We have long known that type 2 diabetes compromises the health and function of multiple organs, including the kidneys, eyes, and heart. Over the past few years, however, convincing evidence also has accumulated about the relationship between diabetes and brain function. For example, type 2 diabetes increases the likelihood that a person will develop dementia, such as Alzheimer disease or vascular dementia.1 Type 2 diabetes can also accelerate mild cognitive decline comparable to effects seen with aging, such as slower processing speeds.2 At present, no “smoking gun” links cognitive decline to diabetes. But current science offers two strong lines of evidence that might explain the connection: one pointing to insulin sensitivity and the other to cardiovascular disease.
We now understand that insulin plays an important role both in regulating brain glucose and in signaling processes within the brain. In fact, the links between insulin regulation and cognition are so strong that some have called Alzheimer disease “type 3 diabetes.”3 Regions affected by Alzheimer disease are especially rich in insulin receptors.4,5 Human research shows that dementia incidence is associated with a low insulin response to a glucose challenge, high fasting plasma glucose (FPG) and 2-hour fasting glucose after an oral glucose tolerance test, and that diabetes increases a person's risk of dementia by about 60%.6,7 In addition, impaired insulin sensitivity is linked with atrophy of the temporal lobe and reduced cognitive performance.8 Interestingly, evidence is emerging that administration of intranasal insulin, which delivers insulin preferentially to the brain, is associated with improved memory performance in younger adults and persons with early Alzheimer disease.5
Type 2 diabetes plays a key role in significantly increasing risk of cardiovascular disease, including atherosclerosis, hypertension, heart failure, stroke, and myocardial infarction. Cardiovascular disease, in turn, increases the risk of dementia and milder cognitive impairments independent of diabetes.9 One illustration of this link is hypertension. Hypertension is a common comorbidity of type 2 diabetes that is associated with atrophy of overall grey matter, the hippocampus, and the frontal cortex.10,11 Hypertension is also strongly associated with leukoaraiosis, a disease of white matter in the brain that is common in aging and associated with slower processing speed.11,12 In a postmortem study in humans with Alzheimer disease, although patients with diabetes had a comparable level of Alzheimer pathology to those without diabetes, the patients with diabetes were more likely to experience cerebral infarctions.13 In short, the risk of clinically diagnosed cardiovascular disease in patients with type 2 diabetes almost assuredly raises their risk of cognitive decline.
My colleagues and I recently analyzed data from a large genetic study to see if evidence of subclinical cardiovascular disease raised the risk of poorer cognitive function a few years later. In our study, subclinical cardiovascular disease was defined as coronary calcification measured using computed tomography. Part of what made this study unique was that we included a measure of subclinical cardiovascular disease, rather than reported cardiovascular events. Also, we studied a group of aging siblings in whom about 80% had type 2 diabetes.
Why is this population important to study? First, because they share some genetic and environmental background, these factors are less likely to explain any observed differences between those with and without diabetes. Second, the siblings without diabetes were not healthy controls, as are most commonly used. Some of our patients also had evidence of subclinical cardiovascular disease, were overweight, or had insulin resistance. Often, comparisons use controls who are largely free of any chronic disease. Although this method helps isolate the effects of the disease, siblings are in many ways a more representative comparison group to use.
Several of our findings could be important for physician assistants (PAs). First, the presence of diabetes was associated with poorer cognitive performance in processing speed, verbal memory, and executive function. That is, patients with diabetes tended to have poorer cognitive performance, even when compared with siblings with similar genetic background and environmental exposures. What role did cardiovascular disease play in this? Adjusting for subclinical cardiovascular disease reduced the association between cognition and diabetes to non-significance and was predictive of lower cognitive performance. Put another way, the variation in subclinical cardiovascular disease was a more powerful predictor of lower cognitive performance than the presence of diabetes. Interestingly, subclinical cardiovascular disease also predicted lower cognitive performance in patients without diabetes.
As a neuroscientist, my primary focus is to elucidate how the brain is affected by a metabolic disturbance in the body. My clinical colleagues and I believe that even in the absence of a clear causal pathway, what we know now about the subclinical risks of type 2 diabetes for the brain can begin to inform clinical practice.
The magnitude of the effects of both diabetes and cardiovascular disease on cognition was relatively small. Almost everyone in our study was above the cutoff for dementia on the Mini-Mental State Examination. Even though these relatively small effects might not be clinically evident, subtle cognitive changes in executive function, verbal memory, and processing speed could affect patients' ability to comprehend and follow through on the complex medical regimens often necessitated by diabetes. Clinicians could slow down their speech for patients who might have slower processing speeds because of risk factors for cardiovascular disease or diabetes. Ask patients to repeat information back to you (“teach back” techniques) or provide patients with written information. Importantly, some patients who will benefit from these modest accommodations might not present with any overt disease. Finally, understanding that diseases of the body, like diabetes and cardiovascular disease, also pose a risk to the brain may motivate patients to make changes toward a more healthful lifestyle.
These results reinforce the idea that disease processes can affect function before they are clinically recognizable. The next time you encounter someone who has risk factors for diabetes, such as borderline hypertension or borderline elevated blood glucose levels, keep in mind that these subclinical changes may already be influencing your patient's ability to understand and follow the important health care instructions you give them. What we are learning about subclinical disease processes gives both providers and patients an impetus to be proactive and make changes in communication methods and lifestyle before disease has taken hold.
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