ReviewImpairments in glucose tolerance can have a negative impact on cognitive function: A systematic research review
Introduction
Glucose is the main neural fuel for the brain and is necessary for cognitive function (Amiel, 1994). Given the long history of evidence showing that glucose consumption can influence cognitive function (Gold, 1995, Hoyland et al., 2007, Messier, 2004, Riby, 2004) it is possible that there is an association between abnormalities in glucose tolerance and impaired cognitive function. For the purpose of this review glucose tolerance is defined as the ability of the body to effectively regulate blood glucose levels and to remove glucose from the blood.
If it is to be argued that abnormalities in glucose tolerance are associated with impairments in cognitive function then it is essential to establish what is meant by abnormalities in glucose tolerance. In the medical domain there are three types of abnormalities in glucose tolerance; diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG), the clinical criteria for which are shown in Table 1.
As shown in Table 1, IGT is a less severe abnormality in glucose tolerance than diabetes, however, both IGT and diabetes have a similar prevalence; by 2010 it is estimated 220 million people worldwide will have diabetes (Zimmet et al., 2001). Whilst diabetes is always preceded by IGT, IGT does not always develop into diabetes. The diagnostic test for these conditions is the Oral Glucose Tolerance Test (OGTT), which involves an oral administration of a 75 g glucose load after a minimum of an 8 h fast (WHO, 1999).
The diagnostic glucose concentration thresholds shown in Table 1 are arbitrary, but derived from estimates of the level at which specific plasma glucose levels lead to an increased risk of negative health outcomes such as microvascular and cardiovascular complications (WHO, 2006). For example, the threshold for type 2 diabetes is determined at the level at which the risk of diabetic retinopathy increases sharply from a risk of almost zero (Gabir et al., 2000). Compared to people with normal glucose tolerance (NGT), people with IGT have a six-fold increased risk of developing type 2 diabetes, and a 1.66-fold increase in the risk of a fatal cardiovascular outcome over the lifespan (Santaguida et al., 2005). Given the strong association between abnormalities in glucose tolerance and adverse health outcomes it seems sensible to examine if these abnormalities are associated with adverse cognitive outcomes. However, it should be noted that the risk of premature mortality and developing type 2 diabetes and cardiovascular disease begins to increase with progressively worse glucose tolerance within the NGT range (Levitan et al., 2005). This highlights that glucose tolerance is a continuum and therefore it is important to examine whether changes in glucose tolerance with the NGT range are associated with changes in cognitive function. The focus of this review is to compare studies of IGT with studies of NGT.
To date, little distinction has been made between NGT studies and IGT studies, and consequently there has been a tendency for the findings from these two different sample groups to be considered collectively. It is important to distinguish these studies in order to determine whether a general worsening of glucose tolerance is associated with a general worsening of cognitive performance, or whether impairments in cognitive function only occur in association with specific abnormalities in glucose tolerance, e.g. IGT or diabetes. Impaired fasting glucose (IFG) is a clinically defined abnormality in glucose tolerance. It is important to point out that whilst IFG and IGT are defined on separate parameters, they can occur concomitantly. Research suggests that IGT and IFG may have a different aetiology with IGT being most strongly associated with reduced insulin sensitivity and IFG with beta cell function (Abdul-Ghani et al., 2006). Therefore, this review will also distinguish studies of IFG to examine the association between glucose tolerance and cognition.
Several reviews have shown that type 2 diabetes is associated with cognitive impairments (Awad et al., 2004, Biessels et al., 2002, Stewart and Liolitsa, 1999, Strachan et al., 1997), and longitudinal research has shown that type 2 diabetes can result in accelerated cognitive decline (Allen et al., 2004, Cukeirman et al., 2005). However, it is difficult to conclude that these reported cognitive impairments are a direct result of abnormalities in glucose tolerance. Rather, cerebrovascular and cardiovascular disease and their related risk factors such as obesity, hypertension, and hypercholesterolemia which often occur in association with type 2 diabetes (Mooradian, 1997, Stolar, 1990), have all been independently associated with cognitive impairments (Elias et al., 1997, Elias et al., 2005, Kumari et al., 2000, Vanhanen et al., 1999). Since IGT is less likely to be associated with cerebrovascular and cardiovascular disease than diabetes, examining cognitive function in association with IGT may shed light on any association between glucose tolerance on cognitive function with reduced influence of these confounders.
In addition, type 2 diabetes develops over a period of years and therefore any associated cognitive deficits are likely to be well established and consequently more severe than those associated with IGT. Examining the relationship between IGT and cognitive function can determine whether small changes in glucose tolerance can impact upon cognition, which is essential in examining the extent to which cognitive function is sensitive to changes in glucose tolerance.
The present review will examine the relationship between cognitive function and glucose tolerance in the non-diabetic range, which to date has not been systematically attempted. There will be particular focus on establishing the specific cognitive domains which may be affected by abnormalities in glucose tolerance. The evidence suggests that memory is one such domain, however, the broadness of memory requires that its specific components (e.g. verbal and spatial) are considered separately. There is a great deal of variability in the measurement of glucose tolerance throughout the literature and therefore the impact that this has is discussed. Evidence also suggests that glucose consumption may impact upon the relationship between glucose tolerance and cognition and therefore studies which administer glucose during testing are distinguished from those that do not. Ageing is known to impact upon both cognitive function and glucose tolerance and evidence suggests that any deleterious effects of abnormal glucose tolerance on cognitive function are likely to increase with ageing. Finally, the potential mechanisms which could account for a relationship between glucose tolerance and cognitive function are presented, however, it is unclear which of these or which combination of these if any are responsible.
Section snippets
Method
A systematic review of the literature was performed using the following search strategy.
Results
Twenty-three studies satisfied the inclusion criteria. These studies can be classified into two main groups; studies examining IGT and IFG in association with cognitive function (Table 2) or studies examining changes in glucose tolerance within the normal range in association cognitive function (NGT studies; Table 3). Table 2, Table 3 show a summary of each of the included studies.
Summary of findings
The evidence presented in this review indicates that glucose tolerance can impact upon cognitive performance. The evidence suggests that certain cognitive domains are more sensitive to the effects of glucose tolerance than others. Poor glucose tolerance appears to be most strongly associated with detriments in verbal memory, particularly logical memory, with delayed and immediate verbal memory being similarly affected. Working memory, vigilance, and attention also appear to be negatively
Concluding comments
In conclusion, the evidence suggests that IGT and poor glucose tolerance are associated with cognitive impairments. The strength of these impairments and the specific cognitive domains which are affected remain to be clearly identified, however, there is good evidence that verbal immediate and delayed memory are affected, as well as logical memory. The NGT studies demonstrate that fluctuations in glucose tolerance within the clinically defined normal range can be associated with changes in
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