Comment ❚
Hyperglycaemia and the brain
Anand Beri MBBS, MRCPsych, MSc
Evidence is accumulating that diabetes worsens cognition and can lead to dementia. The
author discusses some of that evidence in this article: it highlights the importance of early
diagnosis and adequate treatment to prevent cognitive decline.
T
here are almost 3.5 million people who have been
diagnosed with diabetes in the UK.1 Type 2 diabetes accounts for about 90% of all people with diabetes;
it generally appears in people over the age of 40 years.2
The problem is huge and continues to grow. Diabetes
affects many major organs, including heart, blood vessels, nerves, eyes and kidneys.
In the Dutch prospective Doetinchem Cohort Study,
at five-year follow-up, the decline in global cognitive
function in diabetic patients was 2.6 times greater than
that in individuals without diabetes. Elderly patients
with diabetes also showed a reduced cognitive flexibility
compared with individuals without diabetes.3
Arvanitakis et al. report that type 2 diabetes is associated with cognitive impairment, especially in semantic memory and perceptual speed in elderly
non-demented subjects.4 Strachan et al. conducted a
review of published studies in 1997 and found that
verbal memory is the most commonly affected cognitive ability.5 Verbal learning, abstract reasoning and
complex psychomotor functioning were more
impaired in diabetic than in non-diabetic subjects.6
Modest cognitive impairment is already present at
the early stage of type 2 diabetes. Immediate memory,
learning rate and incidental memory appear to be the
most affected in the early stages.7 Furthermore, glycaemic control appears to play a role in determining the
degree of cognitive dys­function detected in patients
with type 2 diabetes.8 A 1% higher HbA1C value (≥7.5%)
was associated with a 1.75-point lower Digit Symbol Substitution Test (DSST) score and a 0.20-point lower Mini
Mental State Examination (MMSE) score.9 The DSST
is a subtest of the Wechsler Adult Intelligence Scale (3rd
edition), which assesses visual motor speed, capacity for
learning, sustained attention, and working memory. A
similar effect of increased HbA1C was demonstrated by
Ravona-­Springer et al. with a decrease of 1.37 points in
the MMSE per unit increase in HbA1C.10
Mortby et al. found blood glucose levels, even in the
high normal range, were associated with lower grey/
white matter regional volumes in the frontal cortices
and poorer cognitive performance.11 They found this
association to be specific to men. They argue for a
rethink of what could be an optimal level of blood glucose (in their sample the blood glucose level range was
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between 3.2 and 6.1mmol/L). Furthermore, duration
of the disease seems to be important in diminished
motor speed tasks in type 2 diabetes patients.12 Compared with normogly­caemics, people diagnosed with
diabetes 15 or more years earlier had significantly
slower processing speed and poorer executive function performance.13
The question as to whether diabetes is a risk factor
for Alzheimer’s disease has produced conflicting
answers. It has long been accepted that type 2 diabetes
increases the risk of stroke, and its effect on cognition
may be mediated through the factors important in cardiovascular disease. In a five-­year longitudinal study,
MacKnight et al. reported that diabetes mellitus at
baseline was associated with incident vascular cognitive
impairment; they did not find an association between
diabetes and incident Alzheimer’s disease.14 On the
other hand, the Honolulu-Asia Aging Study found
diabetes to increase the risk of total dementia by 50%
(RR 1.5 [95% CI 1.01–2.2]). Patients with diabetes
were at greater risk of developing vascular dementia
and the risk of Alzheimer’s disease was increased by
80% (vascular dementia RR 2.3 [1.1–5.0] Alzheimer’s
disease RR 1.8 [1.1–2.9]).15
Type 2 diabetes is associated with hippocampal
and amygdalar atrophy, regardless of vascular
pathology linking it to the development of Alzheimer
neuropathology.16
Improvement in glycaemic control results in moderate improvement in cognition, especially working
memory.17 Verbal learning and memory may improve
with improved glycaemic control.18
A post-mortem study19 demonstrated significantly
fewer neuritic plaques in the brains of diabetic
subjects who received both insulin and oral anti­
diabetic medication.
Antidiabetic drugs were effective in alleviating the
decline in physical and cognitive functioning among
older Mexican Americans with diabetes, especially for
those with a longer duration of the disease.20
Conclusion
The evidence associating diabetes with dementia is
increasing; it is becoming clear that both vascular and
Alzheimer’s types of dementia can be attributed to
Progress in Neurology and Psychiatry September/October 2016
www.progressnp.com
❚ Comment
diabetes. There is also accumulating evidence that
achieving normoglycaemia with medications can lead
to improvement in cognitive ability.
GPs are uniquely placed to diagnose and treat diabetes. Awareness needs to be raised among GPs about
the detrimental effect of untreated diabetes on brain
function. Cognitive decline and dementia should be
added to the list of complications of diabetes, in addition to cardiovascular disease, kidney disease, blindness and limb amputation.
Dr Beri is a Consultant Psychiatrist at 2gether NHS
Foundation Trust, Gloucester.
References
1. Diabetes UK. What is diabetes? (www.diabetes.org.uk/Guide-todiabetes/What-is-diabetes; accessed August 2016).
2. Diabetes UK. What is type 2 diabetes? (www.diabetes.org.uk/Guide-todiabetes/What-is-diabetes/What-is-Type-2-Diabetes; accessed August 2016).
3. Nooyens ACJ, Baan CA, Spijkerman AMW, et al. Type 2 diabetes and
cognitive decline in middle-aged men and women: The Doetinchem
Cohort Study. Diabetes Care 2010;33(9):1964–9.
4. Arvanitakis Z, Wilson RS, Li Y, et al. Diabetes and function in different
cognitive systems in older individuals without dementia. Diabetes Care
2006;29(3):560–5.
5. Strachan MWJ, Deary IJ, Ewing FME, et al. Is type II diabetes associated
with an increased risk of cognitive dysfunction? A critical review of
published studies. Diabetes Care 1997;20(3):438–45.
6. Reaven GM, Thompson LW, Nahum D, et al. Relationship between
hyperglycemia and cognitive function in older NIDDM patients. Diabetes
Care 1990;13(1):16–21.
7. Ruis C, Biessels GJ, Gorter KJ, et al. Cognition in the early stage of type
2 diabetes. Diabetes Care 2009;32(7):1261–5.
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Alzheimer’s disease: implications for treatment. CNS Drugs 2003;17(1):27–45.
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in diabetes-memory in diabetes (ACCORD-MIND) trial. Diabetes Care
2009;32(2):221–6.
10. Ravona-Springer R, Moshier E, Schmeidler J, et al. Changes in glycemic
control are associated with changes in cognition in non-diabetic elderly. J
Alzheimers Dis 2012;30(2):299–309.
11. Mortby ME, Janke AL, Anstey KJ, et al. High “normal” blood glucose
is associated with decreased brain volume and cognitive performance in
the 60s: The PATH through life study. PLoS One 2013;8(9):e73697.
12. van Harten B, Oosterman J, Muslimovic D, et al. Cognitive impairment
and MRI correlates in the elderly patients with type 2 diabetes mellitus.
Age Ageing 2007;36:164–70.
13. Saczynski JS, Jonsdottir MK, Garcia ME, et al. Cognitive impairment:
an increasingly important complication of type 2 diabetes: the age,
gene/environment susceptibility – Reykjavik study. Am J Epidemiol
2008;168:1132–9.
14. MacKnight C,· Rockwood K,· Awalt E, et al. Diabetes mellitus and the
risk of dementia, Alzheimer’s disease and vascular cognitive Impairment
in the Canadian Study of Health and Aging Dement Geriatr Cogn Disord
2002;14:77–83.
15. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and
the risk for dementia and related pathologies: The Honolulu-Asia Aging
Study. Diabetes 2002;51(4):1256–62.
16. den Heijer T, Vermeer SE, van Dijk EJ, et al. Type 2 diabetes
and atrophy of medial temporal lobe structures on brain MRI.
Diabetologia 2003;46(12):1604–10.
17. Ryan CM, Freed MI, Rood JA, et al. Improving metabolic control leads
to better working memory in adults with type 2 diabetes. Diabetes Care
2006;29(2):345–51.
18. Gradman TJ, Laws A, Thompson LW, et al. Verbal learning
and/or memory improves with glycemic control in older subjects
with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc
1993;41(12):1305–12.
19. Beeri MS, Schmeidler J, Silverman JM, et al. Insulin in combination
with other diabetes medication is associated with less Alzheimer
neuropathology. Neurology 2008;71(10):750–7.
20. Wu JH, Haan MN, Liang J, et al. Impact of antidiabetic medications
on physical and cognitive functioning of older Mexican Americans with
diabetes mellitus: a population-based cohort study. Ann Epidemiol
2003;13(5):369–76.
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