VOLUME 11 NUMBER 2 • JUNE 2014
83
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
DMand neurodegeneration and the clinical and research approaches
with the aim to prevent and treat cognitive dysfunction with DM.
Cognitive dysfunction with hypoglycaemia
The brain is an energy-intensive organ. Glucose is the primary fuel
of brain cells. Approximately 25% of total body glucose is required
for proper brain function.
40
The normal range for human blood
glucose concentration is 3.9 to 7.1 mM (1 mM = approximately
18 mg/dl). Hypoglycaemia is defined as blood glucose level below
which brain function deteriorates in most patients (i.e. less than
3 mmol/l or 54 mg/l00 ml).
41
In patients with DM, not only severe hypoglycaemia (blood
glucose level below 2 mM) but also recurrent mild (blood glucose
level 3.2 to 3.6 mM) or moderate (blood glucose level 2.3 to less
than 3.2 mM) hypoglycaemia has deleterious effect on the brain.
3-
11,13-17
Hypoglycaemia is common with intensive insulin therapy. It
has been indicated that the oscillations in glycaemia, owing to the
nature of subcutaneous insulin administration, are more common
and result in increases in the frequency of hypoglycaemia in those
treated for DM.
42
Recurrent mild and moderate hypoglycaemia is
more common than severe hypoglycaemia.
7,10,43
It has been reported
that most hypoglycaemic events were found to be asymptomatic in
90% of children treated with insulin, 98% of those occurring at
night, and the majority of untreated hypoglycaemic events were
associated with a relapse into hypoglycaemia within three hours.
44
Attention, associative learning and mental flexibility are
affected with acute hypoglycaemia.
5
Recurrent mild and moderate
hypoglycaemia is associated with intellectual decline, particularly
performance IQ, impaired mental abilities and memory deficits.
3,45
It was reported that recurrent mild and moderate hypoglycaemia
in children younger than five years old with T1DM may commonly
develop reduced attention, spatial memory and intelligence in
adolescence.
6,8,46
Experimentalandclinicalstudiesindicatethatseverehypoglycaemia
for a least 10 minutes results in microglial activation and oxidative
stress with the release of several neurotoxic substances, including
superoxide, nitric oxide and metalloproteinase, and widespread
neuronal death in the cerebral cortex and hippocampus. Recurrent
moderate hypoglycaemia results in scattered neuronal death in
the second and third cerebral cortex layers and hippocampal CA1
dendritic region, and hippocampal thinning.
14-16,47,48
It has been suggested that cognitive impairment in children and
adults with repetitive mild and moderate hypoglycaemia is due
to deterioration of synaptic injury with an inability to induce or
persistent inhibition of long-term potentiation (LTP) and facilitation
of LTD at the hippocampal CA1 (which plays a crucial role in
memory) in the absence of apparent neuronal somatic injuries.
This in turn results in activity-dependent synapse weakening and
contributes to cognitive impairment.
11,12
Cognitive dysfunction with hyperglycaemia
DM is defined by the presence of symptoms of hyperglycaemia and
fasting plasma glucose (FBG) levels ≥ 7.0 mmol/l or 126 mg/dl or
post-prandial blood glucose (PBG) ≥ 11.1 mmol/l or 200 mg/dl or a
random plasma glucose level ≥ 11.1 mmol/l or 200 mg/dl or glycated
haemoglobin (HbA
1c
) ≥ 6.5%.
49
At the experimental level, detrimental effects on learning and
memory were observed in streptozotocin (STZ) (rodent model of
T1DM) and GK rats,
50
db/db mice and Zucker rats
51
(genetic models
of T2DM), as seen by impaired performance in the Morris water
maze spatial test,
51,52
and inhibitory
53
or active avoidance tasks,
54
and
object-discrimination task tests,
22
all being indicative of impairment
in the hippocampus and related structures.
At the clinical level, children and adults with DM demonstrate
low IQ and reduced performance on various domains of cognitive
function, including verbal relations, comprehension, visual reasoning,
pattern analysis, quantitation, digit forward, digit backward, short-
termmemory, memory for sentences, verbal memory, logical memory,
mental control, associative learning, psychomotor efficiency, problem
solving, mental and motor processing speed, eye–hand coordination
and executive functions.
18-26,55-57
Many authors have reported
that cognitive deficits were correlated with the degree of chronic
hyperglycaemia and improvements in performance of cognitive
testing occurred with improvement in glucose tolerance.
58,59
Wu
et al
.
23
observed that, compared to treatedpatients, untreated
patients with DM had two points of decline over two years on the
mini mental state examination test (MMSE) with duration of illness
< five years and six points of decline on the MMSE with duration
of illness ≥ five years. Cox
et al
.
24
observed that the increase in
blood glucose concentrations to > 15mmol/l was associated with
a marked decline in cognition and poor performance in arithmetic
tasks. The research showed that those with DM had a 1.2- to 1.5-
fold greater rate of decline in cognitive function compared to those
without diabetes.
60
At the neurophysiological level, studies also reported
abnormalities in the P300 component of event-related potentials
(ERPs), a physiological analogue of cognitive testing
25,61,62
and
prolongation in I–III and I–V inter-peak latencies of the auditory
brainstem response (ABR), an indication of central auditory pathway
function
52,63
in patients with T1DM and T2DM, regardless of the
recent metabolic derangement and disease duration.
At the neuroimaging level, structural brain atrophy, particularly in
the limbic structures, such the hippocampus and amygdala, smaller
total brain volume, smaller gray matter volume, larger ventricular
volume, larger white matter lesion volume and accelerated increase
in ventricular volume over time and increased risk for incident brain
infarcts were seen in magnetic resonance imaging (MRI) of the brain
of patients with T2DM and also in patients with early manifestation
of impaired glucose tolerance (i.e. PBG ≥ 140 mg/dl or 7.8 mmol/l
but not over 200 mg/dl or 11.1 mmol/l).
28,38,39,64-66
Studies also reported
that well-controlled middle-aged individuals with T2DM,
20
and non-
diabetic individuals with insulin resistance (IR) (a prediabetic state)
67
had declarative memory deficits and specific hippocampal volume
reduction and deficits in hippocampal synaptic plasticity,
52
which
were correlated with the present deficits in declarative memory.
The aetiology of cognitive impairment in people with
hyperglycaemia is multifactorial. Vascular
27,28
as well as neuro-
degenation
65,66
contribute to cognitive dysfunction with chronic
hyperglycaemia. The following have been suggested as causes
of hyperglycaemia-induced cognitive impairment: chronic
complications such as macro- and microvascular complications
(diabetic vasculopathy),
20,27,28
hyperlipidaemia,
68,69
hypertension,
70,71
insulin resistance (IR) and hyperinsulinaemia,
67
dysregulation of
the limbic–hypothalamic–adrenal pituitary axis (LHPA) with chronic
hypercortisolaemia and impairment in hippocampal neurogenesis,
synaptic plasticity and learning,
72-74
direct toxic effects of chronic
hyperglycaemia on the brain,
25,55
advanced glycation end-products,
inflammatory cytokines, oxidative stress,
29,30
and diabetes-related
depression.
32-35
