Effects of Acute Hypoglycemia on Cognitive Function in T1DM
Effects of Acute Hypoglycemia on Cognitive Function in T1DM
A wide inter-individual variation in cognitive dysfunction is present during hypoglycaemia, although on repeat testing it remains relatively stable within the same subject. A number of factors may modify an individual's cognitive performance during hypoglycaemia, although this has seldom been explored. These factors influence the degree to which an individual becomes cognitively impaired during hypoglycaemia, and the glycaemic threshold at which this commences. They may influence the risk of progression to severe hypoglycaemia, which is more likely to occur if cognitive function becomes severely impaired before an individual perceives the onset of hypoglycaemic symptoms and can initiate self-treatment. However, in people with type 1 diabetes who have impaired awareness of hypoglycaemia, cognitive function is less affected during moderate hypoglycaemia (blood glucose 2.5 mmol/l) and recovery is faster than those with normal awareness.
A number of patient-related factors can influence cognitive performance during hypoglycaemia. One of these is gender. Men with type 1 diabetes appear to experience greater cognitive impairment during hypoglycaemia than women. High IQ was anticipated to be potentially protective, but when 24 non-diabetic patients with differing IQ levels were studied, those with higher IQ had a greater deterioration in cognitive function. Age is an important factor that has not been studied adequately, because of ethical restraints to exposure of elderly people to experimental hypoglycaemia.
Diabetes per se may influence how a person responds to hypoglycaemia, and several studies have compared adults with type 1 diabetes to non-diabetic volunteers. Similar effects were seen on working memory and attention. However, in one study 10 adult males with type 1 diabetes performed more poorly on a battery of cognitive tests than 12 healthy non-diabetic volunteers, although cognitive function at baseline was similar between the two groups. Psychomotor function was found to be less affected in those with type 1 diabetes. Various factors might explain these observed differences including small sample size, differences in experimental protocol, the cognitive tests that were applied and the magnitude of hypoglycaemia that was induced. It is possible that differences between the participants with type 1 diabetes had an influence, such as their prevailing glycaemic control or their state of hypoglycaemia awareness.
Glycaemic control was not shown to influence the effect of hypoglycaemia on cognitive function, or the glycaemic threshold at which cognitive impairment commenced. However, one study that used auditory p300 event-related potentials to assess cognitive function in subjects with type 1 diabetes (7 with strict glycaemic control and 11 with poor control) found the p300 amplitude was significantly reduced at a blood glucose of 2.2 mmol/l only in those with poor control.
The effect of impaired awareness of hypoglycaemia has been investigated in two studies, the earlier of which compared 10 subjects with type 1 diabetes who had normal awareness, with 10 who had impaired awareness of hypoglycaemia. The latter experienced more profound cognitive dysfunction during hypoglycaemia, which persisted for longer following recovery of blood glucose, although these differences were not statistically significant. By contrast, a larger study observed that cognitive function was impaired significantly in those with normal awareness, but not in an impaired awareness group. A significant group difference was noted for two of the cognitive tests. These contrasting results may be explained by methodological differences, including the use and timing of different cognitive tests, and a shorter duration of exposure to hypoglycaemia in the earlier study.
Finally, the rate in fall of blood glucose may modify the response to hypoglycaemia, according to one study in which hypoglycaemia was induced either rapidly or slowly in 11 subjects with type 1 diabetes. The rapid fall in blood glucose provoked a greater magnitude of cognitive dysfunction, along with a lower counter-regulatory response.
Lifestyle factors can influence the severity of cognitive dysfunction during hypoglycaemia, and may provide an opportunity to reduce the level of cognitive impairment and thereby the risk of severe hypoglycaemia. One factor is caffeine intake, which may confer some protection, although the effect has been studied only in non-diabetic volunteers. When alcohol intake was combined with hypoglycaemia (blood glucose 2.8mmol/l) the subsequent cognitive impairment was marked in subjects with type 1 diabetes, although no interaction was found between the effects of alcohol and low blood glucose (i.e. the effects were additive but not synergistic).
Insulin type and species may have an effect, but this has not been investigated extensively and studies were performed in non-diabetic volunteers. One study compared human insulin to the long-acting analogue, insulin detemir, which is more lipophilic and therefore crosses the blood brain barrier more easily. A quicker and greater impairment of cognitive function was observed with insulin detemir in 10 non-diabetic subjects. Earlier studies compared porcine and human insulin. Porcine insulin had a greater impact on both visual and auditory evoked potentials during hypoglycaemia than human insulin, with greater variability in auditory evoked brain response during infusion of human insulin. The significance and clinical relevance of these discrepant effects of different insulins on cognitive function is not known.
Several drugs have been investigated to try to attenuate the cognitive impairment of hypoglycaemia. Memantine (a glutamate receptor blocker used to treat Alzheimer's disease), potassium channel modulators, and GLP-1 have all been utilised but with no apparent preservation of cognitive performance during experimentally-induced acute hypoglycaemia. Intravenous lactate can improve cognition during hypoglycaemia, but at the expense of attenuating counter-regulatory and symptomatic responses. Subjects given oral amino-acids had better cognitive function during, and glucagon response to, hypoglycaemia, but these are not practical methods of protecting cognitive function in everyday life.
4. Factors Which May Moderate Cognitive Effects
A wide inter-individual variation in cognitive dysfunction is present during hypoglycaemia, although on repeat testing it remains relatively stable within the same subject. A number of factors may modify an individual's cognitive performance during hypoglycaemia, although this has seldom been explored. These factors influence the degree to which an individual becomes cognitively impaired during hypoglycaemia, and the glycaemic threshold at which this commences. They may influence the risk of progression to severe hypoglycaemia, which is more likely to occur if cognitive function becomes severely impaired before an individual perceives the onset of hypoglycaemic symptoms and can initiate self-treatment. However, in people with type 1 diabetes who have impaired awareness of hypoglycaemia, cognitive function is less affected during moderate hypoglycaemia (blood glucose 2.5 mmol/l) and recovery is faster than those with normal awareness.
4.1 Non-modifiable or Fixed Factors
A number of patient-related factors can influence cognitive performance during hypoglycaemia. One of these is gender. Men with type 1 diabetes appear to experience greater cognitive impairment during hypoglycaemia than women. High IQ was anticipated to be potentially protective, but when 24 non-diabetic patients with differing IQ levels were studied, those with higher IQ had a greater deterioration in cognitive function. Age is an important factor that has not been studied adequately, because of ethical restraints to exposure of elderly people to experimental hypoglycaemia.
4.2 Diabetes-related Factors
Diabetes per se may influence how a person responds to hypoglycaemia, and several studies have compared adults with type 1 diabetes to non-diabetic volunteers. Similar effects were seen on working memory and attention. However, in one study 10 adult males with type 1 diabetes performed more poorly on a battery of cognitive tests than 12 healthy non-diabetic volunteers, although cognitive function at baseline was similar between the two groups. Psychomotor function was found to be less affected in those with type 1 diabetes. Various factors might explain these observed differences including small sample size, differences in experimental protocol, the cognitive tests that were applied and the magnitude of hypoglycaemia that was induced. It is possible that differences between the participants with type 1 diabetes had an influence, such as their prevailing glycaemic control or their state of hypoglycaemia awareness.
Glycaemic control was not shown to influence the effect of hypoglycaemia on cognitive function, or the glycaemic threshold at which cognitive impairment commenced. However, one study that used auditory p300 event-related potentials to assess cognitive function in subjects with type 1 diabetes (7 with strict glycaemic control and 11 with poor control) found the p300 amplitude was significantly reduced at a blood glucose of 2.2 mmol/l only in those with poor control.
The effect of impaired awareness of hypoglycaemia has been investigated in two studies, the earlier of which compared 10 subjects with type 1 diabetes who had normal awareness, with 10 who had impaired awareness of hypoglycaemia. The latter experienced more profound cognitive dysfunction during hypoglycaemia, which persisted for longer following recovery of blood glucose, although these differences were not statistically significant. By contrast, a larger study observed that cognitive function was impaired significantly in those with normal awareness, but not in an impaired awareness group. A significant group difference was noted for two of the cognitive tests. These contrasting results may be explained by methodological differences, including the use and timing of different cognitive tests, and a shorter duration of exposure to hypoglycaemia in the earlier study.
Finally, the rate in fall of blood glucose may modify the response to hypoglycaemia, according to one study in which hypoglycaemia was induced either rapidly or slowly in 11 subjects with type 1 diabetes. The rapid fall in blood glucose provoked a greater magnitude of cognitive dysfunction, along with a lower counter-regulatory response.
4.3 Potentially Modifiable Factors and Effects of Drugs
Lifestyle factors can influence the severity of cognitive dysfunction during hypoglycaemia, and may provide an opportunity to reduce the level of cognitive impairment and thereby the risk of severe hypoglycaemia. One factor is caffeine intake, which may confer some protection, although the effect has been studied only in non-diabetic volunteers. When alcohol intake was combined with hypoglycaemia (blood glucose 2.8mmol/l) the subsequent cognitive impairment was marked in subjects with type 1 diabetes, although no interaction was found between the effects of alcohol and low blood glucose (i.e. the effects were additive but not synergistic).
Insulin type and species may have an effect, but this has not been investigated extensively and studies were performed in non-diabetic volunteers. One study compared human insulin to the long-acting analogue, insulin detemir, which is more lipophilic and therefore crosses the blood brain barrier more easily. A quicker and greater impairment of cognitive function was observed with insulin detemir in 10 non-diabetic subjects. Earlier studies compared porcine and human insulin. Porcine insulin had a greater impact on both visual and auditory evoked potentials during hypoglycaemia than human insulin, with greater variability in auditory evoked brain response during infusion of human insulin. The significance and clinical relevance of these discrepant effects of different insulins on cognitive function is not known.
Several drugs have been investigated to try to attenuate the cognitive impairment of hypoglycaemia. Memantine (a glutamate receptor blocker used to treat Alzheimer's disease), potassium channel modulators, and GLP-1 have all been utilised but with no apparent preservation of cognitive performance during experimentally-induced acute hypoglycaemia. Intravenous lactate can improve cognition during hypoglycaemia, but at the expense of attenuating counter-regulatory and symptomatic responses. Subjects given oral amino-acids had better cognitive function during, and glucagon response to, hypoglycaemia, but these are not practical methods of protecting cognitive function in everyday life.
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