Interview with David Tanne, MD and Carolyn Apovian, MD
People with diabetes and cardiovascular disease (CVD) are known to be at increased risk for cognitive decline, but worsening cognitive performance occurs even in individuals with insulin resistance (IR) according to a study published in the Journal of Alzheimer’s Disease.1
"The good news is that insulin resistance can be prevented and treated by keeping a healthy lifestyle. Exercising, maintaining a balanced and healthy diet, and watching your weight helps prevent and treat insulin resistance," David Tanne, MD, professor of Epidemiology and Preventive Medicine in the School of Public Health, Tel-Aviv, Israel, told EndocrineWeb.
In a group of individuals with CVD who were followed for 15 years, IR was associated with significantly poorer cognitive performance, and a further decline in cognitive function was noted after just an additional 5 years.1 The association was apparent in the overall group (with diabetes) as well as in those without diabetes at baseline and during follow-up.
"These findings add to the armamentarium of evidence for endocrinologists to provide early, aggressive treatment," Caroline Apovian, MD, professor of medicine and pediatrics at Boston University School of Medicine, in Boston, Massachusetts, told EndocrineWeb. "It's crucial that we head off insulin resistance as early as possible to prevent progression of prediabetes and concomitant cognitive decline."
At the second evaluation, the patients who remained in the study demonstrated cognitive performance that had worsened significantly overall, as well as in all cognitive domains except attention, according to the authors.
Because none of the indices of cerebrovascular disease had an effect on the associations between HOMA-IR and cognitive impairment or decline, the researchers believed there to be a possible non-vascular cause for the cognitive decline.1,2 The findings in this study support prior research showing IR has an important role in the pathogenesis of cognitive impairment and neurodegeneration.3,4
Patients enrolled in this study1 had participated in a secondary prevention trial during the 1990s when they were at a mean age of 57.7;2 all were diagnosed with CVD. The IR was calculated according to the homeostasis method of assessment (HOMA-IR).
After following 489 patients for 15 years (mean age of 72.6 years), a complete cognitive performance evaluation was completed, which yielded composite scores as well as scores for memory, executive function, visual spatial ability, and attention. After an additional 5 years, between 2011 and 2013, a second assessment of cognitive performance and HOMA-IR was collected on 347 of those patients.1
The research team, led by Dr. Tanne, determined the IR by dividing the baseline HOMA-IR measurements into quartiles, controlling for potential confounding variables, and designating those in the top quartile (HOMA-IR > 1.60) to be insulin resistant.1 At baseline, participants in this group had higher BMI, higher systolic blood pressure, and were more likely to have comorbidities, according to the authors.
High levels of HOMA-IR were also associated with increased levels of C-reactive protein and triglycerides, said Dr. Tanne. After adjusting for age, sex, and education, individuals in the IR group had poorer performance overall in cognitive function, particularly in memory and executive function.1 These associations remained statistically significant for the composite and memory scores even after excluding those with diabetes (fasting blood glucose ≥ 126 or a prescription for an antidiabetic agent) and anyone with a history of stroke or dementia at the time of assessment.1
Deterioration in overall cognitive function, memory, and executive function remained even after patients with diabetes, a history of stroke, or dementia, at the second evaluation were excluded. This is notable since IR is a modifiable midlife risk factor, according to the study authors.
Growing evidence points to the role of insulin in the brain in the mechanisms underlying cognitive impairment.2-4 In peripheral hyperinsulinemia, insulin transport to the brain via the blood-brain barrier is reduced, leading to reduced levels of insulin in the brain and disruption of insulin signaling. This leads to impairment of neuronal function, effects on the metabolism of amyloid-β and tau, and increases in inflammation and oxidative stress, which could directly affect neurons.
Diabetes has a long prodromal phase, which allows greater opportunity for prevention and intervention. Given these findings and because IR is a potentially modifiable risk factor, Dr. Tanne told EndocrineWeb, the next step is to examine whether early intervention among high-risk individuals with IR could ameliorate the negative consequences of IR on the brain.
“This epidemiological study confirms what we and others have seen in the lab—elevated insulin impairs endothelial function in the vasculature,” said Dr. Apovian. “Insulin resistance affects every organ system in the body, and its effects on cognitive decline are the result of impaired blood flow to the brain.”
"With endocrinologists on the frontline, as Dr. Tanne said is a healthy diet and exercise is essential; in addition, the best course of treatment for patients with prediabetes and obesity is metformin and a glucagon-like peptide-1 (GLP-1) analog (ie, exenatide, liraglutide) since this combination can preserve the beta cell dysfunction, which is the initial insult, leading to insulin resistance," said Dr. Apovian, stressing the value of prescribing liraglutide, in particular, given it has FDA approval for long-term weight management with no concern for hypoglycemia.
"Lastly, clinicians should consider recommending bariatric surgery to patients who are obese and meet the criteria," Dr. Apovian said since the goal is to preserve physical and mental functioning for the long-term with the best treatment possible.