SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 11 NUMBER 1 • MARCH 2014
7
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
27
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.
35
The rapid fall in blood glucose provoked a greater
magnitude of cognitive dysfunction, along with a lower counter-
regulatory response.
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,
36,37
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).
38
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.
39
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
40
and auditory
41,42
evoked potentials during hypoglycaemia than
human insulin, with greater variability in auditory evoked brain
response during infusion of human insulin.
41
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 cogni-
tive impairment of hypoglycaemia. Memantine (a glutamate recep-
tor blocker used to treat Alzheimer’s disease),
43
potassium channel
modulators,
44
and glucagon-like peptide 1 (GLP-1)
45
have all been
utilised but with no apparent preservation of cognitive performance
during experimentally-induced acute hypoglycaemia. Intravenous
lactate can improve cognition during hypoglycaemia,
46-48
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,
49
but these are not practi-
cal methods of protecting cognitive function in everyday life.
Conclusions
The almost universal deterioration in all domains of cognitive
function during hypoglycaemia can have a profound effect on the
lives of people with type 1 diabetes. The disruption of activities
that require complex cognitive functions has been demonstrated in
studies that mimic real life situations such as those using a driving
simulator,
50,51
and prospective memory tasks,
11
gives credibility to
the conclusion that ‘real life’ situations, and not just experimental
tests, are greatly affected by hypoglycaemia. The emotional and
behavioural changes that are associated with hypoglycaemia
can also influence many daily activities and tasks, cause social
embarrassment and affect quality of life.
Currently there is limited potential to reduce the cognitive
impairmentandemotionalresponsesassociatedwithhypoglycaemia,
and efforts therefore have to be directed towards prevention of
hypoglycaemia through education and the effective use of insulin.
At present, individual risk stratification is not possible but effective
preventative treatments and new insulins may be developed, which
will cause less cognitive impairment.
Funding
This research received no specific grant from any funding agency in
the public, commercial, or not-for-profit sectors.
Conflicts of interest statement
The authors declare no conflicts of interest in preparing this article.
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