Glucose Homeostasis

Plasma glucose concentrations are normally maintained within a narrow range reflecting a balance between glucose production and glucose utilization. Postprandi-ally, glucose is derived from carbohydrate sources in the diet, whereas in the fasting state, glucose is released from the liver, initially through glycogenolysis and, with more prolonged fasting, through gluconeogenesis. The kidney may also contribute to overall endogenous glucose production during the postabsorptive state. The kidney has been shown to release glucose in response to both hypoglycemia (23) and catecholamines (24), as well as being insulin sensitive (25). In the anhepatic phase of surgery for liver transplantation, the kidney is the only source of sustained glucose production (26). However, its overall contribution to endogenous glucose production in health is still not clear.

The mechanisms of glucose homeostasis are controlled by a complex interaction of hormonal and metabolic regulatory processes that act to maintain a constant supply of circulating glucose, vital for the brain, which can neither store nor synthesize much of this substrate. Insulin is an essential hormone in the maintenance of this glucose balance. Portal venous insulin stimulates glycogen synthesis and suppresses gluconeogen-esis, with the effect of decreasing hepatic glucose output. Insulin also has effects on peripheral tissues, with an increase in glucose uptake by adipose tissue and muscle. Decreased hepatic glucose production and an increase in peripheral glucose uptake results in a net decrease in circulating glucose concentrations. One of the earliest responses to a fall in circulating glucose concentration is the curtailment of pancreatic insulin secretion. The inability of the insulin-treated diabetic individual to do this modulating of insulin concentration is the main cause of hypoglycemia in the treatment of type 1 diabetes.

Normally, the effects of insulin are balanced by counterregulatory hormones that oppose the action of insulin and hence prevent a significant fall in glucose. The most important of these hormones is glucagon, which is released from the a-cells of the pancreas immediately when glucose falls below a threshold of 3.6-3.8 mmol/L. Glucagon acts primarily to restore glucose concentrations by increasing glycogenolysis and glu-coneogenesis. The mechanism of control of glucagon secretion is still debated (27). Three potential mechanisms may act individually, or in concert. There may be direct effects of glucopenia and hyperinsulinemia or an indirect stimulatory effect via activation of the sympathetic and parasympathetic nervous systems (27). The evidence suggests a major role for falling insulin concentrations within the pancreas in the a-cell response to acute hypoglycemia. Thus, C-peptide-negative diabetic patients have defective glucagon responses specifically to hypoglycemia (28)—the second major cause of hypoglycemia in children with type 1 diabetes (29).

Release of catecholamines from the adrenal medulla during hypoglycemia is probably under neural control (30). Catecholamines increase hepatic glucose output by a direct effect on the liver and by stimulating lipolysis, providing a substrate for gluconeogenesis (31). Norepinephrine, released through stimulation of the parasympathetic nervous system, can stimulate hepatic glycogenolysis but has a more potent effect on lipolysis (32). Peripheral glucose uptake is diminished through a direct effect of catecholamines on muscle and adipose tissue (33) but also through the provision of alternative substrate in the form of nonesterified fatty acids, glycerol, and ketones. Defects in this third defense against hypoglycemia occur in significant numbers of diabetic patients, further increasing their risk of severe episodes, with loss of cognitive function (34)

Growth hormone (GH) and cortisol are also important but work over a much longer time scale. The control of GH secretion during hypoglycemia is incompletely understood, but is probably mediated by secretion of GH releasing hormone (GHRH) from the hypothalamus, which, in turn, stimulates GH release from pituitary somatotrophs— with a 30- to 60-min time lag (35). Reductions in somatostatin and activation of the autonomic nervous system may also play a role (36-39). GH promotes hepatic glucose production and provides substrates for gluconeogenesis by stimulating lipolysis and ketogenesis (40-42).

Adrenocorticotrophic hormone (ACTH) is released from the hypothalamus in response to hypoglycemia by a complex activation of stimulatory and inhibitory pathways (35). The plasma ACTH concentration peaks approx 45 min after the hypoglycemic

Fig. 1. Schematic representation of counterregulatory responses in healthy diabetic people (left), people with type 1 diabetes and good awareness of hypoglycemia (center), and those with hypogly-caemia unawareness (right). Sympathetic nervous system (SNS) represents sympathetic activation.

nadir (43) and stimulates a rise in plasma cortisol within 30 min, with a peak response achieved after 60-90 min (44). Nevertheless, the effects of cortisol on glucose metabolism generally take several hours to become evident (45). Cortisol augments glucose production during protracted hypoglycemia by stimulating gluconeogenesis (46). It also decreases peripheral glucose utilization and increases plasma free fatty acid and ketone concentrations (46).

Glucagon is the most important hormone during hypoglycemia (see Fig. 1). Epi-nephrine is less important in the hierarchy of hormones, but it becomes crucial for effective glucoregulation in the presence of deficient glucagon release (47). GH and cortisol become more important if hypoglycemia is prolonged (46,48).

There are few studies of glucose counterregulation in the pediatric literature (49-54). These studies have confirmed that glucagon responses during hypoglycemia are also lost in children with diabetes soon after diagnosis. This was even the case in a study of very young children, aged 18-57 mo, who had the shortest duration of diabetes (50). Epinephrine responses have been found to be more variable, although the majority suggest that children have exaggerated epinephrine responses during hypo-glycemia and this has been postulated as a reason for the glycemic lability that can be observed during childhood (49,53) (see Fig. 2). Although this exaggerated response is likely to be associated with initiation of responses at a higher glucose level during hypoglycemia than in adults (53), the main cause of elevated and exaggerated responses to acute hypoglycemia is likely to be poor glycemic control, with counter-regulatory systems accustomed to a higher blood glucose, in general, and therefore responding to "hypoglycemia" at relatively high glucose levels. More recently, adolescents were found to have blunted epinephrine responses during hypoglycemia (54).

Fig. 2. Mean (± SEM) plasma epinephrine concentrations during sequential euglycemic-hypo-glycemic clamp study in 16 children and 11 adults with insulin-dependent diabetes (A) and in 14 children and eight adults without diabetes (B). (Reproduced with permission from ref. 49.)

The reason for the discrepant results compared to the earlier studies may be the result of differences in the techniques of inducing experimental hypoglycemia.

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