REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
84
VOLUME 11 NUMBER 2 • JUNE 2014
DM is a risk for arterial stiffness, and atherosclerotic and
cerebrovascular diseases.
27,28
Experimental and human studies
also indicate that chronic hyperglycaemia results in brain injury
with specific vulnerability to memory and learning processing,
regardless of the vascular pathology. In experimental models, it was
observed that chronic hyperglycaemia and the spontaneous onset
of T2DM caused blood–brain barrier (BBB) disruption, alterations
in insulin transporters and decreases in insulin receptors, which are
expressed in discrete neuronal populations in the CNS, including
the hippocampus.
Impairment of insulin function results in reduction in uptake of
glucose into the neurons, impairment of energy metabolism and
impairment of the brain’s capacity to generate the connections vital
to memory and learning.
3
Reductions in insulin-like growth factor
1 (ILGF-1)
75,76
and brain-derived neurotrophic factor (BDNF) were
observed in rat models of T2DM.
77
IGFs regulate adult brain mass
by maintaining brain protein content, and they support synapses
and are required for learning and memory. It was observed that
replacement doses of insulin and IGFs in diabetic rats could
cross the blood–brain barrier, improve brain atrophy and prevent
hippocampus-dependent memory impairment.
75-77
Researchers
found that insulin and IGF-I were significantly reduced in the frontal
cortex, hippocampus and hypothalamus but not the cerebellum in
post mortem brain tissue from people with DM.
45
It has been indicated that hyperglycaemia causes oxidative
stress, amyloidosis, angiopathy, abnormal lipid peroxidation, it
increases the formation of advanced glycation end-products,
the accumulation of
β
-amyloid and tau phosphorylation, neuro-
inflammation, mitochondrial pathology, an increase in Bax
expression (pro-apoptotic protein) and caspase-3 (apoptotic
element) levels, reduction in Bcl-2 protein levels (antiapoptotic
protein), an increase in the ratio of Bax to Bcl-2, DNA fragmentation
in the cortex and hippocampus, neuronal degeneration and brain
atrophy.
36,37
Recently, it was reported that adults and middle-aged
patients with T2DM had higher concentrations of serum NSE (a
marker of neuronal cell damage), which was significantly correlated
with cognitive deficits, regardless of the level of glycaemic control
and after adjustment of confounders,
25
indicating direct brain injury
due to chronic hyperglycaemia. Several studies have shown higher
serum and cerebrospinal fluid (CSF) levels of NSE and also their
over-expression increases the vulnerability to neurodegeneration,
cerebral hypoxic–ischaemic injury and traumatic brain injury.
78,79
Cognitive dysfunction with hyperinslinaemia
Insulin is a key protein in the control of intermediary metabolism.
It organises the use of fuels for either storage or oxidation. It
influences carbohydrate, lipid, protein and mineral metabolism.
40
Binding of insulin to its receptors phosphorylates many intracellular
proteins and generates a biological response. Insulin acts on cells
thoughout the body to stimulate uptake, utilisation and storage of
glucose.
In the brain, as with peripheral insulin, insulin is in part responsible
for the uptake of glucose into the neurons, which is important for
energy metabolism. Most of the brain’s insulin originates from
systemic blood circulation but to a lesser extent, it is produced in
the brain.
80
Insulin crosses the blood–brain barrier (BBB) using a
saturable transporter.
81
Insulin-sensitive glucose transporters, insulin
receptors and insulin downstream signaling molecules are distributed
throughout the human brain on both neurons and astrocytes.
82
Insulin receptors are densely expressed in the medial temporal
lobe, hippocampus and prefrontal cortex, which mediate long-
term memory and working memory.
83
Insulin affects a wide range
of normal brain functions, such as reward, motivation, cognition,
attention and memory formation. Insulin’s anabolic effect in the
brain includes stimulation of growth, neuronal differentiation,
survival (neurotropism) and remodelling (neuromodulation).
82
The
synapses (which transmit information between neurons) contain
insulin receptors. Insulin serves as a vital element for normal
synaptic structure and function and subsequently for the strength
of connections between neurons. Insulin binds to receptors on the
synapse and together with proper inulin signalling, both contribute
to brain plasticity and the formation of new brain circuitries
essential for learning and memory.
84
Insulin in the brain is degraded
by insulin degrading enzyme (IDE). IDE regulates the generation
and clearance of amyloid
β
(A
β
) from the brain.
85,86
Hyperinsulinaemia is themost common consequence of IR, which
is the main defect in T2DM. It has been indicated that prolonged
exposure of the brain to higher than physiological levels of insulin
may alter signalling and metabolic pathways in a manner that is
deleterious to cognitive circuitry, which mainly depends on proper
metabolic processes.
84
Chronic elevation of insulin concentrations in
the periphery may paradoxically causes a relative hypo-insulinised
state in the brain and the resultant hyper-insulinaemia could
actually impair cognition by disturbing insulin-mediated utilisation
of glucose by cells in the brain. particularly the hippocampus, which
is enriched with insulin receptors. Central hypo-insulinaemia may
promote central inflammation,
β
-amyloid generation and reduced
neuroplasticity.
85
Decrease in levels of insulin degrading enzyme (IDE) was
observed in rat models of T2DM. IDE, an enzyme responsible for
insulin degradation in the brain, also degrades amyloid plaque. As
insulin has a very similar molecular structure to amyloid plaque,
the latter might compete for the benefits of IDE in the presence
of hyper-insulinaemia.
86
Elevated insulin levels are implicated in
the brain cells’ failure to clear
β
-amyloid, the formation of senile
plaques and tau protein phosphorylation.
87-89
Depression accelerates cognitive decline with DM
Epidemiological studies have suggested that diabetic patients
are two- to three-fold more likely to develop depressive illness
when compared to non-diabetic individuals. On the other hand,
individuals with depression have an approximately 60% higher risk
of developing T2DM.
32-34
In general, the prevalence of depression
with DM was estimated to be 31.1%.
90
Co-morbid depression has
been identified as a risk factor for accelerated cognitive decline
among patients with T2DM. Depression has been identified as a risk
factor for dementia among patients with T2DM in all domains.
35
Clinical and research perspectives
The knowledge that diagnosis at an early age, frequency of
hypoglycaemic events, poor glycaemic control and the presence
of risk factors negatively affect cognitive function in DM, will
have important implications for treatment of DM and for research
purposes. Preventive strategies include modification of lifestyle,
patient education, dietary re-orientation (i.e. eliminating high-
glycaemic foods, including processed carbohydrates and sweets,
would sensitise insulin receptors and correct hyperinsulinaemia
91-95
),
stopping smoking, maintaining a healthy body weight, mental
