Effects of intensified metabolic control on CNS function in type 2 diabetes
Introduction
Several reports have indicated that diabetes mellitus type 2 (T2DM) may cause cognitive dysfunction and an alteration in brain signals related to cognitive function (Perlmuter et al., 1984, Reaven et al., 1990, Gregg et al., 2000, Grodstein et al., 2001, Messier, 2005, Kodl and Seaquist, 2008). The distribution of cognitive dysfunction in diabetes may be selective, such that deficits are most likely to be detected in tasks that require fast and accurate processing of novel information (Tun et al., 1987). T2DM has the greatest effects on tasks relying less on semantic structures inherent in the test materials, and more on the ability to elaborate on and process information in a non-structured context (Wahlin et al., 2002). Similarly, in type 1 diabetes (T1DM) psychomotor speed is the most affected cognitive domain (Ryan et al., 1992, Brands et al., 2005, Brismar et al., 2007).
The mechanism for diabetic lesions on brain function is not known but it is likely to be multifactorial. Hypoglycemic events did not cause cognitive decline in a large prospective study of adult patients with type 1 diabetes (Jacobson et al., 2007). In T2DM among older patients, there is some indistinctness concerning mechanisms. This indistinctness is partially due to the association between diabetes and a wide range of other diseases, making it difficult to verify the existence of causes and effects (Jarrett, 1984). Thus, in attempts to examine the impact of diabetes per se on cognitive performance, the influence of related disorders should be accounted for (Strachan et al., 1997). Some possible confounders are myocardial infarction (MI), stroke, transient ischemic attack (TIA), angina pectoris, hypertension, or heart failure. Many of these disorders have been shown to exert an impact on the level of cognitive functioning (Bowler et al., 1994). An association between poor glucose tolerance and memory deficits has been demonstrated both in middle aged and elderly individuals (Convit et al., 2003).
Event-related potentials (ERPs), and in particular the latency of the P300 component, have been used to monitor cognitive decline in dementia (Polich and Pitzer, 1999). Moreover, elderly healthy subjects with reduced glucose regulation have lower P300 amplitude compared to subjects with better glucose regulation, which suggested that peripheral glucose control influences the P300 signal (Knott et al., 2001). Patients with T1DM were found to have an increase in P300 latency (Kramer et al., 1998, Cooray et al., 2008) and even more significantly, a decrease in the auditory N100 amplitude, which correlates with a decrease in psychomotor speed but not with function in other domains (Cooray et al., 2008).
The purpose of the present study was to characterise abnormalities in brain function in T2DM, and to investigate if such abnormalities could be reversed by a 2-month period of intensified glucose control. Metabolic control was assessed by measuring HbA1c, insulin-like growth factor 1 (IGF-1) and IGF-binding protein 1 (IGFBP-1) levels. IGFBP-1 is the most important dynamic regulator of free IGF-1 and was used as a marker of free IGF-1 (Frystyk et al., 2002). Increase in IGFBP-1 would suggest increased metabolic control and insulin sensitivity. Evoked potential recordings and cognitive tests were performed before and after intensified treatment, and with a similar time interval in a control group of patients on regular treatment and in healthy control subjects. Our results indicated that patients with T2DM have similar abnormalities as previously found in T1DM, and suggested that intensified therapy did improve brain function during the short treatment period of 2 months.
Section snippets
Subjects
Patients with T2DM (N = 28) and a group of healthy control subjects (N = 21) were studied. Patients between 50 and 70 years of age that were without diabetes complications (i.e. cardiovascular disease, angiopathy, microangiopathy, retinopathy or nephropathy) were eligible for the study. Patient history, bedside examination and medical notes were used to assess presence of complications in patients. Retinal imaging was used to assess retinopathy. Nephropathy was assessed by measuring serum
Demographic and clinical data
The prevalence of hypertension was higher for T2DM patients compared to healthy controls (p < 0.00008, Table 1). Furthermore, patients had a lower number of years of education. There were no differences between the two groups of patients with diabetes for any of the demographic variables.
Multivariate analysis
Differences at baseline between T2DM patients and healthy controls were studied with MANOVA. In order to reduce the amount of dependent variables in the multivariate analysis the mean power of all frequency bands
Discussion
In the present study we show that T2DM patients have significantly lower scores of verbal episodic memory, verbal fluency and visuospatial ability than healthy control subjects. There was also a tendency towards a reduction in semantic memory. Several of these domains have previously been shown to be affected by both T1DM (Northam et al., 1998, Brismar et al., 2007, Wessels et al., 2007) and T2DM (Perlmuter et al., 1984, Reaven et al., 1990, Grodstein et al., 2001, Munshi et al., 2006),
Role of funding source
None.
Conflict of interest
All authors declare that they have no conflict of interest.
Acknowledgements
The skillful work by nurses, Ms. Raija Bjerkeheim, Ms. Ulla Kylberg and Ms. Marianne Lindh and EEG-technician Ms. Britten Winström-Nodemar is gratefully acknowledged.
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