Cognitive dysfunction in diabetic patients partly explained by hyperglycemia

1-11-2017 • Geijselaers SLC et al., Diabetes Care 2017  

The Role of Hyperglycemia, Insulin Resistance, and Blood Pressure in Diabetes-Associated Differences in Cognitive Performance – The Maastricht Study

Geijselaers SLC, Sep SJS, Claessens D, et al.
Diabetes Care 2017; published online ahead of print

Introduction and methods

Prediabetes and T2DM are associated with cognitive impairment [1]. The underlying pathophysiology is not absolutely clear, although markers of hyperglycemia, insulin resistance (IR) and vascular factors, like BP abnormalities, have been associated with cognitive dysfunction, irrespective of glucose metabolism status [2].
In this analysis of the Maastricht study, it was assessed whether the differences in cognitive performance between subjects with different glucose metabolism can be explained by the presence of hyperglycemia, IR, or BP-related variables. For this purpose, data from the first 3,451 participants included in the Maastricht study between November 2010 and September 2013 were used [3,4]. The glucose metabolism status was determined with a 2-h seven-sample oral glucose tolerance test (OGTT), and it was classified based on the 2006 WHO diagnostic criteria into normal glucose metabolism (NGM), impaired glucose metabolism (prediabetes), and T2DM. Patients with type 1 diabetes were excluded, and patients receiving insulin and those with a fasting glucose level >11.0 mmol/L were excluded from the OGTT, leaving a cohort with 2,531 participants.
Assessment of hyperglycemia was based on a composite index including fasting and post-load plasma glucose, as well as HbA1c, and tissue advanced glycation end products. For assessment of IR, the HOMA-IR index was used. Based on the recommendations of the British Hypertension Society, a composite index of SBP and DBP was used, which was derived from 24-h ambulatory BP data, and was combined with the use of antihypertensive medication. Moreover, a 24-h pulse pressure index was created.
Cognitive performance was measured by a concise neuropsychological test battery that lasts 30 min, and follows the recommendations for the assessment of diabetes-associated cognitive abnormalities [5]. In the current analysis, the raw test scores were standardized and divided into the cognitive domains of memory function, executive function plus attention (EF&A), and information processing speed.

Main results

  • An overall trend towards declining cognitive performance was seen with worsening glucose metabolism status, although only those with diabetes had significantly worse cognitive performance.
  • Compared with individuals with NGM, T2DM patients performed worse in all cognitive domains (adjusted mean differences in composite z scores for memory: 20.087; processing speed: 20.196; EF&A: 20.182; P values <0.032), but individuals with prediabetes did not.
  • The magnitude of diabetes-associated worse performance on memory function was less than half of that observed for processing speed and EF&A, and the differences in memory function were not explained by hyperglycemia or IR, nor by BP–related variables.
  • Hyperglycemia explained differences in performance in the domains of processing speed and EF&A between T2DM patients and NGM individuals, with significant mediating effects of 79.6% (bootstrapped 95%CI: 36.6% - 123.4%) and 50.3% (95% CI: 0.6% - 101.2%), respectively.
  • Differences in processing speed were also partly explained by BP–related variables (mediating effect: 17.7%; 95% CI: 5.6 - 30.1%), while IR had no mediating effects on the association of T2DM with either processing speed or EF&A.
  • The mediating effects of hyperglycemia and BP were partially additive, since any combination of mediators resembled the summed effects of the individual mediators, and the mediating effects of hyperglycemia was more pronounced in patients receiving antihypertensive medications compared with non-users. Moreover, the mediating effects of BP increased with the severity of hyperglycemia.


In participants of the Maastricht study, differences in cognitive performance between T2DM patients and NGM individuals, could be explained by hyperglycemia and partially by BP-related variables, particularly in the domains of processing speed and executive function plus attention, whereas IR has no mediating effects. These findings suggest that the prevention of diabetes-associated deterioration of cognitive performance should focus on early glycemic and BP control.
Find this article online at Diabetes Care


1. Biessels GJ, Strachan MW, Visseren FL, et al. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol 2014;2:246–255
2. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med 2013;369:540–548
3. Schram MT, Sep SJ, van der Kallen CJ, et al. The Maastricht Study: an extensive phenotyping study on determinants of type 2 diabetes, its complications and its comorbidities. Eur J Epidemiol 2014;29:439–451
4. Spauwen PJ, van Boxtel MP, Verhey FR, et al. Both low and high 24-hour diastolic blood pressure are associated with worse cognitive performance in type 2 diabetes: the Maastricht Study. Diabetes Care 2015;38:1473–1480
5. Kessels RP, Brands AM. Neuropsychological assessment. In Diabetes and the Brain. 1st ed. Biessels GJ, Luchsinger JA, Eds. New York, Humana Press, 2010, p. 77–102


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