Dementia and Diabetes: What’s the Connection?

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By Benjamin V. Treadwell, Ph.D.

Cherries with stems making a heart shapeLet’s say you’re eating a nutritious diet (with some good-quality supplements) and exercising regularly. Most of us would still agree it’s important to schedule a complete annual physical with a qualified health professional. Why?

It gives your doctor the advantage over potential threats to your health. He/she can test for specific markers, analyze the results and then recommend an appropriate therapeutic or lifestyle change to prevent a condition or, at least, slow its progress.

Some physicians may skip certain markers, either because their indications are too broad or the options for bringing the levels back to a normal range are limited (or nonexistent). Take C-reactive protein (CRP) for example. At very high levels in the blood, it could indicate anything from a bruise or minor injury to cancer. Testing for this protein, however, may be valuable as a baseline for future comparison.

Two tests that should be performed routinely on most people, especially as we age, make a good introduction to this issue of the Health Journal. Happily, there are a variety of actions to prevent the unhealthy conditions these tests detect.

Two Tests Better Than One

It’s common to measure the amount of glucose in blood samples after a fasting period (12 to 15 hours). A high blood-glucose reading (greater than 110 milligrams per deciliter) may result from impaired glucose metabolism, possibly indicating a diabetic or pre-diabetic condition.

Recent advances in our understanding of diabetes, based on clinical studies, support measuring fasting insulin, along with glucose levels, in blood. New evidence indicates someone’s blood glucose level can be normal while his/her blood insulin level is abnormally high.

Research has shown the condition, known as insulin resistance, results from impaired insulin signaling by cells (fat, liver and muscle) in response to blood glucose. This resistance prompts the pancreas, the insulin-producing organ, to manufacture more of the hormone, which the cells need to absorb glucose for energy.

Insulin resistance can be considered a pre-diabetic condition. The insulin-signaling pathway’s decreased sensitivity places a burden on the pancreas’ beta cells. They must work harder to produce more insulin in order to move glucose from the blood into cells. As the insulin-signaling pathway’s sensitivity deteriorates further, the stress on the pancreas’ beta cells increases. Eventually the condition worsens, leading to type II diabetes.

Moreover, new evidence shows that the insulin-insensitive state found in our liver, fat and muscle cells/tissues corresponds with insulin sensitivity in our central nervous system, as well. This impacts the areas of the brain responsible for cognition, memory and learning.

Insulin Resistance on the Brain

Several studies have suggested that people diagnosed with insulin resistance are more likely to develop dementia. One noted a correlation between the age of onset of the pre-diabetic condition, between 60 and 74, and a spike in the incidence of Alzheimer’s disease (AD). Another found 81% of patients diagnosed with AD also had peripheral (pre-diabetic) insulin resistance.

These reports led a group of investigators to test a hypothesis. They proposed brain insulin resistance occurs early in the development of AD, even when the patient has not been diagnosed with diabetes.

Landmark Test Results

The team collected data from two groups of subjects. The first, 90 nuns and priests, is taking part in the longitudinal (extending until their deaths) Religious Order Study (ROS). With periodic testing to measure mental acuity, 30 have demonstrated normal function and 29 have demonstrated mild cognitive impairment (MCI). Thirty-one were diagnosed with AD after death.

The research team recognized the challenge of testing with human brain tissue samples. They obtained permission from their subjects ahead of time to allow removal of specific tissues immediately after their natural deaths for ex vivo (living tissue in solution outside the body) analysis.

The researchers used biochemical measurements to analyze a specific area of the brain, the hippocampus (responsible for memory, learning and cognition). They wanted to determine how responsive the cells were when exposed to insulin.

The team pooled the results (to date) from the ROS group with those from a cross-sectional study (no tests performed while the subjects were living) of a group of University of Pennsylvania subjects. In the U Penn Study, the researchers conducted the same experiment to measure the insulin response of hippocampal tissues from 24 normal brains and 24 diagnosed with AD.

The brain cells’ ability to respond to insulin diminished as cognitive impairment became more severe in both the ROS and U Penn groups. Tissue samples from subjects diagnosed with late stage AD showed the most dramatic decline. The investigators also observed that insulin resistance was an early event involved in the development of AD in humans.

On The Signaling Pathways

Additionally, the study revealed a significant link between the decrease in insulin response/sensitivity and slower activation of the insulin-signaling pathway, critical to regulating glucose levels. In fact, all of the many signaling-specific molecules and enzymes involved were impaired in subjects with dementia, as compared to those with normal memory/learning ability.

The research team examined another important metabolic signaling pathway, also glucose-activated and already identified as affected by diabetes. Known as the insulin-like growth factor pathway (IGF-1), it’s involved in the synthesis and health of tissues, including neuro-synapses and neuro-transmitters. Like the insulin-signaling pathway, IGF-1 was impaired in subjects with dementia and decreased insulin sensitivity.

Very Important Insulin

Our understanding of insulin’s role in our health is obviously growing. It’s not confined to transporting glucose out of the blood stream and into peripheral tissues (liver, fat tissue, muscle) for energy production and storage (after conversion to glycogen and fat). We’re also learning about the hormone’s importance to the brain’s memory and learning centers.

(Aside: A recent report, from the Veterans Affairs Puget Sound Health Care System in Seattle, described the almost immediate positive effects on mental function in AD patients who received insulin delivered by nasal spray. The rapid result was attributed to more direct transport to brain tissues via the nasal capillaries.)

There’s growing evidence that insulin resistance in tissues promotes insulin resistance in the brain. The research, highlighted in this Health Journal, reinforces the link between the condition in the brain and impaired insulin and IGF-1 signaling pathways, critical to maintaining brain health and function. Interestingly, the researchers also discovered participants could have impaired insulin/IGF-1 metabolic pathways in the brain, yet normal blood-glucose levels.

Ounce of Prevention

All of this evidence is compelling. It seems to indicate early detection and treatment of insulin resistance could help prevent not only diabetes, but also dementia, including AD.

Which takes us back to the beginning of this article and including a simple test in your annual physical exam: a fasting blood-insulin measurement. By combining it with a blood-glucose test (also referred to as HOMA-IR, homeostasis method assessment – estimated insulin resistance), your health professional can make a more accurate diagnosis, as well as recommend therapies.

In addition to diet and exercise, a number of prescribed drugs are proving effective for insulin resistance, including Metformin, currently used to treat diabetes. There is preliminary evidence that suggests taking several natural plant-derived substances, like resveratrol and fisetin, may help to improve insulin sensitivity. Recent studies indicate the nutrient berberine may be especially effective, too.

Ask Ben

Dr. Treadwell answers your questions.

question: I have read in a recent newspaper article about the positive effects of exercise on memory. Would you please comment on this observation and how you think exercise may act to improve memory? – MT

Recent studies have indicated aerobic exercise (and resistance/weight training to some extent), may positively affect brain function, including memory. (See Juvenon Health Journal Volume 10, Number 2, “The Aging Brain: Moderate Exercise For Maximum Memory.”)

In terms of general brain health, physical activity improves blood-to-brain circulation by increasing blood flow. More blood not only provides more nutrients, but it also elevates the levels and function of insulin, insulin-like growth factor and their corresponding receptors. All of these are critical to maintaining youthful-like cells (neurons) and their capacity for taking up fuel. The fuel (primarily glucose) supplies the brain’s need for a constant energy supply.

Speaking of neurons, several trials have shown that exercise seems to stimulate their growth, previously thought to be impossible in adults. Production of an exercise-induced, hormone-like substance in the brain, known as brain-derived neurotropic factor (BDNF), may promote this stimulation.

A nutrient, fisetin, has also been shown to grow new brain cells in human cell culture and animal studies. (See Juvenon Health Journal Volume 10, Number 11, “On Your Mind: Strawberry Fields For Memory.) The highest concentrations of this polyphenol (naturally occurring chemical) and flavonoid (antioxidant plant pigment compound) are found in strawberries.

As you can see, how to best support brain function and health, especially as we age, is an active area of research. The precise mechanism(s) involved are just beginning to be understood and there’s a lot more work to be done. For the time-being, however, indications are that a moderate exercise program (with the OK of your health professional) will benefit your memory.

Send your questions to [email protected].
For more questions and answers, click here.

Dr. Benjamin V. Treadwell is a former Harvard Medical School professor and member of Juvenon’s Scientific Advisory Board.

Research Update

“Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline” recently appeared in an article in The Journal of Clinical Investigation. Published by a team from prominent Philadelphia, New York and Chicago institutions (two universities, a medical center and a hospital), the article reports on significant findings related to the insulin-signaling pathway and dementia.

The researchers were familiar with earlier work, which had associated the incidence of the pre-diabetic condition in older people with insulin resistance, mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In fact, an estimated 37% of the U.S. population between ages 60 and 74 is pre-diabetic, correlating with the age span at which the incidence of AD spikes.

The team also knew that brain insulin resistance had yet to be directly demonstrated as a causal factor of AD. They designed a two-part study to show the condition is an early and common feature of AD, even when diabetes is not present.

A group of older nuns participated in part one, the Religious Orders Study (ROS). In this ongoing, longitudinal (from life to death) experiment, the subjects took periodic written and verbal tests designed to measure cognition and detect early stages of MCI. At their deaths, brain tissue was biochemically analyzed ex vivo.

In part two, a cross-sectional study, researchers at the University of Pennsylvania followed the same ex vivo protocol to examine brain tissue from very recently deceased subjects.

Extensive histological examination established whether AD was present in the subjects from either study group. Specific assays measured the activity of the insulin-signaling pathway and insulin sensitivity in tissues taken from the hippocampus (memory-learning area of the brain).

The assays produced landmark findings. The subjects diagnosed with MCI in the ROS group showed impaired insulin signaling. In the AD-diagnosed tissues from both groups, impairment was more intense.

The authors of the report conclude that insulin resistance in the brain occurs early in the development of dementia. They also maintain that peripheral (pre-diabetic) insulin resistance is likely to lead to insulin as well as IGF-1 (insulin-like growth factor) resistance in the memory-learning area of the brain, the hippocampus.

The results of this study do not mean AD is inevitable for diabetics. They do indicate, however, a predisposition to developing some level of dementia. They also emphasize how important it is to measure blood-insulin levels on a regular basis.

When insulin sensitivity/resistance is identified early, the doctor/patient can take action to help prevent its progression to type II diabetes, MCI and/or AD. For example, as also mentioned by the researchers, the drug Metformin has proven to be safe and very effective in improving insulin sensitivity.

Read abstract Here

This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.