European Journal of Applied Sciences 4 (1): 01-05, 2012

ISSN 2079-2077
© IDOSI Publications, 2012

Mechanism Linking Cognitive Impairment and Diabetes mellitus

T.M. Vijayakumar, G.B.N. Sirisha, M.D. Farzana Begam and M.D. Dhanaraju

Department of Pharmacy Practice, GIET School of Pharmacy, NH-5,

Chaitanya Nagar, Rajahmundry-533296, Andhra Pradesh, India

Abstract: Diabetes mellitus is an important risk factor for mild cognitive impairment (MCI) and subsequent
Alzheimer’s disease (AD). Severe diabetes is more likely to be associated with poorly controlled blood sugar,
which can damage nerve cells in the brain and lead to cognitive impairment. In addition, impairment in verbal
memory was found to be associated with history and duration of Type 2 diabetes. The purpose of this article
is to present a comprehensive review of the literature regarding the subject of cognitive dysfunction in diabetes
mellitus. Hyperglycemia alters function through a variety of mechanisms including polyol pathway activation,
increased formation of advanced glycation end products (AGEs), diacylglycerol activation of protein kinase
C and increased glucose shunting in the hexosamine pathway. The same mechanisms may be operative in the
brain and induce the changes in cognitive function that have been detected in patients with diabetes. The
pathogenesis of cognitive dysfunction is only partially understood. Although many studies suggested that
changes in cerebral structure and function in diabetes are related to hyperglycemia-induced end organ damage,
macrovascular disease, hypoglycemia, insulin resistance and amyloid lesions may play a role in some patients.
As new knowledge is gained and can be applied to develop a new and improved ways to prevent and treat all
of the hyperglycemia-related complications of diabetes.

Key words: Cognition % Dementia % B-Amyloid % Alzheimer’s disease % Insulin Resistance

INTRODUCTION especially in the hippocampal region of the brain which

involves in learning and memory [9]. Insulin is transported
Diabetes mellitus is a complex metabolic disease that across the blood-brain barrier via specific receptors. It
can have devastating effects on organs in the body [1-3]. may inhibit synaptic activity in the brain. Insulin has been
Diabetes mellitus is associated with slowly progressive found to reversibly reduce cholinergic activity of straital
end-organ damage in the brain. Mild to moderate neuronal cultures and to accelerate turnover of
impairments of cognitive functioning has been reported monoamines in the brain [10]. Increased insulin
both in type I DM and in patients with type II DM [4-5]. concentrations also appear to boost the levels of beta-
Abnormalities in cognitive function mediated by amyloid, a protein involved in the formation of senile
frontal lobe (executive functions), including a number of plaques that can lead to Alzheimer’s [11]. Certain organ
complex behaviors such as problem solving, planning, systems are predisposed to greater levels of oxidative
organization, insight, reasoning and attention are noted stress. The brain is one of the organs systems most
in patients with diabetes [6]. Glucose is the primary susceptible to damage by free radicals because of its high
substrate for brain energy metabolism [7]. Neurons in oxygen consumption rate, its abundance of easily per
brain are unable to store or synthesize glucose and oxidized lipid membranes [12]. Moreover, brain tissue
therefore, the needed glucose is obtained from systemic which has relatively little antioxidant protection also
circulation and subsequently transported across the contains high levels of polyunsaturated fatty acids
blood brain barrier [8]. When diabetes strikes and (PUFA) making it more vulnerable to oxidative insult [13].
insulin’s signal is ignored by cells, the brain may not get In diabetes condition, elevated levels of blood glucose
the large amount of glucose energy it needs especially for and insulin may provide a pro-oxidant environment.
memory. Loss of brain cells and memory function result Glucose reacts with oxygen to generate a range of reactive

Corresponding Author: T.M. Vijayakumar, Department of Pharmacy Practice,

GIET School of Pharmacy, NH-5, Chaitanya Nagar, Rajahmundry - 533 296, India.
Tel: +91 883-2484444, 6577444, Fax: +91 883-2484739.
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 Europ. J. Appl. Sci., 4 (1): 01-05, 2012

oxygen species (notably super oxides, hydroxyl radicals limbic system of the brain; in epidemiological studies of
and hydrogen peroxide) that can damage the constituents non-diabetic adults, hyperinsulinaemia has been
of cells. The higher the glucose levels the greater the associated with poorer cognitive performance and an
damage. Thus people with poor glucose regulation are increased risk of AD.
exposing their systems to potentially harmful oxidative
stress and also as age increases, the harm continues to Linkage Between Acute Hyperglycemia and Cognitive
accumulate unless we actively counteract [14]. Oxidative Impairment: Hyperglycemia has also been proposed to
stress has been shown to cause cell damage and neuronal cause end organ damage through increases in reactive
death in animal models and cell culture [15]. The oxygen species, in particular superoxide, which could then
association of diabetes mellitus with impaired cognitive lead to increased polyol pathway activation, increased
function suggests that diabetes mellitus may contribute formation of AGEs, activation of protein kinase C and
to Alzheimer disease (AD) [16].The purpose of this article increased glucose shunting in the hexosamine pathway
is to present a comprehensive review of the literature [19]. Hyperglycaemia is the hallmark of all types of
regarding the subject of cognitive dysfunction in diabetes diabetes and could cause cognitive decrements by several
mellitus. different mechanisms. Acute changes in blood glucose
are known to alter regional cerebral blood flow and could
Relation Between Insulin and Cognitive Function: also cause osmotic changes in cerebral neurons. These
Insulin resistance is a condition that impairs insulin same mechanisms may be operative in the brain and
function. AD has been called “type 3 diabetes” because induce the changes in cognitive function that have been
a defect in insulin signaling is associated with the detected in patients with diabetes (Fig. 1).
accumulation of patho-logical beta-amyloid peptide (A$)
and hyperphosphorylated tau protein. IDE (insulin- Diabetic Complications and Cognitive Decline: The first
degrading enzyme) is a protease involved in the degree relatives of non-insulin dependent diabetes
degradation of A$ and insulin and A$ may compete for mellitus patients are at the risk of accelerated
degradation. IDE expression found in the post-mortem atherosclerosis and micro vascular disease [20]. The
hippocampus of AD patients who expressed the APOE g4 recognized association between type 2 diabetes and
allele was reduced by 50% compared with g4 in AD macro and microvascular disease is pertinent to the
patients and controls [17]. Oxidative stress and pathogenesis of dementia. The former could cause
microinflammation mediate insulin resistance in the brain cognitive impairment because of the increased incidence
through the pathway of docosahexaenoic acid (DHA) of embolic stroke [21]. Many of the clinical complications
and, thus, omega-3 fatty acids may also be protective [18]. of diabetes are caused by small and large vessel
Individuals with pre-diabetic states (e.g. impaired glucose pathology [22]. In particular “peripheral” microvascular
tolerance or fasting hyperglycemia) or early type 2 complications of diabetes arising outside the brain appear
diabetes typically have elevated circulating plasma insulin to be correlated with corresponding microvascular
concentrations because of peripheral insulin resistance, changes in the brain. For example, diabetic retinopathy
which is in turn related to central obesity. Insulin and retinal microvascular abnormalities were associated
receptors are found in high concentrations within the with various MRI signs such as small focal white matter

Fig. 1: Possible mechanisms related to cognitive decline in diabetes mellitus patients

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hyperintensities and lesions. Likewise, the presence of

micro albuminuria in the general population has been
associated with significantly lower cognitive function
score [23]. Investigations and subsequent clinical
diagnosis of microvascular complications such as
nephropathy, retinopathy and neuropathy are regularly
made in patients with diabetes. However, early
investigations of potential cognitive impairment at
specialist memory clinics are not routinely undertaken in
patients who do not show obvious signs of dementia.
The early identification of clinically relevant cognitive
impairment in diabetic patients is essential because of
available symptomatic treatment, the need to educate
patients and cares and the need to instate required
supportive measures.

Role of Amyloid and Insulin Resistance in Cognitive Fig. 2: Role of insulin in the pathogenesis of Cognitive
Dysfunction: The mechanisms through which insulin impairment
resistance might alter cognitive function remain uncertain,
but effects on neurotransmission and memory formation amyloid angiopathy and capillary basement membrane
have been hypothesized [24]. Patients with Alzheimer’s thickening [29]. Several studies have also examined the
disease have a decrease in cerebral spinal fluid insulin incidence of Alzheimer’s type pathology in the brains of
levels, suggesting that there may be impaired insulin people with diabetes. Thus, the main anatomical
transport across the blood brain barrier or increased alterations related to diabetes appear to be the
insulin catabolism that accounts for the impaired central consequence of elevated blood glucose and changes due
insulin action [25]. Another potential mechanism through to cerebral infarcts are linked to hyperinsulinaemia as a
which insulin resistance may indirectly contribute to vascular risk factor. However, in contradiction to these
cognitive dysfunction is by promoting the formation of statements, hippocampal volume was positively
senile plaques found in Alzheimer’s disease. Intracellular associated with the metabolic syndrome and with visceral
neurofibrillary tangles and extracellular senile plaques fat volume in particular, in a group of 48 middle-aged to
composed of $-amyloid are the pathological hallmarks of elderly non-dementia patients with diabetes [30]. Among
Alzheimer’s disease [26]. $- Amyloid is formed from the these subjects, the metabolic syndrome was not
cleavage of amyloid precursor protein (APP), produced in associated with any cognitive alterations.
neurons, by the enzymes $- and (-secretase. $-Amyloid
is eventually degraded by the insulin-degrading enzyme. Recurrent Episodes of Hypoglycemia: Glucose is the
In addition, there is a growing body of evidence that predominant fuel utilized by the central nervous system.
insulin and insulin resistance can affect the metabolism of Because the brain cannot synthesize glucose nor store
APP and $-amyloid, thus potentially increasing the more than a few minutes ' supply as glycogen, the brain
burden of cerebral senile plaques [27]. The requires a continuous supply of glucose from the
pathophysiological mechanisms (Fig. 2) suggest how circulation. Therefore, disruption of the supply of
diabetes-related factors and comorbid conditions can exogenous glucose will rapidly cause functional
affect the brain. Vascular disease and alterations in disturbances [31]. Repetitive episodes of moderate to
glucose, insulin and amyloid metabolism seem to be severe hypoglycemia have been implicated as one
important factors and could be potentially modifiable. possible etiology of cognitive dysfunction in diabetes.
This is significant because the risk of hypoglycemia
Brain Structural Abnormalities: In autopsy series, increases as efforts to achieve the level of glycaemia
macroscopic brain infarcts are more common in people necessary to minimize the risk of developing the micro
with diabetes than in people without the disorder [28]. vascular complications of diabetes are intensified [32].
Additionally, diabetes is associated with pathological During acute hypoglycemia episodes, it has been shown
changes in the cerebral microvasculature, including that performance on immediate verbal memory, immediate

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visual memory, working memory, delayed memory; visual- 4. Biessels, G.J. and L.J. Kappelle, 2005. Increased risk
motor skills, visual-spatial skills and global cognitive of Alzheimer’s disease in Type II diabetes: insulin
dysfunction are all impaired [33-34]. One possible reason Induced pathology? Biochemical Society
that some studies found an association between frequent Transaction, 33: 1041-4.
hypoglycemia and cognitive dysfunction and others did 5. Kappelle, J.L., R.H. Heine, J.M. Dekker, G. Nijpels,
not is that the positive investigations may have included R.P.C. Kessels, R.J. Biessels et al., 2008.
subjects with diabetes onset earlier in life. Patients with Cognitive Functioning in Elderly Persons with Type
type I diabetes diagnosed at less than 5 year of age may 2 Diabetes and Metabolic Syndrome: the Hoorn
have more severe and frequent hypoglycemia episodes Study. Dementia and Geriatric Cognitive Disorders,
than those diagnosed at ages older than 5 year, these 26: 261-9.
younger patients have been found to have worse 6. Munshi, M., L. Grande, M. Hayes, D. Ayres,
cognitive dysfunction. S. Emmy, R. Capelson, L. Susan et al., 2006.
Cognitive Dysfunction Is Associated with Poor
CONCLUSION Diabetes Control in Older Adults. Diabetes Care,
29: 1794-99.
In conclusion, Evidence from neurocognitive testing 7. Fellows, L.K. and M.G. Boutelle, 1993. Rapid
suggests that cognitive dysfunction should be listed as changes in extracellular glucose levels and blood
one of the many complications of diabetes, along with flow in the striatum of the freely moving rat. Brain
retinopathy, neuropathy, nephropathy and cardiovascular Res., 604: 225-231.
disease. In the clinical approach to individual patients 8. McNeill, G., A. Avenell, M.K. Campbell, J.A. Cook,
with diabetes that present with complaints of cognitive P.C. Hannaford, M.M. Kilonzo, M. Mary et al., 2007.
disturbances a number of basic principles are important: Is Antioxidant Therapy a Viable Alternative for
first, diabetes should be regarded as “a risk factor” rather Mild Cognitive Impairment? Examination of the
than as “the cause” of cognitive decline. Therefore, the Evidence. Dementia and Geriatric Cognitive
diagnostic evaluation should be identical to that in other Disorders, 24: 1-19.
patients with cognitive complaints. 9. Mendelsohn, A.B., S.H. Belle, M. Ganguli and
G.P. Stoehr, 1998. Use of Antioxidant Supplements
ACKNOWLEDGEMENT and Its Association with Cognitive Function in a
Rural Elderly Cohort. American J. Epidemiol.,
Authors would like to thanks KIMS medical college, 148: 38-44.
Amalapuram and Pradeep Diabetic Care hospital, 10. Russo, V.C., P.D. Gluckman, E.L. Feldman and
Rajahmundry for their kind support and providing G.A. Werther, 2005. The insulin-like growth factor
necessary guidance for manuscript preparation. system and its pleiotropic functions in brain. Endocr.
Rev., 26: 916-943.
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