Cerebral Adaptation

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When hypoglycaemia occurs, the stimulus for counterregulation appears to be a fall in the cerebral metabolic rate of glucose. Boyle et al. (1994) measured arteriovenous differences in glucose concentration in the human brain during hypoglycaemia to show that the rate of uptake of glucose (and by implication of metabolism) falls before most of the counterregula-tory responses and cognitive changes occur. They also demonstrated that this fall in metabolic rate of the brain was reduced in healthy volunteers who were made acutely hypoglycaemic following a period of 56 hours of protracted moderate hypoglycaemia, suggesting that the metabolism of the human brain can adapt to prolonged exposure to low blood glucose. This enables the brain to maintain its metabolism and continue to function in response to subsequent hypoglycaemia. A further study in diabetic patients showed that diabetic patients with strict glycaemic control and impaired awareness of hypoglycaemia were able to maintain the rate of cerebral uptake of glucose during experimental hypoglycaemia, while others with normal symptomatic awareness exhibited a marked fall in cerebral uptake of glucose, associated with symptomatic and counterregulatory hormonal responses (Figure 8.2) (Boyle et al., 1995). These data led to the hypothesis that impaired awareness of hypoglycaemia and defective glucose counterregulation may result from an adaptation in the sensitivity of the cerebral glucose sensor, which allows it to sustain its metabolic rate (and so not trigger counterregulation) during subsequent hypoglycaemia (see Chapter 7).

However, the expectation that patients with impaired awareness of hypoglycaemia will show an increase in brain glucose metabolic rate at any given blood glucose concentration has not been supported by neuroimaging studies. In studies utilising positron emission tomography that used various tracers for glucose to measure either the metabolic rate of brain glucose or glucose tracer uptake in humans, several investigators have failed to find differences during euglycaemia or hypoglycaemia that could be in accord with prevailing glycaemic control (Cranston et al., 2001; Segal et al., 2001). One study found evidence during hypoglycaemia of a difference in the change in uptake of the glucose tracer, de-oxyglucose, in the brain region around the hypothalamus in intensively-treated diabetic subjects who had impaired awareness of hypoglycaemia (Cranston et al., 2001), which is of interest because animal studies have implicated this region (among others) in sensing hypoglycaemia. In more recent studies, the difference in brain glucose metabolism in subjects with impaired awareness of hypoglycaemia was a failure of increase of cerebral metabolic rate during hypoglycaemia, associated with a failure to generate or perceive symptoms (Bingham et al., 2005). These data are compatible with the concept that cortical activation is important for perception of symptoms and that this fails in people who develop a loss of awareness of

Figure 8.2 Changes from baseline (mean ± SD) in (a) glucose uptake in the brain and (b) hypoglycaemia symptom scores, and plasma concentrations of (c) epinephrine and (d) pancreatic polypeptide during hypoglycaemia in patients with type 1 diabetes with differing degrees of glycaemic control (black bars), and in non-diabetic subjects (grey bars). Reproduced from Boyle et al. (1995) with permission. Copyright © 1995 Massachusetts Medical Society

Figure 8.2 Changes from baseline (mean ± SD) in (a) glucose uptake in the brain and (b) hypoglycaemia symptom scores, and plasma concentrations of (c) epinephrine and (d) pancreatic polypeptide during hypoglycaemia in patients with type 1 diabetes with differing degrees of glycaemic control (black bars), and in non-diabetic subjects (grey bars). Reproduced from Boyle et al. (1995) with permission. Copyright © 1995 Massachusetts Medical Society hypoglycaemia. It is becoming evident that changes in symptomatic responses and cortical function in hypoglycaemia are driven by complex mechanisms associated with, but not exclusively controlled directly by, the changes in the glucose metabolic rate of neurones. Some cognitive functions are better preserved than others during hypoglycaemia in subjects who have previous experience of hypoglycaemia than in hypoglycaemia-naive subjects who have normal counterregulation (Fanelli et al., 1993; Boyle et al., 1995). This does not entirely fit the clinical picture of patients becoming significantly confused during hypoglycaemia while remaining asymptomatic.

One measure of cognitive function, the choice reaction time, does not appear to adapt, and when hypoglycaemia is induced slowly, it deteriorates at similar levels of blood glucose in most subjects, irrespective of their previous glycaemic experience and their state of hypogly-caemia awareness (Maran et al., 1995). Other measures of cognitive function also deteriorate at similar levels of blood glucose in diabetic subjects who have had very disparate experiences of preceding glycaemia (Widom and Simonson, 1990; Amiel et al., 1991; Hvidberg et al., 1996). The ability of the brain to adapt its metabolic and functional capacity according to previous glycaemic experience varies across different regions of the brain. Regions of the brain that detect hypoglycaemia, and some parts of the cerebral cortex, may be able to adapt more effectively to antecedent hypoglycaemia than other areas, to sustain glucose metabolism during subsequent exposure. As blood glucose falls this would effectively destroy the normal protective hierarchy of corrective and symptomatic responses that precede cognitive impairment, replacing it with the dangerous situation whereby cognitive impairment is the initial response to hypoglycaemia, with autonomic responses not occurring until the blood glucose declines to a much lower level. In this situation the patient becomes too confused and unable to recognise the warning symptoms and so take appropriate corrective action (Figure 8.3).

Glycaemic Thresholds
Figure 8.3 The change in hierarchy of responses to hypoglycaemia (a) before and (b) after intensified insulin therapy in type 1 diabetes mellitus

The magnitude of the change in glycaemic thresholds for various functions of the brain in response to strict control of diabetes is variable. Where glucose thresholds for cognitive dysfunction do alter in people with impaired awareness of hypoglycaemia, the differences between the blood glucose thresholds for the symptomatic and autonomic responses and those for the onset of cognitive impairment are much smaller. As a result, the window of opportunity for the patient to recognise that hypoglycaemia is developing is much narrower, giving less time for corrective action to be taken. As described above, the molecular mechanisms controlling the thresholds for activation of the various components of the counterregulatory responses remain the subject of intense research.

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