Is Alzheimer's Disease a Type of Diabetes?

Insulin Mimetics for Brain Support

Is Alzheimer’s Disease
a Type of Diabetes?

Proof that the brain produces insulin sheds
new and provocative light on a complex question
By Will Block

any people believe that good things come in threes: a three-ring circus, the Three Stooges, the three branches of government, etc. Perhaps our special affinity for the number three comes from the fact that space has three dimensions, or that Christian faith centers on the Trinity. Whatever the reason, the other side of the coin (uh-oh, only two sides!) is that many people also believe that bad things come in threes, such as the three branches of government, three strikes and you’re out, and the “fact” (baloney!) that the deaths of prominent people tend to come in threes.

The truth is that most things, good or bad, come in arbitrary numbers that have no bearing on our cultural biases. Take diabetes mellitus, for instance. There’s type 1 diabetes, a severe, chronic disease that strikes in childhood or adolescence, and there’s type 2 diabetes, a milder (but ultimately terribly destructive) form of the disease that typically develops in adulthood. These two diseases are quite different in nature, even though both are disorders of glucose (blood sugar) metabolism that result in hyperglycemia, or excessively high glucose levels. (For more on these diseases, see the sidebar “The Types of Diabetes.”)

The Types of Diabetes

The common denominator in the two types of diabetes mellitus is chronically high blood glucose levels due to a malfunction in the body’s production or use of insulin, the hormone that regulates glucose levels by facilitating the transport of glucose molecules from the bloodstream into our cells. (Although that is the role for which insulin is best known, it also has several other roles of great importance in human physiology.)

Type 1 diabetes (insulin-dependent diabetes mellitus, or IDDM), was formerly called juvenile-onset diabetes because it strikes children and adolescents. It’s caused by the destruction of pancreatic beta cells (usually the result of an autoimmune reaction), which manufacture most of the body’s insulin. The result is severe insulin deficiency, which can be remedied only by frequent, carefully timed insulin injections and meticulous diet control. (Since insulin is a protein, it cannot be taken orally, because digestive juices decompose most proteins into their constituent amino acids.) There is no prevention and no cure for this disease.

Type 2 diabetes (non-insulin-dependent diabetes mellitus, or NIDDM), which is much more common, was formerly called adult-onset diabetes because it generally develops during adulthood, usually in midlife or beyond, when the effects of a sedentary lifestyle start to kick in with a vengeance. The term is a misnomer now because so many young adults, and even adolescents—and even children—are developing this “age-related” disease. The truth is, type 2 diabetes is caused not so much by age as by obesity and lack of exercise (both are epidemic in our society). What does that suggest? That type 2 diabetes is almost entirely, easily, preventable!

Type 2 diabetes is a more complicated disease than type 1. It’s the end result of a condition called insulin resistance, which is a gradually developing failure of the body’s cells to respond adequately to insulin. In an attempt to compensate for this failure, the pancreas works overtime to produce more insulin. As a result, people in the earlier stages of type 2 diabetes typically have hyperinsulinemia, or excessive levels of insulin in the blood. Eventually, in the later stages of the disease, the pancreas “burns out,” resulting in sharply diminished insulin production. This causes glucose levels to rise even more, and a bad situation is made much worse: the patient is left with both insulin resistance and insulin deficiency—a deadly combination.

Type 3 diabetes—if that is a legitimate term—is discussed in the accompanying article.

There are also several types of diabetes mellitus that don’t rate a number. One is a transient form of the disease associated with pregnancy, called gestational diabetes, which disappears after the baby is born. The causes of other, less common forms of the disease include: genetic defects in beta-cell function or insulin action; certain diseases of the pancreas, such as pancreatitis and cystic fibrosis; certain disorders of endocrine function; drug or chemical toxicities; infections; and genetic syndromes, such as Down syndrome.

Regardless of the origin or type of diabetes, the potential consequences are severe and often life-threatening, notably cardiovascular disease, kidney disease, nerve damage, and blindness. These dreadful outcomes are due in large part to injury and functional impairment of the blood vessels supplying the organs and tissues in question. When such injury affects the brain (cerebrovascular disease), the result is neuronal damage, which can lead to cognitive impairment, or worse: dementia. The same scenario can occur through microvascular impairment caused by hypertension or stroke.

Type 3 Diabetes—A Startling Proposal

Type 1 and type 2—that’s it. Or is it? Perhaps not, according to neuropathologist Dr. Suzanne M. de la Monte and her colleagues at the Rhode Island Hospital and Brown Medical School in Providence. In a pair of papers just published in the Journal of Alzheimer’s Disease, they propose that there may be a third, significantly different type of diabetes—type 3—that originates in the brain and that is intimately linked with Alzheimer’s disease.1,2


The Rhode Island researchers
concluded that the impairments
associated with Alzheimer’s are
mediated by depletion of insulin
and insulin-like growth factors.


As startling as that is, the idea that diabetes and Alzheimer’s disease are related in some way is not new. It has long been known, for example, that one of the many dire consequences of type 2 diabetes, especially in older adults, is cognitive impairment.3 This suggests that impaired glucose metabolism damages brain cells. That’s hardly surprising, since it damages all kinds of cells throughout the body, and brain cells are more dependent than most others on high levels of glucose metabolism for healthy function.

It’s Hard to Establish Correlation, Let Alone Causation

But does cognitive impairment necessarily lead to Alzheimer’s? No, but it is a warning sign of the possibility—the probability if it progresses to the clinically defined condition known as mild cognitive impairment (MCI), a common precursor to Alzheimer’s. An important question is whether or not diabetes and Alzheimer’s disease are, in fact, causally linked. The answer is: we don’t know, because there is so much conflicting and confusing evidence. Some studies are highly suggestive of such a link, whereas others provide no such evidence.

Not in question, however, is the link between diabetes and vascular dementia.4 This third-most-common type of dementia (after Alzheimer’s disease and dementia with Lewy bodies) is caused by impaired cerebral blood circulation, which can lead to damaging ministrokes or, occasionally, to big ones. Vascular dementia often occurs in conjunction with Alzheimer’s or other types of dementia, with which it has a number of symptoms in common. This can make accurate diagnoses difficult (although new brain-imaging techniques are very helpful). That, in turn, makes it difficult to establish even correlations, let alone causations, between a given type of dementia and some other disease, such as diabetes.


Dr. Suzanne M. de la Monte
The Evidence for Causation Is Growing

Although the causal link between type 2 diabetes and Alzheimer’s disease is still an open question, there is growing evidence that it’s real. In an extensive review of the literature on this subject, Dr. de la Monte and her colleague Dr. Jack R. Wands made the following observations (among many others):1

  • In the brains of Alzheimer’s patients, there are extensive abnormalities in insulin signaling, the cascade of biochemical reactions launched by insulin when it begins the process of glucose transport into our cells. One manifestation is the decreased activity of “downstream effectors,” i.e., molecules that participate in the reaction sequence. The underlying basis for these abnormalities is unknown, but there is abundant reason to believe that …
  • The primary culprit is insulin resistance, a progressive inability of our cells to respond adequately to insulin. This condition leads not only to impaired glucose metabolism and, therefore, to deficits in cellular energy production, but also to increased levels of certain deleterious enzymes, increased oxidative stress (from free radicals), advanced glycation of proteins (a harmful process), and reduced neuronal survival (cell death).
  • Despite conflicting and inconclusive data from epidemiological and pathological studies regarding a causal role of insulin resistance in Alzheimer’s disease, compelling support for this premise is provided by evidence that peripheral administration of either glucose or insulin can improve memory and cognition in Alzheimer’s patients.

Alzheimer’s Is Mediated by Insulin Depletion and Insulin Resistance

Based on their analysis, the Rhode Island researchers concluded that the neurodegeneration and cognitive impairment associated with Alzheimer’s are “fundamentally mediated” by depletion of insulin and insulin-like growth factors (small proteins very similar to insulin, with overlapping but not entirely duplicative functions) 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.


The researchers settled the long-
standing question of whether or not
insulin is produced in the brain as
well as the pancreas: it is.


In addition to the kinds of damage described above, this advanced level of insulin resistance injures the cerebral microvasculature (arterioles and capillaries), resulting in impaired blood flow and compromised function of the blood-brain barrier. It also contributes to the accumulation, in certain regions of the brain, of amyloid-beta, a harmful protein commonly known as senile plaque. These plaque deposits, a hallmark of Alzheimer’s disease, cause neurotoxic cell death. (For some surprising facts regarding the significance of amyloid-beta, see the sidebar “A Molecular Link Between Diabetes and Alzheimer’s” in the article “Avoiding Diabetes Can Help You Avoid Alzheimer’s” in the August 2004 issue.)

Insulin Is Produced in the Brain

In conjunction with their review of the literature, the researchers undertook to settle the long-standing question of whether or not insulin is produced in the brain as well as in the pancreas (it was already known that the insulin-like growth factors are produced in the brain). Their experiments showed that insulin is produced in various regions of the brain (although not in the frontal cortex). The highest production is found in the hippocampus, a brain region strongly associated with memory, learning, and other cognitive functions, and in the hypothalamus, which regulates a variety of involuntary physical and emotional functions, such as sleep, mood, sex drive, and appetite. (See the sidebar “Your Brain Produces Insulin Too.”)

Your Brain Produces Insulin Too

The brain is a wondrous organ in more ways than we can imagine (with our brains). In addition to the many functions we’re all aware of (thanks to our brains), the brain turns out to be a prolific manufacturer of hormones that are already produced elsewhere in the body. For example, the pancreas and the gut produce a variety of neuroendocrine polypeptide hormones, i.e., small-protein hormones that act in some way on the nervous system. The brain produces every one of them too; the last one to be verified was insulin.

Based on indirect evidence, it had long been believed that the brain produced insulin, but proof was lacking until now. In an elegant series of experiments with postmortem human brains (both normal and Alzheimer’s-afflicted), as well as with cell cultures from rat brains, Dr. de la Monte and her colleagues in Rhode Island showed that the brain does, in fact, synthesize insulin, as well as the insulin-like growth factors and the insulin receptors in the neuronal (brain-cell) membranes.1

Thus, the actions of insulin in the brain do not necessarily depend on the availability of peripheral insulin from the pancreas. In fact, even though it’s known that peripheral insulin and insulin-like growth factor I (IGF-I) can gain access to the brain by crossing the blood-brain barrier, it has not been established whether these molecules are actually taken up by neurons of the central nervous system.2 It is thus possible that the insulin used by the brain for glucose metabolism is entirely “home-grown.”

References

  1. 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.
  2. 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.

Furthermore, the brains of Alzheimer’s victims, compared with those of age-matched controls, showed evidence of a strikingly diminished production of insulin as well as of neuronal insulin receptors. This would inevitably lead to a degradation of the entire insulin-signaling pathway—a clear manifestation of insulin resistance—and, therefore, to reduced brain metabolism, which is one of the best-documented abnormalities in Alzheimer’s disease.5

Alzheimer’s = Brain Diabetes = Type 3?

These observations, and many others of a highly technical nature, led Dr. de la Monte and her colleagues to suggest that Alzheimer’s disease is actually a neuroendocrine disorder that resembles type 2 diabetes but is more complex.* They view it as “brain diabetes” and propose that it be called type 3 diabetes.


*The concept, as they envision it, applies to what is called sporadic Alzheimer’s (representing the vast majority of cases), but not to Alzheimer’s associated with a family history of the disease or the presence of a particular gene that is implicated in some cases.


This is a startling idea, sure to provoke scientific controversy. Indeed, the two papers mentioned above were followed, in the same journal, by a thoughtful commentary from three experts at Case Western Reserve University in Cleveland.5 They agree with the findings of a close interaction between diabetes and Alzheimer’s, and they point out that not only is type 2 diabetes apparently a significant risk factor for Alzheimer’s, but the opposite is also true: Alzheimer’s patients are at higher risk for type 2 diabetes.


Dr. de la Monte and her colleagues
suggest that Alzheimer’s is actually a
neuroendocrine disorder that
resembles type 2 diabetes. They view
it as “brain diabetes” and propose
that it be called type 3 diabetes.


Nonetheless, they argue that, for various reasons, the causal link between these two diseases is still inconclusive, and the mechanisms through which diabetes may impact Alzheimer’s are still not well understood. They conclude that “… it is premature to refer to Alzheimer’s disease as type 3 diabetes at the current time.” It’s a safe bet that we’ll be hearing from many other experts on this question.

Insulin Could Use Some Help

Whether it originates in the pancreas or the brain, insulin is important to our health because of its crucial role in maintaining healthy blood sugar levels. Despite its exalted status in human physiology, however, insulin is not above accepting some assistance in the form of nutritional supplements that can help normalize blood sugar levels and combat insulin resistance. Most notable in this regard are cinnamon (especially its MHCP component), green tea (especially its EGCG component), mulberry leaves, the antioxidants lipoic acid and quercetin, and the mineral chromium, among others.* By availing yourself of these valuable nutrients, you may be able to reduce your risk for type 2 diabetes—and perhaps even type 3 diabetes, aka Alzheimer’s disease.


*For information on some of these nutrients, see “Revitalize Yourself: Cinnamon Extract for Healthy Blood Sugar” (March 2002), “Lipoic Acid Helps Fight Diabetes” (December 2003); “For Good Health, Resist Insulin Resistance!” (June 2004), and “Mulberry Helps Control Blood Sugar, and More” (November 2004).


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. Strachan MW, Deary IJ, Ewing FM, Frier BM. Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care 1997;20(3):438-45.
  4. Hassing LB, Johansson B, Nilsson SE, Berg S, Pedersen NL, Gatz M, McClearn G. Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer’s disease: a population-based study of the oldest old. Int Psychogeriatr 2002;14:239-48.
  5. Zhu X, Perry G, Smith MA. Insulin signaling, diabetes mellitus, and risk of Alzheimer disease. J Alzheimer’s Dis 2005;7:81-4.

Caution: If you have diabetes, do not take any supplement that may affect your blood sugar levels without first consulting your physician. Diabetes is a serious disease requiring careful professional management.


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

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