Early Alzheimer's Pathology May Trigger Diabetes

Liam Davenport

April 21, 2016

Individuals with Alzheimer's disease (AD) may be at increased risk of developing type 2 diabetes because of impairments in insulin signaling in the hypothalamus, say US investigators in findings that turn on its head the presumed association between diabetes and AD.

Using a mouse model of AD, investigators found that younger mice exhibited early signs of metabolic dysregulation that were accompanied by increased insulin resistance in the hypothalamus. Importantly, these mice also had increased serum levels of branched chain amino acids (BCAAs); BCAA levels are typically elevated in obese and/or diabetic humans.

The research was led by Christoph Buettner, MD, PhD, associate professor of medicine, endocrinology, diabetes, bone disease, and neuroscience, Icahn School of Medicine at Mount Sinai, New York City, and was published online February 26 in Alzheimer's and Dementia.

Real Possibility

Given that previous studies have indicated that insulin resistance can occur in human brains, Dr Buettner told Medscape Medical News that it is a "real possibility" that some cases of type 2 diabetes in humans could be triggered by AD pathology.

Furthermore, inasmuch as the typical age of onset of type 2 diabetes is earlier than that of AD, it may be that the pathologic processes of AD are occurring in the brain much earlier than the symptoms and are leading to some cases of type 2 diabetes via brain insulin resistance.

Dr Buettner therefore hopes that elevated serum levels of BCAA "will turn out to be a good biomarker of brain insulin resistance in patients with Alzheimer's disease," which is the subject of further study by the research team.

The findings suggest that not only should clinicians be aware of the risk for AD in patients with type 2 diabetes but also that clinicians treating patients suspected of having AD should be aware of the potential for developing type 2 diabetes.

For the study, Dr Buettner and colleagues conducted a series of experiments in wild-type and APP/PS1 mice. These mice have two genetic mutations that cause amyloid deposits by 6 and 7 months of age and abundant plaque formation by 9 months of age. The researchers tested the two groups of mice at 5 months of age, which equates to 30 years of age in humans, and at 11 months, which corresponds to 55 years in humans.

Glucose tolerance testing indicated that when 5-month-old APP/PS1 and wild-type mice were fed a standard chow, they had similar glucose excursions. However, APP/PS1 mice had significantly greater glucose excursions than wild-type mice after receiving a high-fat diet (HFD) for 4 weeks. A similar pattern was observed in 11-month-old mice.

Interestingly, insulin tolerance testing revealed that although insulin sensitivity in younger APP/PS1 mice was similar to that in wild-type mice of the same age, 11-month-old APP/PS1 that were fed an HFD had significantly worse insulin tolerance at 60 minutes than wild-type mice. This was reflected in significantly worse fasting glucose and insulin levels.

Metabolic Dysregulation

Tests conducted when the mice were transitioning from the fasted state to the fed state showed that although glucose excursions in 5-month-old APP/PS1 mice were similar to those in wild-type mice, postprandial insulin levels remained elevated 2 hours after feeding in APP/PS1 mice. Triglyceride levels were also increased in these mice.

Crucially, the team found that the results were not affected by body weight, food intake, and adiposity, and APP/PS1 mice did not have impairments in lipid homeostasis compared with wild-type mice.

However, the team did find that hypothalamic insulin signaling was impaired in 5-month-old APP/PS1 mice, a fact that could be contributing to impairment in glucose homeostasis. These mice also had significantly higher levels of circulating BCAAs than wild-type mice while being fed regular chow.

Older APP/PS1 mice fed an HFD tended to have increased expression of genes linked to endoplasmic reticulum signaling, autophagy, and inflammation in the prefrontal cortex. This was not seen in younger APP/PS1 mice, suggesting that these pathways are unlikely to be involved in AD-related metabolic dysregulation.

AD, Metabolism Link

Dean M. Hartley, PhD, director of science initiatives in the Medical and Scientific Relations Division of the Alzheimer's Association, described the putative connection between AD and the development of type 2 diabetes as "an intriguing hypothesis."

He noted that diabetes is, in itself, "extremely important for individuals with Alzheimer's disease, because they're often dealing with many comorbidities, and for that reason, trying to keep their general health up is extremely important."

Discussing the idea that pathologic processes associated with presymptomatic AD may be causing some cases of diabetes, Dr Hartley observed that PET scanning studies have shown that amyloid can accumulate 20 years prior to the appearance of clinical symptoms.

"So one of the questions for the field is, What comes first? With studies indicating associations with diabetes, hypertension, amyloid, and neural inflammation, I suspect that what will happen is we'll find variations of those, depending on the population that we're looking at," said Dr Hartley.

He added that, as well as "beginning to get a handle on" the impact of race and ethnicity, as well as diabetes and heart disease, on an individual's risk for AD, "the additional complication is that we now know there are mixed dementias."

In other words, patients may not have pure AD but could have AD and vascular dementia, or AD and Parkinson's disease.

Dr Hartley said that "energy metabolism is at the heart" of it, with recent MRI studies indicating that hyper- and hypometabolism occurs early in AD in various parts of the brain, such as the hippocampus.

Moreover, recent clinical trials have shown that nasal insulin can improve memory in people with mild cognitive impairment, although it is not yet clear whether the effect is long term.

For Dr Hartley, all this underlines the need for more funding for AD research to "get us answers like we have for cancer or for heart disease."

The study was supported by the National Institute on Aging, the American Diabetes Association, and the Cure Alzheimer's Fund Research Consortium. The authors and Dr Hartley report no relevant financial relationships.

Alzheimers Dement. Published online February 26, 2016. Abstract

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