Counterregulation During Hypoglycaemia

The potentially serious effects of hypoglycaemia on cerebral function mean that not only are stable blood glucose concentrations maintained under physiological conditions, but also if hypoglycaemia occurs, mechanisms have developed to combat it. In clinical practice, the principal causes of hypoglycaemia are iatrogenic (as side-effects of insulin and sulphony-lureas used to treat diabetes) and excessive alcohol consumption. Insulin secreting tumours (such as insulinoma) are rare. The mechanisms that correct hypoglycaemia are called coun-terregulation, because the hormones involved oppose the action of insulin and therefore are the counterregulatory hormones. The processes of counterregulation were identified in the mid 1970s and early 1980s, using either a bolus injection or continuous infusion of insulin to induce hypoglycaemia (Cryer, 1981; Gerich, 1988). The response to the bolus injection of 0.1 U/kg insulin in a normal subject is shown in Figure 1.3. Blood glucose concentrations decline within minutes of the administration of insulin and reach a nadir after 20-30 minutes, then gradually rise to near normal by two hours after the insulin was administered. The fact

Blood Glucose Nadir
Figure 1.3 (a) Glucose and (b) insulin concentrations after intravenous injection of insulin 0.1 U/kg at time 0. Reproduced from Garber et al. (1976) by permission of the Journal of Clinical Investigation

that blood glucose starts to rise when plasma insulin concentrations are still ten times the baseline values means that it is not simply the reduction in insulin that reverses hypogly-caemia, but active counterregulation must also occur. Many hormones are released when blood glucose is lowered (see below), but glucagon, the catecholamines, growth hormone and cortisol are regarded as being the most important.

Several studies have determined the relative importance of these hormones by producing isolated deficiencies of each hormone (by blocking its release or action) and assessing the subsequent response to administration of insulin. These studies are exemplified in Figure 1.4 which assesses the relative importance of glucagon, adrenaline (epinephrine) and growth hormone in the counterregulation of short term hypoglycaemia. Somatostatin infusion blocks glucagon and growth hormone secretion and significantly impairs glucose recovery (Figure 1.4a). If growth hormone is replaced in the same model to produce isolated glucagon deficiency (Figure 1.4b), and glucagon replaced to produce isolated growth hormone deficiency (Figure 1.4c), it is clear that it is glucagon and not growth hormone that is responsible for acute counterregulation. Combined alpha and beta adrenoceptor blockade using phento-lamine and propranolol infusions or adrenalectomy (Figure 1.4d), can be used to evaluate the role of the catecholamines. These and other studies demonstrate that glucagon is the most important counterregulatory hormone whereas catecholamines provide a backup if glucagon is deficient (for example in type 1 diabetes, see Chapters 6 and 7). Cortisol and

Cryer Counter Regulation

Figure 1.4 Glucose recovery from acute hypoglycaemia. Glucose concentration following an intravenous injection of insulin of 0.05 U/kg at time 0; after (a) saline infusion (continuous line) and somatostatin, (b) somatostatin and growth hormone (GH), (c) somatostatin and glucagon, (d) combined alpha and beta blockade with phentolamine and propranolol infusions or adrenalectomy, (e) somatostatin with alpha and beta blockade, and (f) somatostatin in adrenalectomised patients. Saline infusion = continuous lines; experimental study = broken lines. Reproduced from Cryer (1981) courtesy of the American Diabetes Association (epinephrine = adrenaline)

Figure 1.4 Glucose recovery from acute hypoglycaemia. Glucose concentration following an intravenous injection of insulin of 0.05 U/kg at time 0; after (a) saline infusion (continuous line) and somatostatin, (b) somatostatin and growth hormone (GH), (c) somatostatin and glucagon, (d) combined alpha and beta blockade with phentolamine and propranolol infusions or adrenalectomy, (e) somatostatin with alpha and beta blockade, and (f) somatostatin in adrenalectomised patients. Saline infusion = continuous lines; experimental study = broken lines. Reproduced from Cryer (1981) courtesy of the American Diabetes Association (epinephrine = adrenaline)

growth hormone are important only in prolonged hypoglycaemia. Therefore if glucagon and catecholamines are both deficient, as in longstanding type 1 diabetes, counterregulation is seriously compromised, and the individual is defenceless against acute hypoglycaemia (Cryer, 1981).

Glucagon and catecholamines increase glycogenolysis and stimulate gluconeogenesis. Catecholamines also reduce glucose utilisation peripherally and inhibit insulin secretion. Cortisol and growth hormone increase gluconeogenesis and reduce glucose utilisation. The role of the other hormones (see below) in counterregulation is unclear, but they are unlikely to make a significant contribution. Finally, there is evidence that during profound hypoglycaemia (blood glucose below 1.7 mmol/l), hepatic glucose output is stimulated directly, although the mechanism is unknown. This is termed hepatic autoregulation.

The depth, as well as the duration, of hypoglycaemia is important in determining the magnitude of the counterregulatory hormone response. Studies using 'hyperinsulinaemic clamps' show a hierarchical response of hormone production. In this technique, insulin is infused at a constant rate and a glucose infusion rate varied to maintain blood glucose concentrations within ±0.2 mmol/l of target concentrations. This permits the controlled evaluation of the counterregulatory hormone response at varying degrees of hypoglycaemia. It also demonstrates that glucagon, catecholamines and growth hormone start to be secreted at a blood glucose concentration of 3.5-3.7 mmol/l, with cortisol produced at a lower glucose of 3.0mmol/l (Mitrakou et al., 1991). The counterregulatory response is initiated before impairment in cerebral function commences, usually at a blood glucose concentration of approximately 3.0 mmol/l (Heller and Macdonald, 1996).

The magnitude of the hormonal response also depends on the length of the hypogly-caemic episode. The counterregulatory hormonal response commences up to 20 minutes after hypoglycaemia is achieved and continues to rise for 60 minutes (Kerr et al., 1989). In contrast, this response is attenuated as a result of a previous episode of hypoglycaemia (within a few days) (reviewed by Heller and Macdonald, 1996) and even by prolonged exercise the day before hypoglycaemia is induced. Galassetti et al. (2001) showed that in non-diabetic subjects three hours of moderate intensity exercise the previous day markedly decreased the counterregulatory response to hypoglycaemia induced by the infusion of insulin, and that the reduced counterregulatory response was more marked in men than in women.

Although the primary role of the counterregulatory hormones is on glucose metabolism, any effects on fatty acid utilisation can have an indirect effect on blood glucose. Thus, the increase in plasma epinephrine (adrenaline) (and activation of the sympathetic nervous system) that is seen in hypoglycaemia can stimulate lipolysis of triglyceride in adipose tissue and muscle and release fatty acids which can be used as an alternative fuel to glucose, making more glucose available for the CNS. Enoksson et al. (2003) demonstrated that patients with type 1 diabetes, who had lower plasma epinephrine responses to hypoglycaemia than non-diabetic controls, also had reduced rates of lipolysis in adipose tissue and skeletal muscle, making them more dependent on glucose as a fuel and therefore at risk of developing a more severe hypoglycaemia.

The complex counterregulatory and homeostatic mechanisms described above are thought to be mostly under the control of the central nervous system. Evidence for this comes from studies in dogs, where glucose was infused into the carotid and vertebral arteries to maintain euglycaemia in the brain. Despite peripheral hypoglycaemia, glucagon did not increase and responses of the other counterregulatory hormones were blunted. This, and other studies in rats, led to the hypothesis that the ventromedial nucleus of the hypothalamus (VMH), which does not have a blood-brain barrier, acts as a glucose-sensor and co-ordinates counterregulation (Borg et al., 1997). However, evidence exists that other parts of the brain may also be involved in mediating counterregulation.

It is now clear that glucose-sensing neurones can involve either glucokinase or ATP-sensitive K+ channels (Levin et al., 2004). In rats, the VMH has ATP-sensitive K+ channels which seem to be involved in the counterregulatory responses to hypoglycaemia, as injection of the sulphonylurea, glibenclamide, directly into the VMH suppressed hormonal responses to systemic hypoglycaemia (Evans et al., 2004).

The existence of hepatic autoregulation suggests that some peripheral control should exist. Studies producing central euglycaemia and hepatic portal venous hypoglycaemia in dogs have provided evidence for hepatic glucose sensors and suggest that these sensors, as well as those in the brain, are important in the regulation of glucose (Hamilton-Wessler et al., 1994). However, this topic is somewhat controversial and more recent studies on dogs have failed to demonstrate an effect of hepatic sensory nerves on the responses to hypoglycaemia (Jackson et al., 2000). Moreover, studies in humans by Heptulla et al. (2001) showed that providing glucose orally rather than intravenously during a hypoglycaemic hyperin-sulinaemic clamp actually enhanced the counterregulatory hormone responses rather than reduced them.

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