More on insulin metabolism plus some final “big picture” thoughts on what is creating this epidemic of cns inflammation and insulin resistance
In concluding this review of the impact of suboptimal insulin and glucose metabolism on the brain and its tendency to lead to the development of amyloid beta (Aβ) and other adverse changes consistent to Alzheimer’s disease/senile dementia, is it enough to say that the relationship is a simple issue of aberrant insulin activity and too much or too little glucose? A recently published paper entitled “Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer’s disease brain” by Abolhassani et al (1) suggests no. In fact, according to the authors, the insulin mediated disturbances in glucose metabolism in the brain create damage through mechanisms briefly discussed in part VIII of this series, mitochondrial dysfunction and oxidative damage. Therefore, I would now like to expand my brief discussion on mitochondrial dysfunction and oxidative damage that I initiated in part VIII by providing some highlights from the Abolhassani et al (1) paper. Before doing so, though, I would like to answer a question that you might have – Why is it necessary to have such a detailed understanding of the process? For me, the answer lies in the old saying: “Just because you pulled the knife out of the wound does not mean the wound will heal.” What do I mean by this? It may be that optimizing insulin and glucose metabolism, which we, as nutritional and functional medicine practitioners, have been doing very well now for decades, may not be enough from either a preventive or therapeutic standpoint. Why? I would suggest that long term disturbances in insulin and glucose metabolism will have a ripple effect creating collateral metabolic damage that will not self-correct once insulin and glucose metabolism is optimized. Instead, other complementary interventions not directly related to insulin/glucose metabolism may be required. Since, as suggested above, this “collateral damage” involves mitochondrial function and oxidative processes, these other complementary interventions could take the form of other modalities we have successfully used for years to both enhance mitochondrial function and reduce excessive oxidative activity.
With this introduction in mind, I would now like to review the Abolhassani et al (1) paper.
IMPAIRED CNS GLUCOSE METABOLISM AND ITS RELATIONSHIP TO MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE DAMAGE
The first quote I would like to feature considers concepts I have discussed previously in this series that relate to insulin/glucose metabolism in the context of mitochondrial function and oxidative activity:
“While an adult human brain typically weighs only about 2% of the body weight, a resting brain consumes more than 20% of all the oxygen, thus indicating a 10-fold greater energy requirement than other tissues. This high demand for energy in the brain is mainly achieved by ATP production during oxidation of glucose or oxidative phosphorylation in the mitochondria. It is well documented that impaired glucose metabolism or mitochondrial dysfunction is one of the major pathological changes observed in various neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) or Huntington’s disease (HD), thus suggesting that regulation of glucose metabolism and maintenance of mitochondrial homeostasis are critical for brain function.”
Where is most energy stored in the brain? The authors comment:
“In the brain, astrocytes are the main energy reservoirs, accumulate glycogen, and help to sustain high-energy demands associated with neuronal activity.”
Because of these high energy demands, Abolhassani et al (1) suggest that, in the AD brain, disturbances in glucose metabolism and mitochondrial function co-exist:
“…regulation of glucose metabolism and maintenance of mitochondrial homeostasis are concomitantly impaired in astrocytes and neurons, respectively, in an AD brain.”
How does suboptimal insulin activity relate to brain mitochondrial activity?
“It is strongly suggested that impaired insulin production and signaling in AD brain…cause brain mitochondrial dysfunction due to severe impairment of glucose or glycogen metabolism.”
“Current research indicates that mitochondria are the primary metabolic platform which can malfunction during insulin resistance.”
The next quote provides more detail on how suboptimal glucose activity affects mitochondrial activity in the AD brain:
“In AD brains, two essential glucose metabolic pathways in mitochondria, Krebs cycle and oxidative phosphorylation are known to be distressed. Abnormal Krebs cycle and/or oxidative phosphorylation cause(s) not only glucose hypometabolism but also the increased generation of reactive oxygen species (ROS), oxidative damage, and programmed cell death such as apoptosis. Because mitochondria are also the main location that suffer from ROS, oxidative stress further exacerbates mitochondrial dysfunction and this vicious circle is more prone to occur and has been demonstrated to be an event occurring before the appearance of senile plaques and the onset of clinical manifestations.”
How does oxidative stress in the brain demonstrate itself? As noted by the authors, one way is through the detection of the DNA oxidation repair marker 8-oxoG:
“Reflecting the increased oxidative stress in the AD brain, various oxidized bases in DNA have…been detected. Among the various oxidized bases detected in either nuclear or mitochondrial DNA prepared from postmortem AD brains, the 8-oxoG accumulates in both, and is recognized as the most pronounced marker in AD brain. Immunohistochemical examination of postmortem AD brains revealed that cytoplasmic accumulation of 8-oxoG is evident in hippocampal CA1 and CA3 pyramidal neurons, and in neurons in the temporal cortex, where Aβ is also highly accumulated. Accumulation of 8-oxoG in the AD brain is an early event, occurring before the onset of dementia.”
Before continuing, please note again the last sentence in the above quote. It suggests the presence of 8-oxoG in brain is highly suggestive that an asymptomatic patient may be at significant risk for developing AD. Since a similar marker of DNA oxidative damage repair, 8-OHDG, is measured in the urine on organic acids tests offered by certain labs, could organic acids testing be used to assess AD risk in our patients? If urine levels of DNA oxidative damage repair products accurately reflect DNA oxidative damage in the brain, the answer should certainly be yes. Fortunately, the answer to this question was answered in the paper “Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia” by Gackowski et al (2). The authors state:
“Urinary excretion of oxidative DNA damage repair products (8-oxo-2′-deoxyguanosine and 8-oxoguanine) were higher in patients with mixed Alzheimer disease/vascular dementia than in the control group.”
Since this paper makes some excellent points about the nutritional/supplemental implications of this finding, I will return to a discussion on it later.
What more can be stated about 8-oxoG in the brain? Consider the following from the Abolhassani et al paper (1):
“Among the various types of oxidative lesions found in nucleic acids, 8-oxoG is one of the major sources of spontaneous mutagenesis. The buildup of 8-oxoG in DNA is caused by direct oxidation of guanine in DNA itself or through the incorporation of 8-oxoG from nucleotide pools in which 8-oxo-2′-deoxyguanosine triphosphate (8-oxo-dGTP) is generated under oxidative conditions. 8-oxo-dGTP can be utilized by DNA polymerases as a precursor for DNA synthesis, consequently, 8-oxoG is incorporated into the nascent strand opposite adenine and cytosine in the template with almost equal efficiency, resulting in an A:T to C:G transversion of 8-oxoG containing template DNA.”
Of course, just because 8-oxoG is found in significant amounts in the AD brain, this does not necessarily indicate cause and effect. Does evidence exist that suggests 8-oxoG contributes to the brain degeneration seen with AD patients? Abolhassani et al (1) point out:
“Observations in neurodegenerated postmortem brains and studies using animal models for various neurodegenerative diseases have shown that 8-oxoG accumulation in nuclear or mitochondrial DNA in neurons under oxidative conditions somehow results in neurodegeneration…”
“Oka et al. demonstrated that accumulation of 8-oxoG in nuclear and mitochondrial DNA triggers two distinct cell death pathways that are independent of each other.”
In what parts of the brain does 8-oxoG preferentially accumulate? The authors note:
“Under oxidative conditions, 8-oxoG is highly accumulated in mitochondrial DNA but also in the nuclear DNA of neurons…”
“…microglial proliferation can be induced under inflammatory responses in the brain with an increased production of ROS; therefore, microglia accumulate 8-oxoG in nuclear DNA.”
Of course, it would seem logical that, if increased oxidative stress is present in the AD patient, levels of key antioxidant nutrients would also be affected. In the paper mentioned above by Gackowski et al (2) this is exactly what was reported based on research with 18 patients with mixed Alzheimer’s disease/vascular dementia compared to controls. As was mentioned above, urinary DNA damage biomarkers were elevated in these patients. What about vitamin C levels? The authors state:
“In good agreement with this finding the concentration of vitamin C in blood was also reduced in mixed Alzheimer’s disease/vascular dementia patients when compared with the control group, while no changes in the concentration of α-tocopherol was detected.”
Why is this finding on vitamin C significant? Consider the following:
“Vitamin C is found at 10 fold higher level in the brain than plasma, emphasizing the significant role for this antioxidant in the central nervous system. Indeed, vitamin C may be a critical cofactor of dopamine beta-hydroxylase and also may protect membrane phospholipids acting as a scavenger of ROS. It has been found that vitamin C can cross the blood-brain barrier via the GLUT1 receptor, in its oxidized form and is retained in brain tissue in the form of ascorbic acid. Therefore, it is possible that decreasing blood concentration can also be responsible for a decrease in vitamin C concentration in the brain.”
It was also found that vitamin A levels were impacted:
“In our study we also found decreased concentration of vitamin A in patients with mixed Alzheimer’s disease/vascular dementia in comparison with the control group.”
With the above in mind, Gackowski et al (2) hypothesize:
“Our results suggest that simple treatment of these patients with antioxidant vitamins may likely present a strategy for preventing/slowing progression of the disease.”
SOME FINAL, BIG PICTURE THOUGHTS ON ALZHEIMER’S DISEASE
As you have undoubtedly noticed during this series, the biochemistry and physiology of Alzheimer’s disease/senile dementia is incredibly intricate and complicated, creating the all too common response among much of the general population and many in the practitioner community that this complexity makes it almost impossible to come up with any truly practical and cost-effective interventions that can be employed on a mass population basis even for prevention, let alone treatment. It is my hope that this series has given you reason to believe that this is not necessarily true. It is my belief that the many papers I have presented make it clear that what we do every day with our patients in a very effective and predictable manner in relationship to reducing inflammation and optimizing insulin metabolism can have a major impact on the sometimes daunting rate of neurodegeneration that we are now seeing in elderly populations in this country.
However, while distilling the complexities of Alzheimer’s disease/senile dementia down to issues of inflammation and dysinsulinism does provide a more simple and practical framework upon which to operate with patients, can we distill these complexities down even further to a practical and useful sound-bite? As suggested by the title of their review paper, “Brain under stress and Alzheimer’s disease,” Mravec et al (3) suggest that the answer to this question is yes. Can it be helpful in terms of assisting both preventively and therapeutically to approach the problem under the simple premise that Alzheimer’s disease/senile dementia is nothing more than brains under stress? Mravec et al (3) present a detailed and fascinating treatise as to why it will serve us to regard our patients at risk for neurodegenerative diseases in such a manner.
Mravec et al (3) begin their paper by reviewing the sobering statistics on Alzheimer’s disease:
“It occurs in two forms, a familial (early-onset) AD that are determined genetically, and a far more common sporadic (late-onset) AD that is determined multifactorially. Both forms result in severe cognitive decline and completely disable the patients in the latest stages. The sporadic form of AD represents the most common cause of dementia in elderly, currently accounting for more than 95% of all AD cases and affecting nearly 40 million people worldwide.”
Next the authors review what many consider the primary causational factors, all which have been covered in this series:
“Research on AD is focused on the role of amyloid plaques and neurofibrillary tangles in synaptic and neuronal loss that is accompanied by cognitive decline. The main constituents of extracellular amyloid plaque, amyloid β40,42, is produced by the cleavage of amyloid precursor protein (APP).”
What do the authors have to say about the neurofibrillary tangles?
“On the other hand, neurofibrillary tangles are composed of aberrant tau proteins. Tau is a microtubule-associated protein with an important role in the stabilization of the neuronal cytoskeleton. During physiological conditions, the functions of tau protein are modulated by the activities of protein kinases and phosphatases that determine the extent of phosphorylation of this protein. However, if tau protein is hyperphosphorylated and truncated it may aggregate and form neurofibrillary tangles.”
The other main issue of concern according to Mravec et al (3) is what has been the main focus of this series:
“In addition, the role of mitochondrial dysfunctions, defects of the endolysosomal and autophagic systems, neuroinflammation, oxidative stress, altered insulin signaling in the brain, and increased permeability of the blood-brain barrier in AD-related neuropathology has been investigated as well.”
What’s the problem with all of these, including the issues that form the primary substance of this series? The authors comment:
“The main weakness of the above-mentioned hypotheses is the fact that they focus on pathological processes that are consequences, rather than primary etiological factors. It is likely that a combination of several factors (e.g. age-related changes at the level of gene expression, infectious agents, toxic compounds, and head trauma) affects the neuronal milieu and initiates neuropathological processes leading to the formation of toxic tau and amyloid β species, reduction of synaptic plasticity, and neuronal loss resulting in development of sporadic AD.”
Of course, while many may consider this approach to AD refreshingly new and innovative, it is really nothing new to us. For, we operate under the primary functional medicine guideline that understanding the relationship between AD and issues such as amyloid plaques, toxic tau, neuroinflammation, mitochondrial dysfunction, oxidative stress, and dysinsulinism has little practical use without an understanding of the environmental issues that inevitably play powerful contributing roles. Therefore, Mravec et al (3) make it clear that we need to spend less time and effort on the pathology and suboptimal biochemistry and physiology of AD and more on the causes, collectively described by the authors using a term with which we are all familiar, “chronic stress”:
“Chronic stress is considered a key factor participating in the development of various somatic and neuropsychiatric diseases.”
Next, the authors discuss the impact of chronic stress, which is nothing new to us:
“It is well documented that inappropriate intensity and duration of the stress response may participate in the development of somatic (e.g. hypertension, metabolic and gastrointestinal diseases) and neuropsychiatric disorders (e.g. anxiety, depression, PTSD). Importantly, recent studies have also elucidated mechanisms and pathways by which the stress response participates in the development of AD-related neuropathology.”
The stress response and allostatic load
Mravec et al (3) next discuss Alzheimer’s disease/senile dementia in terms of a subject near and dear to my heart, as evidenced by my many writings and lectures on the subject over the years, allostatic load. In introducing the subject the following is stated:
“The stress response, if inappropriate in intensity or duration, may result in allostatic overload of virtually any organ (including the brain) and compromise its functions. These alterations may initiate and/or potentiate directly or indirectly neuropathological changes in the brain. It can be hypothesized, that in predisposed individuals…, allostatic overload may participate in the development of AD-related neuropathology as well.”
The authors continue:
“…we hypothesize that repeated stress-related allostatic overload may affect brain function at three basic levels: (a) at the cellular level, it may compromise proteostasis (e.g. tau protein), organelles homeostasis, and induce epigenetic changes in neuronal DNA; (b) at the tissue level it may affect intracellular communication (synaptic contacts), number of cells (reduction of neuronal density), composition of the extracellular matrix (accumulation of amyloid plaques), and neuroinflammation; (c) at the systemic levels it may alter the brain’s regulation of behavior (cognitive decline).
We hypothesize that allostatic overload may also participate in the development of AD indirectly via induction of alterations in peripheral tissues and organs. Additionally, deregulation of immune function, insulin resistance, cardiovascular, and gastrointestinal disorders, as well as other pathological processes induced by chronic stress may also profoundly affect brain homeostasis.”
How does stress-related allostatic overload specifically create adverse neurologic changes? According to Mravec et al (3), the answer lies in the fact that stressors induce release of neurotransmitters and neuromodulators:
“Stressors induce complex activation of brain pathways accompanied by the release of various neurotransmitters and neuromodulators. Moreover, some signaling molecules (hormones) are released into the periphery and are transported to the brain via humoral pathways.
Coordinated action of neurotransmitters, neuromodulators, and hormones released in stressful situations creates the basis for adequate neuroendocrine and behavioral stress response. However,…alterations in the release of these compounds may lead to development of brain neuropathology.”
What are the neurologic responses to stressful situations that lead to brain dysfunction when operating suboptimally? What follows are highlights of the answer to this question by Mravec et al (3).
Glutamate excitotoxicity and neuronal loss
An important factor I have not discussed in this series in relationship to neurologic changes that could lead to neurodegeneration is glutamate release, which often occurs with stressful situations. What can be stated about glutamate? Mravec et al (3) point out:
“L-glutamate, the main excitatory neurotransmitter in the central nervous system, is released from more than 50% of the synapses in the brain. Glutamate participates in virtually all brain activities, including formation of memory. Moreover, glutamate also plays a role as an intermediary metabolite in the detoxification of ammonia and as a precursor for the synthesis of proteins. Tissue homeostasis of extracellular glutamate levels is precisely maintained, because exaggerated glutamate release into the synaptic cleft induces an excitotoxic effect resulting in the death of postsynaptic neurons.”
Of course, excessive glutamate release will often be seen in acute situations such as brain trauma and stroke. But what about the chronic situations we most often encounter with our patients prone to Alzheimer’s disease/senile dementia? The authors suggest:
“Besides acute excitotoxicity, in vitro and in vivo experiments have shown that even a 10% chronic increase in extracellular glutamate concentration reduces neuronal survival, particularly in the context of aging. This chronic excitotoxic effect may be driven by multiple factors such as sensitization of NMDA receptors, a decrease of glutamate reuptake capacity, and increases in glutamate release. Importantly, altered glutamatergic neurotransmission accompanies the development of AD. For example, there is a stimulatory effect of amyloid βon NMDA receptors.”
How specifically might glutamate adversely affect brain function?
“Both acute and chronic stress enhances glutamate release within the brain, specifically in the prefrontal cortex and hippocampus. Whereas the enhancing effect of acute stress is mediated mainly by glucocorticoids activating presynaptic glutamatergic nerve endings, chronic stress exerts its effect most probably via altering regulation of glutamate release termination.”
Reduced brain norepinephrine levels
As we all know, norepinephrine is a key hormone released with any stressful situation. It also functions as a neurotransmitter. However, according to Mravec et al (3), it also plays a major role in maintaining brain health:
“Norepinephrine (NE)…significantly participates in the maintenance of brain tissue homeostasis by modulating synaptic plasticity, neurogenesis, activity of astrocytes and microglia, energy metabolism, cortical perfusion, and permeability of the blood-brain barrier.”
What is the main source of NE in the brain?
“The main source of NE in the brain is the locus coeruleus (LC).”
The authors then point out that reduced levels of NE in the brain can be a risk factor for the development of AD:
“It is suggested that reduced tissue levels of NE in the brain participates in the alteration of the above-mentioned homeostatic regulation and therefore may participate in the development of AD-related neuropathology.”
Why does reduced production of brain NE occur in chronically stressed individuals? To answer this question it must be first noted that not only does the LC produce NE but it also metabolizes it:
“Activity of the LE neurons is accompanied by re-synthesis, release, and degradation of NE.”
Unfortunately, chronic activation of the LC may lead to an overload of the ability of the LC to metabolize and detoxify NE. Ultimately, this loss of the ability to detoxify leads to degeneration of the LC and a decrease in NE production, which, as I mentioned, is correlated with the development of AD:
“…chronic, stress-induced repeated activation of the LC may lead to an allostatic overload of the de-toxicant capacity of LC neurons. Consequently, degeneration of these neurons may significantly reduce NE levels in the brain, followed by deterioration of brain homeostasis and development of AD-related neuropathology.”
Corticotrophin-releasing factor, cortisol and the brain
As I mentioned earlier in this series, suboptimal cortisol production and function is linked with both aberrant behavior and neurodegeneration. How does stress induced cortisol production specifically lead to AD development? It has to do with hyperphosphorylation of tau which, as I mentioned, is linked with the development of neurofibrillary tangles:
“We have found that corticotrophin-releasing factor (CRF) potentiates tau phosphorylation during acute stress, whereas in animals exposed to chronic stress, CRF exerts an opposite effect. This effect is dependent on type 1 CRF receptors. Furthermore, CRF-induced phosphorylation of tau protein interferes with neuronal energetics as it impairs axonal transport of mitochondria.”
Of course, CRF is what leads to cortisol production. What can be stated about cortisol specifically?
“…persistently elevated glucocorticoid levels during chronic stress may reduce synaptic plasticity and the number of neurons in the hippocampus. This effect is mediated by several mechanisms, including attenuation of brain-derived neurotrophic factor.”
It also should be noted, as I have pointed out previously, glucocorticoids do not always act in ways to that reduce inflammation, as is commonly assumed:
“…in contrast to the classical view of glucocorticoids as potent anti-inflammatory compounds, recent findings have shown that glucocorticoids could induce or potentiate neuroinflammation.”
Indirect responses to stress and the brain
As I have mentioned before in various newsletters and lectures, to truly understand any chronic illness we must consider them from a systems-based way of thinking. What do I mean by systems-based thinking? As an analogy, considered a cancelled baseball game. Initial reactions to this may lead us to think that the adverse impact is limited to the players who may not get paid and the fans who might be inconvenienced. However, does this initial reaction accurately reflect reality? Most certainly no. The reality is that, if the game is cancelled, the people who sell the hot dogs and beer and the people who work in the parking lot do not get paid. In turn, they have less money to buy groceries and gas, which leads to financial hardships to the owners of the gas stations and grocery stores. Also, the restaurants and hotels that cater to the people going to the game will lose business, creating still another adverse financial ripple effect.
This systems-based thinking can also be applied to chronic illness generally and specifically to Alzheimer’s disease/senile dementia. What I have discussed so far in this series right up to this point in my review of the Mravec et al (3) are issues that directly affect the brain. However, as noted by Mravec et al (3), Alzheimer’s disease/senile dementia would not be the problem that it is if the factors that only have a direct impact on the brain were solely responsible. In fact, Alzheimer’s disease/senile dementia is so big and complicated because of systems-based, indirect realities. One good example of this, according to Mravec et al (3) is the relationship between cardiovascular function and the brain:
“Atherosclerosis and hypertension …compromise perfusion of the brain, alter function of the blood-brain barrier, and may participate in the development of AD.
Brain hypoperfusion may be accompanied by excessive release of glutamate, inducing an excitotoxic effect on neurons. In addition, hypoxia increases phosphorylation of tau protein by activation of GSK-3. Moreover, atherosclerosis- and hypertension-related alterations at the level of the blood-brain barrier compromise clearance of amyloid β from brain tissue potentiating AD neuropathology.”
Still another example would be the effects of suppressed adaptive immune function:
“Stress exerts complex changes in activity of the immune system. Whereas some immune functions are exaggerated, others are attenuated. As mentioned above, stress may induce neuroinflammation by different mechanisms. However, chronic stress may also exert suppression of immune function within the periphery with several negative consequences; including reactivation of pathogens. It has been suggested that some pathogens, including herpes simplex virus type 1, cytomegalovirus, chlamydophila pneumonie, spirochetes, and periodontal pathogens may participate in the development of AD.”
Of course, fitting into this indirect classification would be type 2/3 diabetes and obesity, as I have discussed extensively in this series. This is duly noted by Mravec et al (3), who review the vast majority of key points in relation to insulin metabolism I have pointed out.
Indirect responses to stress and the brain – the impact of altered gastrointestinal function
Before presenting some final thoughts about this paper and the series in general, I wanted to review still another section of the Mravec et al (3) paper that I feel is both so important and so under-appreciated that it will form the basis of my next Moss Nutrition Report series – the gut-brain connection. As you will see from the quote that follows, chronic stress-induced disturbances in gut integrity can be a major instigator of neuroinflammation:
“During physiological conditions, the potential pro-inflammatory effect of gut microbiota is strictly restricted. However, chronic stress induces changes in permeability of the gastrointestinal tract barrier leading to release of microbiota pro-inflammatory molecules into the blood stream.”
Could these microbiota-induced pro-inflammatory mediators have an impact of the creation of Alzheimer’s disease/senile dementia? The authors provide this suggestive information from animal studies:
“…experiments employed germ-free animals indicate that host microbiota can regulate formation of amyloid plaques in the brain…”
SOME FINAL THOUGHTS ON BRAIN FUNCTION AND ITS CONNECTION WITH NEUROINFLAMMATION AND DYSINSULINISM
When I first started writing this series my primary goal was to dispel the prevailing assumption among most in the general population and many in both the clinician and research communities that behavioral and neurodegenerative disorders were deep, dark, mysterious entities where, because so little is known about them in terms of both cause and treatment, their occurrence is mainly a matter of back luck and bad genes. Because of this, it should come as no surprise to anyone that fear of loss of brain function is becoming a national obsession, generating seemingly endless conversation among baby-boomers, a seemingly endless procession of reports from researchers on the nightly news telling us more research is needed, and a seemingly endless amount of commercials advertising both natural substances and pharmaceuticals that supposedly deal with the problem in a highly efficacious, cost effective manner. However, as I stood on the side of the road watching this parade of fear-based talk, researchers telling us more research is needed, and advertisements of the latest brain health panacea, I felt, based on my reading of research studies that can be found in any average medical library where, much to my amazement and frustration, few besides me tend to go, something was missing. What was that something? It was the inescapable conclusion that must be drawn based on the studies I was reading that behavioral and neurodegenerative disorders are not deep, dark mysterious entities that defy even a basic understanding that would lead to prevention and, possibly, resolution or amelioration of certain symptoms. In contrast, these disorders are highly predictable outcomes that primarily revolve around chronic inflammation and insulin/glucose imbalances. Furthermore, much, if not most of the chronic inflammation and insulin/glucose imbalances have a close etiologic relationship with the way we interact with our environment.
Hopefully, after reviewing in this series a selective sampling of, I would suspect, the hundreds if not thousands of studies on the relationship between brain function, inflammation, and insulin/glucose imbalances, I hope I have convinced you that my hypothesis of logic, predictability, and understanding that, even now, seems to be at odds with prevalent thinking among the public and many of the “experts,” has validity. However, is it enough to prove that behavioral and neurodegenerative disorders are intimately related to neuroinflammation and insulin/glucose imbalances? Despite all that I have stated in this series, I emphatically state the answer is no!! Why? In order for the information I have presented to have practical application, another question must be answered – Why is there such a high incidence of neuroinflammation and insulin/glucose imbalances in the first place?
Unless we can answer this question and take effective preventive measures, there are not enough pharmaceuticals and supplements in the world that, alone, will make a significant dent in what is truly, as you have undoubtedly seen in your practices, a metabolic epidemic. This is why I was so glad to have discovered the Mravec et al (3) paper I just reviewed. First, it tells us that inflammation and dysinsulinism is not just a metabolic “light switch” that is “turned on” at random in certain selected individuals suffering from Alzheimer’s disease and, by logical extension, the vast majority of neurologic illnesses and dysfunctions. Rather, neuroinflammation and dysinsulinism occur based on allostatic load principles that tell us our ailments are the result of not only the accumulation of commonly known environmental stressors such as poor diet, lack of exercise, and too much worry but also the accumulation of stressors we do not normally associate with chronic neurologic dysfunction such as infection and excessive toxic and electromagnetic exposure. Furthermore, while these stressors can have a direct impact on the brain, just as often they affect the brain through a more circuitous, systems-based mechanism that involves suboptimal metabolism of factors such as glutamate, norepinephrine, and cortisol plus cardiovascular dysfunction and, because it is so under-appreciated it may be the most notable, gastrointestinal dysfunction. In other words, as functional medicine and allostatic load principles have long told us, behavioral and neurodegenerative illnesses are not isolated mysterious entities but much like every other chronic illness in that they are local manifestations of a whole body that has lost its way metabolically due to the fact its coping mechanisms simply could not keep up with many of the hostile elements in the world around us.
Of course, I realize that it may initially appear that this parting message is unduly negative. I prefer to view it as realistic. For, to me, it leads us to the powerfully positive message that, by following the allostatic load guidelines that suggest we take the approach of both reducing cumulative environmental load and optimizing allostatic response mechanisms that revolve around hormones such as cortisol, epinephrine, and insulin plus the cardiovascular, gastrointestinal, detoxification, and immune systems, we can make major inroads in reducing human suffering.
As I pointed out, the next Moss Nutrition Report will be the beginning of a new series that features one of the most fascinating and clinically important research subjects of our time, the gut-brain connection.
Moss Nutrition Report #275 – 08/01/2017 – PDF Version
- Abolhassani N et al. Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer’s disease brain. Mechanisms of Ageing and Development. 2016;published online ahead of print.
- Gackowski D et al. Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia. J Neurological Sci. 2008;266:57-62.
- Mravec B et al. Brain under stress and Alzheimer’s disease. Cell Mol Neurobiol. 2017;Published online ahead of print July 11 2017.