Mechanisms Of Counterregulatory Failure

At the onset of type 1 diabetes, hormonal counterregulation is usually normal but within five years of diagnosis, glucagon responses to hypoglycaemia become markedly impaired or even absent, although a glucagon response can occur if the hypoglycaemic stimulus is sufficiently profound (Frier et al. 1988; Hvidberg et al. 1998). After ten years of diabetes, patients usually have a sub-optimal epinephrine response to compound the absent glucagon response to a fall in blood glucose (White et al., 1985) (Figure 6.10). Thus, patients with type 1 diabetes of long duration are at risk of severe and prolonged neuroglycopenia during hypoglycaemia as a direct consequence of inadequate glucose counterregulation. Although attenuated growth hormone and cortisol responses are less common, they are late manifestations in terms of diabetes duration.

As mentioned previously, these defects in glucose counterregulation are not 'all or nothing' changes but can be influenced by the prevailing standard of glycaemic control and by the frequency of hypoglycaemic episodes. Various theories relate to the clinical observation that blood glucose thresholds for the release of counterregulatory hormone levels can change after periods of recurrent hypoglycaemia (Cryer, 2005). These may relate to changes at the level of the CNS, which co-ordinates the usual responses to low blood glucose levels. At present there is little evidence to suggest that the alterations associated with recurrent hypoglycaemia occur at glucose sensors outside the CNS, for example, within the portal vein.

type 1 diabetes 1-5 years

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type 1 diabetes 1-5 years

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type 1 diabetes 14-31 years

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Figure 6.10 Influence of duration of diabetes on glucagon and epinephrine responses to hypoglycaemia in patients with type 1 diabetes (•) after (a) 1-5 years (glucagon response is blunted whereas epinephrine release is preserved); and (b) with long-standing diabetes, both responses become severely impaired. o = non-diabetic controls. Reproduced from Textbook of Diabetes, 2nd edition (1997) Pickup J. and William G. (eds) by permission of Blackwell Science Ltd. Data sourced from Bolli et al. (1983). Copyright © 1983 American Diabetes Association. Reprinted with permission from The American Diabetes Association

Systemic Mediator

The systemic mediator theory suggests that a substance is released in response to hypogly-caemia which attenuates subsequent sympathoadrenal responses to further episodes of hypo-glycaemia. The initial candidate for this was cortisol, based on two observations: first, the attenuating effect of antecedent hypoglycaemia on later sympathoadrenal responses is absent in patients with primary adrenocortical failure; and second, in healthy volunteers, following infusions of cortisol (to supraphysiological levels) during euglycaemia, adrenomedullary epinephrine secretion and muscle sympathetic neural activity were reduced during subsequent hypoglycaemia (Davis et al., 1996; 1997). However, this effect of cortisol is lost if the prevailing cortisol levels are lowered towards those seen during hypoglycaemia or if recurrent hypoglycaemia is induced in animals that are genetically modified to have absent adrenocortical responses (Raju et al., 2003; McGuiness et al., 2005).

Brain Fuel Transport

This mechanism is based on the hypothesis that following antecedent hypoglycaemia, glucose transport from blood into brain tissue is increased - in animals by increasing GLUT-1 transport across the brain microvasculature (McCall et al., 1986; Kumagai et al., 1995). In patients with type 1 diabetes whose treatment resulted in near normal glucose levels, impaired awareness of hypoglycaemia can develop - such patients are at increased risk of seizures and coma. Boyle etal. (1995) tested the hypothesis that during hypoglycaemia, these patients would have normal glucose uptake in the brain and consequently that sympathoadrenal activation would not occur, resulting in impaired awareness of hypoglycaemia. They found that there was no significant change in the uptake of glucose in the brain among the patients with type 1 diabetes who had the lowest HbA1c levels. Conversely, glucose uptake in the brain fell in patients with less well-controlled type 1 diabetes. The responses of plasma epinephrine and pancreatic polypeptide and the frequency of symptoms of hypoglycaemia were also lowest in the group with the lowest HbA1c values. They concluded that during hypoglycaemia, patients with nearly normal HbA1c values have normal glucose uptake in the brain, preserving cerebral metabolism, reducing the responses of counterregulatory hormones, and causing impaired awareness of hypoglycaemia (Boyle et al., 1995). However, these findings occurred after days of prolonged hypoglycaemia which is in contrast to the clinical observation that attenuated sympathoadrenal responses occur within hours of a hypoglycaemic event.

More recently, studies using positron emission tomography have found no change in blood-to-brain glucose transport 24 hours after an episode of hypoglycaemia and no differences between individuals with and without hypoglycaemia awareness (Segel etal., 2001; Bingham et al., 2005). It remains possible, however, that there are changes in the transport of alternative cerebral fuels following antecedent hypoglycaemia.

Brain Metabolism

It has been hypothesised that brain metabolism per se is altered following an episode of hypoglycaemia. Most research in this area has focused on the ventromedial nucleus of the hypothalamus. Glucose deprivation in the VMH (by administration of 2-deoxyglucose) activates the sympathoadrenal system and increases glucagon secretion whereas local perfusion

Delivery

Caffeine

Figure 6.11 Caffeine may act by uncoupling brain glucose demand (increased) and substrate delivery (decreased) through its actions on adenosine receptors. Reproduced from Brain Research Reviews, 17, Nehlig et al., 139-169, Copyright (1992), with permission from Elsevier

Utilisation

Caffeine

Figure 6.11 Caffeine may act by uncoupling brain glucose demand (increased) and substrate delivery (decreased) through its actions on adenosine receptors. Reproduced from Brain Research Reviews, 17, Nehlig et al., 139-169, Copyright (1992), with permission from Elsevier of the area with glucose suppresses these responses during systemic hypoglycaemia (Borg et al., 1995; Borg et al., 1997). The mechanisms involved are unknown but may be a consequence of increased glucokinase activity to enhance glucose metabolism in neurones in the region (Gabriely and Shamoon, 2005). However, it is likely that brain metabolism in areas and other signalling mechanisms within the CNS are influenced by recurrent antecedent hypoglycaemia (Cryer, 2005).

The brain glycogen supercompensation hypothesis suggests that after a single episode of hypoglycaemia, there is a rebound increase in glycogen formation in brain astrocytes to provide additional substrates (e.g. lactate) for brain metabolism (Choi et al., 2003). Alterations of substrate delivery to the brain do appear to influence the magnitude of the hormonal counterregulatory response to hypoglycaemia in healthy volunteers and in patients with type 1 diabetes. Infusions of acetazolamide, a potent cerebral vasodilator, markedly attenuates these responses (Thomas et al., 1997) whereas ingestion of modest amounts of caffeine (to reduce substrate delivery) augments the responses (Debrah et al., 1996). The mechanisms of the latter is unknown but may involve antagonism of central adenosine receptors with uncoupling of brain blood flow (i.e., substrate delivery) and brain glucose metabolism (i.e., brain glucose demand) resulting in relative cerebral neuroglycopenia (Figure 6.11). This is discussed in more detail in Chapter 5.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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