the essential principle, which we now know to be cortisol, was the pressor substance isolated from the adrenal medulla (Addison, 1855;Davenport, 1982).In this review, we examine the importance of adrenaline as a metabolic hormone that mobilizes energy stores in the form of glucose and free fatty acids during the counterregulatory response to hypoglycaemia (Cryer, 1981). Pharmacology of adrenalineAdrenaline is best known to pharmacologists as a sub...
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