Insulin and AD- Part XXVIII of a XXVIII Series on AD
(2/13/07)-Susan Craft, PhD, and her colleagues at the University of Washington, Seattle, has been studying the link between insulin levels and memory. Insulin is a hormone that helps regulate blood sugar. Obesity, high blood pressure and diabetes are associated with a condition called insulin resistance, in which the body needs more and more insulin to balance sugar levels. The reaction is akin to building up a resistance to a drug.
When insulin levels are controlled, the insulin can act in certain areas of the brain to enhance memory and cognition. Disruption of insulin regulation increases the risk for cognitive impairment.
Insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin, which is directly useful in reducing high blood glucose levels as in diabetes. Elevated levels of insulin in the body can go straight to the brain, causing inflammation and increasing levels of a protein, beta amyloid 42, seen in abundance in patients with Alzheimer's disease,
The 42-peptide form of beta amyloid plaques appearing in certain regions of the brain is a hallmark of AD. Craft and her team have found evidence that persistently high levels of insulin (hyperinsulinemia) are associated with inflammation in the brain and trigger an accumulation of 42-peptide form of beta amyloid, commonly called "the bad form" of beta amyloid.
In the brain, there is an insulin degrading enzyme which clears both insulin and beta amyloid. However, it generally prefers to degrade insulin as opposed to the beta amyloid. The greater the amount of insulin, the more the enzyme degrades the insulin, leaving the beta amyloid peptides to accumulate and form plaques.
Craft then investigated certain proteins -peroxisome proliferators-activated receptors (PPARs)- that act as transcription factors inducing the proliferation of peroxisomes in cells. The net result of PPARs is a lower insulin level and enhanced antiinflammatory effect. Since inflammation is a potential factor in AD progression, Craft believes PPARs may prove valuable in reversing cognitive loss concomitant with AD.
(Note: "A transcription factor is a protein that regulates the binding of RNA polymerase and the initiation of transcription. A transcription factor binds upstream to either enhance or repress transcription of a gene by assisting or blocking RNA polymerase binding.") (Wikipedia on line, accessed Feb. 1, 2007)
The antiinflammatory effect is the result of the inhibition of PPAR on NF-kappa B activation. Nuclear Factor kappa B (NF-?B) is a primary transcription factor and is involved in cellular responses to stimuli such as stress, cytokines, and free radicals. NF-?B plays a key role in regulating the immune response to infection.
PPAR-gamma agonists have been proposed as anti-inflammatory agents owing to inhibition of NF-kappa B activation. Julie Davidow, writing in the Seattle Post-Intelligencer (August, 9, 2005), states: "When your blood sugar is too high, it damages your blood vessels. This damage may first become evident in the tiny vessels of your eyes and feet, but it can also affect your brain. Small-vessel damage in the brain often contributes to vascular dementia…A modest increase in insulin makes more glucose available to brain cells, resulting in improved memory. But if you're insulin resistant and the level of insulin in your bloodstream remains high, the brain takes measures to slow the transport of insulin across the blood-brain barrier. That reduces the amount of insulin in the brain, making less glucose available to nourish brain cells. Excessive insulin in the bloodstream may trigger increased production of beta-amyloid, a segment of a protein the body normally makes. In Alzheimer's disease, beta-amyloid builds up in the brain, forming clumps, or amyloid plaques. Excess insulin may also be responsible for brain cells' failure to clear beta-amyloid."
Neil Osterweil, (Senior Associate Editor, MedPage Today August 08, 2005) at http://www.medpagetoday.com/Neurology/AlzheimersDisease/tb1/1506) quoted Dr. Mark A. Fishel on his study of the role of insulin: "Our findings suggest that insulin-resistant conditions such as diabetes mellitus and hypertension may increase the risk for Alzheimer's disease, in part through insulin-induced inflammation." He concludes his article by reporting, "The results, if confirmed, suggest that the current epidemic of diabetes and insulin resistance syndromes could cause an upsurge in the prevalence of Alzheimer's in the future, the authors contended".
The studies of Craft and Fishel have caught the eye of drug companies. They have begun to investigate the role of peroxisomes in AD.
The therapeutic use of PPARs in the treatment of Alzheimer’s is something that will take multiple clinical research trials. It represents a new avenue of approach that only time will tell if it is effective in meeting the needs of individuals with AD.
For some additional articles on Alzheimer's disease please see the following:
See: Alzheimer's Disease Part I-Medications for Alzheimer's.
See: Alzheimer’s Disease Part II- Selegiline and AD.
See: Alzheimer's Disease Part III- Use of Gingko Biloba in memory problems of Alzheimer patients
See: Part IV-Alternative Treatments for AD
See: Part V-Possible New Drugs for Alzheimer's Disease
See: Part VI-Early Diagnosis
See: Part VII-Metrifonate
See:Alzheimer's Disease PartVIII - Implications of Longer Life Expectancies
See: Alzheimer's Part IX-Ethical Care Principles
See: Alzheimer's Disease-Part X-Estrogen and Alzheimer's Disease
See: Alzheimer's Disease Part XI-Pocket Smell Test (PST)
See: Alzheimer's Disease Part XII-MAO-B
See: Alzheimer's Disease Part XIII -Critical Flicker Fusion Threshold Test
See: Alzheimer's Disease Part XIV-Donepezil
See: Alzheimer's Disease Part XV-Cerebrolysin
See: Alzheimer's Disease Part XVI-MCI
See: Alzheimer's Disease Part XVII-Summary
See: Alzheimer's Disease Part XVIII-NO Releasing NSAIDs
See: Alzheimer's Disease Part XIX-Vitamin E
See: Alzheimer's Disease-Part XX-Clinical Trials
See: Alzheimer's Disease-Part XXI- AD and the Brain
See: Alzhemer's Disease-Part XXII-Lewy Bodies Disease
See: Alzheimer's Disease-Part XXIII-HMG
See: Alzheimer's Disease-Part XXIV-A Prequel
See: Alzheimer's Disease-Part XXV- Plus Psychosis
See: Alzheimer's Disease-Part XXVI- Amyloid-beta Hypothesis Controversy
See: Alzheimer's Disease-Part XXVII- AD and Diabetes
FOR AN INFORMATIVE AND PERSONAL ARTICLE ON PRACTICAL SUGGESTIONS WHEN SELECTING A NURSING HOME SEE OUR ARTICLE "How to Select a Nursing Homes"
Harold Rubin, MS, ABD, CRC, Guest Lecturer
posted February 13, 2007
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