Impact of glucose metabolism and birth size on cognitive performance in elderly subjects☆
Introduction
It is widely accepted that type 2 diabetes is a risk factor for cognitive impairment [2], [3]. However, the underlying mechanisms are diverse and not fully understood. Both micro- and macrovascular disease may affect the brain in subjects with diabetes [4], [5]. Common co-morbidities of diabetes, such as depression and macrovascular disease, could be mediators between diabetes and cognitive impairment. However, it is also possible that hyperglycaemia and hyperinsulinaemia per se can affect brain tissue and its metabolism [6], [7].
Type 2 diabetes develops gradually through different stages of impairment in glucose and insulin metabolism. Several studies have focused upon the impact of manifest diabetes on cognition [7]. Yet, evidence regarding the effect of pre-diabetic stages is more scarce and equivocal. A few studies have shown that impaired glucose tolerance has a negative impact on cognitive performance [8], [9]. However, the reviewed literature is not consistent [10], [11].
It is not known which aspect of the complex cluster of diabetes and its co-morbidities mainly accounts for the association between diabetes and cognitive impairment. Likewise it is not known which subjects with diabetes eventually develop cognitive impairment and which ones are likely to be spared [3].
The concept of early life origins of adult disease has received considerable attention during the past decades. According to the original “Foetal origins hypothesis” suboptimal conditions in utero, often reflected by a small size at birth, lead to adaptive changes in the foetus, which may have adverse consequences in later life [12]. Type 2 diabetes is just one of the many diseases that have been associated with a small body size at birth. A low birth weight has been shown to modify the effect of previously known risk factors on adult disease [13], [14] and mounting evidence exists linking low birth weight with alterations in cognitive abilities at various stages in life [15], [16]. Therefore, we hypothesised that birth weight may modify the association between type 2 diabetes and cognitive impairment.
Our major study objective was to investigate the impact of different degrees of impairment in glucose regulation as well as duration of diabetes on cognitive performance. Depressive symptoms and coronary heart disease were explored as potential mediators of the association. Our second aim was to explore the association of birth weight with cognitive performance and whether birth weight modifies the relationship between type 2 diabetes and cognitive impairment.
Section snippets
Methods
This study is part of the Helsinki Birth Cohort Study. Extensive data from birth records, child welfare clinic records, school health care records as well as national Finnish registers are available for a cohort of 8760 people born in Helsinki during 1934–1944. 2003 randomly selected subjects from the cohort took part in clinical examinations during the years 2001–2004. The study procedures have been described in detail previously [17], [18], [19].
For the present study, we performed a standard
Cognitive testing
We used a standardised language independent computerised battery of cognitive tests (CogState®, version 3.0.5). This battery has been validated and shown to be a sensitive indicator of mild impairments in the following cognitive domains: psychomotor speed, attention, working memory and episodic learning and memory [22], [23], [24]. The test consists of five tasks where subjects were asked to pay attention to playing cards on a computer screen. Each task consists of 30–50 repeated stimuli
Statistical analyses
Skewed variables were log-transformed in order to obtain normality. The distribution of the correct responses to the WM task was such that 792 (64.1%) of the subjects had made zero to one errors, whereas the remaining 443 subjects had an error rate ranging between 2 and 26 out of 30 possible. We dichotomised the variable with a cut point at two errors. Reaction times (in all tasks) and accuracy of performance (in WM and AL tasks) in the CogState test were treated as outcome variables. Accuracy
Results
Table 1. shows the characteristics of the study participants according to glucose tolerance. Age, sex and education were strongly associated with the cognitive test scores and were therefore added into all regression models as described below. Being female, being older, and having a lower educational attainment correlated with longer reaction times and fewer correct responses. Median test performance scores are shown in Table 2.
Glucose tolerance and cognitive performance
We grouped the subjects according to different stages of impaired glucose regulation (IFG/IGT, new DM and known DM) and compared each group with subjects who had normal glucose tolerance as the referent. Subjects with IFG/IGT or new DM did not differ from the NGT group on any of the tasks, whereas those with known DM had longer reaction times in all the tasks, except for the SRT and DA tasks (Table 3). Further, subjects with known DM had fewer correct responses than NGT subjects in the WM and
Differences between subjects with known and newly diagnosed DM
Subjects with known DM differed from those with new DM in several aspects. After controlling for sex, age and education those with known DM more often had a diagnosis of CHD, higher BMI, higher BDI scores and were born with a lower birth weight. However, their level of education was similar to that of the newly diagnosed subjects (Table 1).
The year of diagnosis was available for the majority of the subjects with previously diagnosed diabetes (63/77 subjects = 82%). Mean duration of diagnosed DM
Tests of mediation
We tested CHD and depressive symptoms as potential mediators of the association between diabetes and poor cognitive performance. A history of CHD was associated with a longer reaction time in the AL task (9.6%, p = 0.002) and weakly associated with the CRT task (3.9%, p = 0.058). When presence of CHD was added to the models predicting cognitive performance together with different categories of glucose tolerance the effect of known DM on AL reaction time was rendered non-significant (Table 2). Using
Birth weight and cognitive performance
Birth weight showed a negative linear association with reaction time in the DA task (−3.8%/kg, 95% CI = −6.5 to −1.1, p = 0.005) and with hit rate in the AL task (−1.5%/kg, 95% CI = −0.1 to −2.9, p = 0.036) after adjustment for age, sex and gestational age. Further adjustment for CHD, DM, depressive symptoms and education did not influence the result. When we added interaction terms between birth weight and the different stages of glucose tolerance to the regression models there was a significant
Discussion
In this large community-based sample derived from the Helsinki Birth Cohort Study we found no association between newly diagnosed diabetes or lesser impairments in glucose regulation and cognitive performance. However, subjects with known diabetes had a consistently poorer level of performance than subjects with normal glucose tolerance in most of the tested cognitive domains. Simple reaction time and divided attention were not associated with known DM in our sample.
As shown in Table 1 the
Strengths and weaknesses
The strengths of this study include a large sample size, sensitive assessment of cognition and the OGTT which allowed classification of the subjects into different glucose tolerance categories. IGT and DM have been linked to cognitive impairment in several previous studies [7], but not many studies have shown such a marked difference between old and new DM. To our knowledge we are the first ones to show that a low birth weight enhances the adverse effects of DM on cognition.
We are aware that
Conclusion
Our results confirm earlier studies that relate a longer duration of diabetes to impaired cognition [10], [35]. The association is only partly mediated by the presence of CHD. Moreover, we add to the previous literature by introducing birth weight as a vulnerability factor enhancing cognitive decline in type 2 diabetic subjects. The fact that cognitive impairment was not seen among newly diagnosed diabetics is encouraging. Subjects with a longer duration of diabetes had higher blood glucose, a
Conflict of interest
There are no conflicts of interest.
References (34)
- et al.
Risk of dementia in diabetes mellitus: a systematic review
Lancet Neurol.
(2006) - et al.
Ageing and diabetes: implications for brain function
Eur. J. Pharmacol.
(2002) - et al.
Effect of age and glucoregulation on cognitive performance
Neurobiol. Aging
(2003) - et al.
Exercise protects against glucose intolerance in individuals with a small body size at birth
Prev. Med.
(2004) Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging.
Neurobiol. Aging
(2005)- et al.
Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies
Diabetes Care
(1997) - et al.
Stroke in patients with diabetes mellitus
Diabetes Metab. Res. Rev.
(2004) - et al.
Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes
Diabetologia
(2007) - et al.
The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function
J. Clin. Exp. Neuropsychol.
(2004) - et al.
Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men
Diabetologia
(1995)
Diabetes and cognitive function in a middle-aged cohort: findings from the Whitehall II study
Neurology
A Biethnic Community Survey of cognition in participants with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance: the New Mexico Elder Health Survey
Diabetes Care
Fetal origins of coronary heart disease
BMJ
Size at birth and resilience to effects of poor living conditions in adult life: longitudinal study
BMJ
Neuropsychological follow-up into young adulthood of term infants born small for gestational age
Med. Sci. Monit.
Birth weight and cognitive function in the British 1946 birth cohort: longitudinal population based study
Br. Med. J.
Patterns of growth among children who later develop type 2 diabetes or its risk factors
Diabetologia
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Part of this data has been presented in an abstract form at the 5th World Congress on Prevention of Diabetes and its Complications (June 1–4, 2008 Helsinki, Finland) [M. Paile-Hyvärinen, K. Räikkönen, E. Kajantie, D. Darby, H. Ylihärsilä, M.K. Salonen, et al., Impact of glucose metabolism and birth size on cognitive performance in elderly subjects, in: Abstract Book of 5th World Congress on Prevention of Diabetes and its Complications, Helsinki, Finland, 2008, pp. 214–224].