More Evidence that Alzheimer’s Is Type 3 Diabetes

The Use of Nutrients Is Expanding

More Evidence that
Alzheimer’s Is Type 3 Diabetes

Impaired insulin signaling is linked to reduced
acetylcholine levels and thus to cognitive impairment
By Will Block

hings are not always as they seem." Whether you regard that as Truth or merely a truism, you would probably agree that, when we’re dealing with the most complex object in the known universe, it’s hard to know exactly what things are, as opposed to how they seem. The object in question is, of course, the human brain (and if there are any alien beings tuned in to our scribblings here on Earth, they’re probably having a horselaugh at our high opinion of our own brains).

Although it’s difficult for our brains to understand themselves, some of our best ones keep trying, and sometimes pieces of the puzzle come together to reveal something new and significant. That was true when Dr. Suzanne de la Monte, a neuropathologist at Rhode Island Hospital and a professor of pathology at Brown Medical School in Providence, proposed a provocative theory last year. Based on a review of the literature and her own research, she and her colleagues suggested that Alzheimer’s disease may actually be a distinct type of diabetes, which they dubbed type 3 diabetes.1,2

Alzheimer’s Entails Impaired Insulin Signaling

An article on this subject (“Is Alzheimer’s Disease a Type of Diabetes?”) appeared in the May 2005 issue of Life Enhancement. Let’s recap the basic ideas and then see what’s new. First of all, the idea that Alzheimer’s disease (AD) may be a kind of “brain diabetes” is not new—it was proposed by German neuroscientists in the 1990s. It was known that there is a significant decline in glucose metabolism (a hallmark of diabetes) in the brains of Alzheimer’s patients and that enhancing this process by administering glucose or insulin could improve memory and other cognitive functions. It was also known that type 2 diabetes is, in fact, a risk factor for AD. Recently the converse was discovered: AD predisposes its victims to type 2 diabetes.3

All this is strong evidence of a correlation, but not necessarily a causation, between the two diseases. To establish the latter requires evidence of molecular mechanisms that explain such a linkage, and the jury is still out on that. In any case, it’s obvious that neither disease necessarily causes the other, because it’s possible (and common) to have either one without the other—thus there are certainly other factors at work. It’s significant, though, that some degree of cognitive impairment is characteristic of type 2 diabetes, indicating that the disease affects the brain in a manner perhaps similar to that of Alzheimer’s disease (or dementia in general).*


*A causal link between type 2 diabetes and vascular dementia is well established (and not surprising, considering the destructive effect of diabetes on the body’s vasculature). Such a link with AD is still controversial, however, and is complicated by the fact that AD and vascular dementia have much in common, can coexist with each other, and are often difficult to diagnose differentially.


In fact, there is no doubt regarding the similarity, because it’s well known that a characteristic feature of Alzheimer’s brains is impaired insulin signaling, the very thing that causes impaired glucose metabolism in type 2 diabetes. Insulin signaling is the cascade of biochemical reactions launched by insulin when it initiates the process of glucose transport from the bloodstream into our cells. The primary culprit in impaired insulin signaling is insulin resistance, a progressive inability of our cells to respond adequately to insulin. This condition can lead to a host of metabolic problems, up to and including cell death.

The Brain’s Insulin Production Is Curtailed in Alzheimer’s . . .


PET (positron emission tomography) scans illustrating impaired glucose metabolism in Alzheimer’s disease.
It had long been thought that all of our insulin was produced by the pancreas, and it was known that insulin could gain access to the brain by crossing the blood-brain barrier. It was assumed, but not proved, that this “peripheral” insulin was actually utilized by the brain’s neurons in facilitating glucose transport. That question has become somewhat less important, however, since Dr. de la Monte and her colleagues discovered that the brain produces its own insulin. The brain also produces the vital insulinlike growth factors (small proteins very similar to insulin, with overlapping but not entirely duplicative functions); like insulin itself, these growth factors are necessary for neuronal survival.

In Alzheimer’s brains, however, the production of insulin and the insulinlike growth factors (IGFs) is severely curtailed, as is the production of the neuronal receptors upon which they critically depend in order to accomplish their biological functions. This surely impairs the insulin signaling pathway and, therefore, glucose metabolism (the primary source of our cells’ chemical energy) in the brain. Impaired brain metabolism is one of the best-documented abnormalities in Alzheimer’s.

. . . Leading to Neurodegeneration and Cognitive Impairment

The Rhode Island researchers concluded that the neurodegeneration and cognitive impairment associated with AD are fundamentally mediated by the depletion of insulin and IGFs in the central nervous system, and by the secondary loss of neurons that are dependent on these molecules. Furthermore, they believe that a separate and independent component is the insulin resistance that occurs in type 2 diabetes. All of which (and much more) led them to propose that Alzheimer’s disease is not just a brain version of type 2 diabetes, as had previously been suggested, but a distinct form of the disease unto itself: type 3 diabetes.

The idea that Alzheimer’s is a neuroendocrine disease—a disease based on a dysfunction of the nervous system’s production and utilization of an endocrine hormone (in this case, insulin)—has provoked some healthy skepticism.4 New evidence seems to strengthen the case, however. It comes from an impressive series of experiments conducted by the Rhode Island researchers and published in the Journal of Alzheimer’s Disease.5

Insulin Reductions Correlate with Alzheimer’s Features

The study involved 45 individuals, all of them dead, with postmortem diagnoses of brain function ranging from normal aging to Alzheimer’s disease of varying degrees of severity; these degrees are ranked on the so-called Braak scale, from 0 (normal function) to 6 (severe dementia). For the purposes of the study, the individuals were divided into four groups: controls (Braak 0–1), Braak 2–3, Braak 4–5, and Braak 6. Using powerful techniques of molecular biology, the researchers obtained the following results in brain-tissue samples taken from the frontal cortex, an area that is hard hit by AD:

  • The expression of the genes coding for insulin, insulinlike growth factor-I (IGF-I), and insulinlike growth factor-II (IGF-II) declined strongly with increasing Braak stage, i.e., the brain’s own production of these three proteins declined strongly.* Marked reduc- tions were seen even in the early stages of the disease, and in the Braak 6 cases, the levels were 60–85% lower than in the controls.


*Measuring gene expression in the brain cells rather than the levels of the proteins themselves enabled the researchers to restrict their observations to effects that were due to these proteins produced by the brain, thus excluding any effects due to the same proteins that had been produced elsewhere in the body and that had entered the brain. This was a crucial feature of the study.


  • Similar declines occurred in expression of the genes (and, therefore, the brain’s production of the proteins) coding for the neuronal cell-surface receptors for insulin, IGF-I, and IGF-II. In Braak 6 the levels were 50–85% lower than in the controls.
  • The dramatic reductions in the brain’s production of insulin and the IGFs were strongly correlated with the loss of neurons in the AD victims’ brains.
  • The reductions were also strongly correlated with reduced production of a protein called tau (a decrease of which is characteristic of AD) and with increased production of a protein called amyloid precursor protein; the latter spawns amyloid-beta, a neurotoxic protein that constitutes the bulk of the senile plaques found in the brains of AD victims at autopsy. Increased levels of amyloid precursor protein are associated with oxidative stress in neurons, and oxidative stress is caused by, among other things, impaired insulin signaling.
  • The reductions were also strongly correlated with decreased chemical binding between insulin, IGF-I, and IGF-II and their respective neuronal receptors, and these decreases were correlated with increasing amounts of cholesterol in the cell membranes. (High cholesterol levels, and hence atherosclerosis, are associated with both diabetes and AD.)
  • The reductions were correlated with impaired brain metabolism, as measured by reduced levels of ATP (adenosine triphosphate), the master energy molecule of life processes, which is produced by glucose metabolism in our cells’ mitochondria. Mitochondrial dysfunction is caused by, among other things, impaired insulin signaling. (Conversely, impaired insulin signaling can be caused by mitochondrial dysfunction arising from, e.g., gene mutations or aging.)

Diabetes in Middle Age Leads to Cognitive Decline

As Americans continue to grow larger and softer, eating more and exercising less, an inexorable chain of events has been unleashed. Obesity is becoming ever more prevalent, and its average age of onset is steadily declining. Running in parallel with those factors is type 2 diabetes, which afflicts more and younger people every year, because obesity is by far the greatest risk factor for diabetes. With diabetes comes a host of other diseases and disorders, including cognitive decline, often leading to dementia.

It has long been known that older adults with diabetes have poorer cognitive function, on average, than similarly aged adults without diabetes, so it should come as no surprise that the same situation prevails in middle-aged adults as well. That conclusion was reached in a recently published study by researchers in England, who examined the ties between diabetes and cognitive decline in 5647 men and women, average age 56.1

In tests of cognitive function, the men with diabetes were 2.45 times more likely to do poorly than men without diabetes; for women, that factor was 1.83. These relationships were found to be independent of potentially confounding factors, such as age, social position, health-related behaviors, and vascular problems (e.g., hypertension). No cognitive decline was seen, however, in individuals with impaired glucose tolerance, the precursor condition to diabetes.

The researchers noted that the decline in cognitive function with diabetes became apparent in as little as 2 1/2 to 5 years after the initial diagnosis. They attributed the decline to the metabolic abnormalities associated with the disease. The good news, however, is that, at least in older diabetic individuals, and most probably in younger ones as well, cognitive deficits are ameliorated when the disease is treated.2,3

References

  1. Rauscher M. Diabetes may zap cognitive ability in middle age. Reuters Health, Dec. 1, 2005.
  2. Gradman TJ, Laws A, Thompson LW, Reaven GM. Verbal learning and/or memory improves with glycemic control in older subjects with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc 1993;41: 1305-12.
  3. Naor M, Steingruber HJ, Westhoff K, Schottenfeld-Naor Y, Gries AF. Cognitive function in elderly non-insulin-dependent diabetic patients before and after inpatient treatment for metabolic control. J Diabetes Complic 1997;11:40-6.

A Link between Insulin Signaling and Acetylcholine Production . . .

Finally, the researchers discovered that the reductions in insulin and the IGFs correlated with reductions in expression of the gene coding for choline acetyltransferase (ChAT), the enzyme responsible for the brain’s synthesis of acetylcholine. This would lead to reduced levels of that vital neurotransmitter, whose depletion in the brains of AD victims is a hallmark of the disease. Reduced acetylcholine levels are strongly linked to impairment of memory and other cognitive functions. The primary therapy for AD has been with agents, notably galantamine, that increase acetylcholine levels and enhance its functional activity.

Taking another tack, the researchers treated cultured brain cells with insulin and the IGFs, and they found that this increased the expression of the gene coding for ChAT. Furthermore, it decreased expression of the gene coding for acetylcholinesterase (AChE), the enzyme responsible for degrading acetylcholine in the brain. Thus, both of these effects would tend to increase acetylcholine levels and, therefore, improve the patient’s condition, at least for awhile.

. . . Means a Link with Cognitive Impairment


Insulin
Since the synthesis of acetylcholine depends upon adequate supplies of the nutrient choline and of a compound called acetyl coenzyme A, and since the latter is produced in our cells by the process of glucose metabolism, which is driven by insulin and IGF stimulation, it’s apparent that acetylcholine production depends on the efficient functioning of the insulin-signaling pathway. This pathway, however, is substantially impaired even in the early stages (Braak 2–3) of Alzheimer’s disease, as the Rhode Island researchers have now discovered. Thus there appears to be a direct link between impaired insulin signaling and cognitive impairment in AD. The authors concluded,
Altogether, the results suggest that impairments in insulin, IGF-I, and IGF-II-stimulated signaling and associated reductions in energy metabolism (ATP) and ChAT expression represent major abnormalities that develop early in the course of AD and progress with severity of neurodegeneration. From the standpoint of therapeutic intervention, treatment with ligands [molecules that bind to receptors] that specifically enhance insulin/IGF-I/IGF-II signaling mechanisms in the brain may help to improve viability and function of neuronal cells at risk for AD-type neurodegeneration. … The results … support our hypothesis that AD represents a neuroendocrine disease that shares features with types 1 and 2 diabetes mellitus, and which we refer to as “type 3 diabetes.”

New Avenues for Prevention and Treatment?

Anything that can improve insulin function by mimicking insulin’s actions or by enhancing its effects is potentially of value in preventing or combating type 2 diabetes and, presumably, type 3 diabetes, aka Alzheimer’s disease. In the nutritional supplements arena, the most potent such agent is a class of polyphenolic bioflavonoids called procyanidins (type A), which are found in the water-soluble portion of cinnamon powder (along with a related insulin-mimetic compound, methylhydroxychalcone polymer, or MHCP). These agents are known to combat insulin resistance and help normalize blood sugar levels, as well as lipid levels. [See, e.g., “Revitalize Yourself: Cinnamon Extract for Healthy Blood Sugar” (March 2002), “For Good Health, Resist Insulin Resistance!” (June 2004), and “Controlling Blood Sugar with Cinnamon” (December 2005).]

Another nutrient that helps enhance insulin function is the amino acid arginine, which has been shown to increase insulin sensitivity through its role as the body’s primary source of nitric oxide (NO). Arginine is also well known for its effectiveness in protecting against cardiovascular disease by reducing blood pressure and improving blood flow, again via its production of NO. [See “Arginine Boosts Insulin Sensitivity and Cardiovascular Function” (October 2001).]

It’s gratifying to know that supplements such as these are readily available, without a prescription, to help combat several of the major chronic degenerative diseases that afflict many aging individuals. That one of these diseases, Alzheimer’s, may be a distinct type of diabetes is fascinating to know, and such knowledge may open new avenues for prevention and treatment.

References

  1. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimer’s Dis 2005;7:45-61.
  2. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands, JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimer’s Dis 2005;7:63-80.
  3. Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 2004;53: 474-81.
  4. Zhu X, Perry G, Smith MA. Insulin signaling, diabetes mellitus, and risk of Alzheimer disease. J Alzheimer’s Dis 2005;7:81-4.
  5. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimer’s Dis 2005;8:247-68.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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