Insulin Resistance and Cancer

Insulin Resistance and Cancer

“…metabolic endotoxemia is able to influence adipose tissue physiology in human obesity by decreasing the expression of factors related to lipid handling and lipogenesis as well as by increasing the expression of proinflammatory markers.” ^[i]
—Clemente-Postigo Mercedes et al.

Previously, I reviewed how diet alters the gut microbiome that triggers systemic inflammation through the process called metabolic endotoxemia. Beyond that, I laid out the connection between inflammation, hormone imbalances, and obesity. In the crazed world of pandemics, obesity is the real pandemic. Most don’t look at obesity as a disease. But, it is clear that obesity is the pathway to the lack of wellness or dis-aise.

Diet, gut microbiome, metabolic endotoxemia, and insulin resistance connection.

It all begins in the gut. More, it all starts with what we put into the gut, via the mouth, to populate and maintain the gut microbiome.

Gut

• Gut dysbiosis is the term for imbalanced gut bacteria previously discussed. Gut Dysbiosis causes chronic local and systemic inflammation, which can lead to cancer ^{[ii] [iii]}.
• Gut dysbiosis contributes to local and systemic cancer ^[iv].
• The gut microbiome causes insulin resistance and as a result, hyperinsulinemia ^{[v] [vi] [vii] [viii]}.
• Lipopolysaccharide (LPS) is the bridge between the imbalanced gut microbiome (gut dysbiosis) and systemic inflammation, called metabolic endotoxemia.
• Lipopolysaccharide (LPS), a gram-negative bacteria surface antigen that originates from the gut, activates Toll-like 4 receptors (TLR-4) and causes systemic insulin resistance ^{[ix] [x]}.
• Lipopolysaccharide (LPS) activates Toll-like 4 receptors (TLR-4) to increase cancer invasion, growth, and metastasis ^{[xi] [xii]}. Just an aside, for all you nerds like me, it does this through the activation of the PI3k/Akt, MyD88 intracellular pathways, and NK-kappaB inflammatory signaling.

Because our focus at An Oasis of Healing is cancer, the connection of metabolic endotoxemia to cancer is our focus. The details are specific, and the relationship is clear. It is not enough to show the result, but the receipts of the process as well.

Inflammation

You will hear me say that inflammation is the bed in which cancer lies. This statement is, without question, true. But, it is essential to understand that inflammation alone is not the enemy. It is the chronic, unregulated, and dysfunctional inflammation of cancer that is the problem. Remember, cancer co-opts and adulterates normal biochemical processes for its benefit and survival, at the detriment of the rest of the body. The immune system and hormones are perfect examples of this, and I have written and discussed both previously, so I encourage you to check them out in our previous blog posts and podcasts.

When I reference inflammation here and in any cancer discussion, I reference this same chronic, unregulated, and dysfunctional inflammation.

Inflammation drives insulin resistance

• Inflammation increases insulin resistance. Research points to insulin resistance as one of the major causes of elevated insulin levels, also known as hyperinsulinemia, to drive an increase in insulin signaling ^{[xiii] [xiv]}. In fact, hyperinsulinemia circles back around and to further trigger inflammation—a self-feeding cancer setup loop. These feedback loops are quite common in cancer.
• Insulin resistance, obesity, and type II diabetes are birds of a feather that flock together. Obesity is associated with an increase in NK-kappaB activation and inflammatory signaling characteristic of type II diabetes. As a result, there is a direct increase in insulin resistance, insulin levels, and insulin signaling, another close self-feeding loop common to cancer ^[xv]. Obesity, chronic inflammation, and type II diabetes are all associated with cancer.
• It is chronic inflammation that connects insulin resistance and hyperinsulinemia to cancer ^[xvi].

 The connection between inflammation and cancer is well documented. Inflammation is not linked just to cancer but is at the core of every chronic disease. How is this inflammation triggered?

• Lipopolysaccharide (LPS)

Lipopolysaccharide, or LPS as it is better known, is an endotoxin from gram-negative bacteria that originate in the gut. The overgrowth of gram-negative bacteria in the gut results in an increase in the production and release of the bacterial toxin, called LPS, that is then transmitted systemically throughout the body. Overgrowth or imbalance of gut bacteria is commonly called dysbiosis. The important take-home point is that elevated LPS equals systemic inflammation. This connection of gut LPS to systemic inflammation is the classic “leaky gut.”

How does LPS stimulate inflammation? Lipopolysaccharides (LPS) stimulate other immune cells to produce inflammatory signals. Specifically, LPS stimulates TNF-alpha, IL-1beta, IL-6, and iNOS. These inflammatory signals, induced by LPS, stimulate the genetic production of inflammation through Nuclear factor-κB (NF-κB) transcription factor activation. Nuclear factor-κB is one of the central genetic pathways to produce pro-inflammatory signaling ^[xvii].

It is an elevation in systemic LPS that drives this whole metabolic dysfunction show. Gut sourced, elevated systemic LPS is the cause of insulin resistance ^{5 9 [xviii] [xix] [xx]}, metabolic cross-talk, and dysfunction found in metabolic endotoxemia. Contrary to the common perception, LPS induced insulin resistance is not confined to the lower gut but can result from periodontitis in the upper gastrointestinal tract ^[xxi]. I have mentioned the LPS—TLR4 signaling several times. It is interesting to note that LPS drives insulin resistance via toll-like receptor 4 (TLR-4). Why is this interesting? It is the same TLR-4 that can drive maximum to tolerated chemotherapy-induced metastasis ^{[xxii] [xxiii] [xxiv] [xxv]}. It starts to paint a disturbing pro-metastatic connection between metabolic endotoxemia and full-dose chemotherapy. It was John Adams that said, “facts are a stubborn thing.”

• Inducible Nitrogen Oxide Synthase (iNOS)

Inducible Nitrogen Oxide Synthase is one of three enzymes, iNOS, eNOS, and nNOS, producing and regulating nitric oxide levels. They are also known as NOS1, NOS2, and NOS3. In Dr. Suess’ world, they would be known as thing 1, thing 2, and thing 3. The difference between these three forms of NOS is that when iNOS is turned on, in contrast to eNOS and nNOS, it never turns off ^[xxvi]. Nitric oxide is a very short-lived signaling molecule in the body. Most are aware of its positive effects on the cardiovascular system. The marketing push of beet pills and beet drinks to elevate NO levels seems to dominate marketing today. But, when it comes to cancer, there is a dark side of iNOS and NO. In cancer, iNOS can contribute to cancer through genotoxicity, inhibition of apoptosis, angiogenesis support, increase in invasion, limited immune response in the local tumor microenvironment. As a result, iNOS and NO play a role in the growth and spread of cancer ^[xxvii].

• Tumor Necrosis Factor-alpha (TNF-alpha)

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory signal called a cytokine. This inflammatory signal produces many of the chronic diseases associated with aging, particularly cancer. What is the connection to insulin? Tumor Necrosis Factor-alpha causes insulin resistance ^{[xxviii] [xxix] [xxx]}. The ensuing metabolic dysfunction will increase systemic insulin receptors, systemic insulin levels, and systemic glucose levels. The same TNF-alpha activates NF-kappaB signaling discussed below, and it is the inflammation, miscommunication, and metabolic dysfunction that lead to carcinogenesis ^[xxxi].

• NF-kappaB

Inflammation is the bed in which metabolic dysfunction and disease exist, including cancer and diabetes. Nuclear factor κB (NF-κB) is the genetic transcription factor at the heart of this metabolic endotoxemia inflammatory cascade. Metabolic endotoxemia stimulates NF-κB signaling, which is critical to the systemic pro-inflammatory response and metabolic dysfunction resulting in disease. The same metabolic endotoxemia NF-κB inflammation signaling triggers insulin resistance, obesity, and diabetes ^{[xxxii] [xxxiii] [xxxiv]}. The same metabolic endotoxemia, NF-κB pro-inflammatory cascade, is also a central contributor to carcinogenic transformation and progression ^{[xxxv] [xxxvi] [xxxvii]}. Stop and think about that for a moment. The dietary-induced alteration in the gut microbiome is the cause of systemic inflammation, metabolic endotoxemia, that drives the initiation and spread of cancer. I hope this provides a different perspective of the impact of what you put in your mouth.

It just so happens that vitamin C deficiency contributes to gut-induced metabolic endotoxemia. Cancer is a state of deficiency, including vitamin A, vitamin D, and vitamin C, to list a few. Vitamin C support inhibits the cascade of gut dysbiosis, metabolic endotoxemia, NF-κB pro-inflammatory signaling cascade ^{[xxxviii] [xxxix]}.

• Interleukin-6 (IL-6)

Interleukin-6 (IL-6) is another cytokine, inflammatory signal. I have written extensively on the cytokine storm, also known as inflammatory burst, associated with maximum to tolerated chemotherapy induction of metastasis. Yes, you read that right. Full-dose chemotherapy will cause the metastatic spread of cancer, at the same time that it shrinks a primary tumor. That is like taking ten steps back with every one step forward because 90% of morbidity and mortality in cancer results from metastasis.

Interleukin-6 is at the heart of this cytokine storm, or inflammatory burst. At its basic concept, cytokine storm or burst is the collateral damage to the body resulting from the immune system over reaction. In metastasis, this is because of the overzealous inflammatory response generated by excessive chemotherapy. This has also been a hot topic in the current COVID-19 pandemic secondary to the same viral-induced IL-6 inflammatory burst that causes significant lung damage, including blood clots, that is the cause of most morbidity and mortality of this disease. Co-existing blood clotting (thromboemboli) is also a significant contributor to morbidity and mortality. Enough of COVID-19 and 2020, though. The point here is to focus on cancer. Interleukin-6 is the link between insulin resistance and cancer in obese individuals ^{[xl] [xli]}. In that link, IL-6 is the cause of insulin resistance in cancer ^[xlii]. The result of this connection is the initiation of cancer (carcinogenesis), growth of cancer, and spread of cancer.

Insulin resistance drives hyperinsulinemia ^{[xliii] [xliv] [xlv] [xlvi]}

Hyperinsulinemia is the elevation of insulin levels in the systemic circulation. Hyperinsulinemia is the attempt by the body to overcome the lack of insulin receptor response to the signal of insulin. This scenario is the previously mentioned insulin resistance. Specifically, the pancreas works to compensate for the resistance of insulin receptors through an increase in insulin levels. Of course, it could be the result of a diet high in sugar. But, let us assume that diet is not the issue.

To better understand insulin resistance, hyperinsulinemia, and their relationship, think of this analogy for those who have children. How many kids cleaned their rooms the first time, asked? Unless your kids are extra-human, they don’t; they don’t listen, and they don’t act. That is a resistance to the communication signal. What is the natural next step in the attempt to get the point across? We, as parents, naturally raise our voice to get the attention of our children to the immediacy of the request to clean their rooms. Because, of course, we assume that they didn’t hear us. There is no way that they ignored the request? This analogy is what the pancreas is doing in the drive of hyperinsulinemia in response to insulin resistance. The pancreas is raising its voice, insulin, to overcome the body’s lack of response, cleaning the rooms, insulin resistance.

Though there is clear evidence that points to insulin resistance as the precipitating factor that leads to compensatory hyperinsulinemia ^[xlvii], this simple approach in cancer is likely too linear and overly simplistic in scope to be completely accurate. It is better to think of this on a level of quantum physics. Not that this is quantum physics, but that it works on a more grand complex scale beyond what we can imagine. Yes, brevity is the soul of wit; but we are not dealing with humor, wit, but complex biochemistry and physiology.

The more likely scenario is that insulin resistance and hyperinsulinemia co-exist simultaneously. We often try to oversimplify the complex biochemistry and physiology in the human body to understand the body’s complexity better. This attempt to understand the complex is not a bad thing. However, all too often, what ends up happening is that we lose sight of the forest to focus on the trees. As an attempt to understand the complex, the simple yet false explanation becomes a reality in mind. In an attempt to understand, we may confuse and replace the oversimplified explanation for the complex reality; this may inadvertently replace complex biochemical truth with oversimplified falsity and propagate false truth. We must simultaneously keep the focus on the –Forrest and the trees.

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It is chronic inflammation, insulin resistance, hyperinsulinemia, and obesity that set the stage for type II Diabetes. Diet, gut microbiome, metabolic endotoxemia, and type II Diabetes

Most do not look at obesity as a disease classification. It is a lack of wellness—also known as dis-aise as discussed in the previous blogpost. Obesity is the outward physical manifestation of the inward metabolic dysfunction that highlights the lack of wellness. An ICD10 diagnostic code is not required to detect the lack of wellness. Disease as a mere diagnostic code concept is only a recent phenomenon brought to you by the American Medical Association (AMA)—thanks, but no thanks AMA. An honest reflection would have to question what this labeling has brought the general public because obesity is at record numbers. The introduction of the disease concept or the ICD10 code of disease has done nothing to resolve any disease; ever heard of any disease being placed on the endangered species list? Look at cancer. The war on cancer was declared in 1971 by President Nixon. Billions, if not trillions, of dollar, have been spent on this “war”. Yet, the war on cancer has been raging for 50 years. The same can be said of obesity. If this war on obesity and cancer were an actual battlefield, there would need to be a change in command to correct this battlefront.

What is obesity? First, overweight is defined as a body mass index (BMI) between 25 – 30. Obesity is defined as a BMI above 30. As if obesity is not enough, there are mild, moderate, and severe classifications of obesity. According to the latest CDC statistics, obesity is increasing at an alarming rate, with the adults in 16 states exceeding the 35% obese mark. According to the same CDC, 51.6% of the U.S. adult population is classified as either obese or severely obese. And why is this important? Obesity is the double doorway that leads to disease.

Just as in obesity, insulin resistance as a dis-aise would be missed on most. Insulin resistance is the down regulation of the insulin receptor presence and response to the pancreas created, produced, and released insulin hormone. Research by Patrice D. Cani has clearly shown that metabolic endotoxemia drives insulin resistance ⁵. But the connections don’t end there. Insulin resistance, obesity, and inflammation are inseparable. They are the three stooges, Larry, Curly, and Moe, of disease. It is hard to say which comes first; instead, they all occur together as a part of the downstream effects of metabolic endotoxemia: again, I look at it as kind of a quantum physics process. I have written on each impact separately.

The inevitable next step of the inseparable insulin resistance, obesity, and inflammation is diabetes. Once that snowball starts rolling downhill, the metabolic dysfunction momentum is an almost unstoppable force, and diabetes is simply the next stop on the metabolic endotoxemic dysfunction debacle. Not to suggest that diabetes is a linear, sequential process, but metabolic endotoxemia opens the flood gates.

The connection between a high-fat diet, high calorie or poor calorie diet, metabolic endotoxemia, and diabetes is easily provable by the evidence cited in this post alone. The additional connection of gut dysbiosis (altered gut microbiome) provides greater insight into the mechanism of how. The chronic low-grade inflammation of LPS induced metabolic endotoxemia results from gram-negative bacteria in the gut. The levels of LPS in metabolic endotoxemia are estimated at 10-50% of that found in sepsis ^[xlviii] at a 2-3 fold increase in blood LPS. Specifically, a high-fat diet is shown to cause an imbalance in the gut microbiome—a high gram-negative to gram-positive ratio ^[xlix]. This gut microbiome imbalance, not necessarily a spike in gram-negative bacteria, results in increased LPS mediated metabolic endotoxemia. Systemic LPS, through the leaky gut, triggers inflammation signaling discussed above.

The clear implication here is diabetes, but other diseases are also implicated. There can also be a reduction in gram-negative and some gram-positive bacteria; just more gram-positive bacteria are reduced compared to the gram-negative in the gut microbiome population. As so often is the case, it is about the balance. In addition, the bacteria species Bifidobacterium, which is vital in the health and integrity of the gut mucosal lining, levels decrease. The impact here is an increase in the leakiness of the gut lining to LPS, and the result is systemic endotoxemia. The same effect is going to apply to a high-calorie or a poor-calorie diet. In contrast, a high fiber diet, i.e., that found in a plant-based diet, will blunt the high-fat mediated gut microbiome imbalance that induces metabolic endotoxemia and produces diabetes ^{[l] [li]}. That is the association and connection between diet, gut microbiome, metabolic endotoxemia, and diabetes. It is an honest review of the evidence on a plant-based and high-fiber diet that points to diet as a direct means to counter this metabolic endotoxemic run-away train. This evidence suggests that diet and nutrition are more than calories and macronutrients, but a therapy that affects metabolic change for good or bad.

Where is diabetes in all of this? Diet affects the gut microbiome. Whether a pure diet or a poor diet, the gut microbiome balance is the effect. An imbalanced gut microbiome is called dysbiosis. The result is a leaky gut that can lead to systemic inflammation called metabolic endotoxemia. Metabolic causes insulin resistance. Hyperinsulinemia is the result of insulin resistance. Obesity is the result of metabolic endotoxemia, insulin resistance, and hyperinsulinemia. Type II diabetes is the result. Type II diabetes increases systemic inflammation, and the positive feedback loop for dis-aise is set.

And finally, what is the connection to cancer? The link to cancer is a direct one. Chronic inflammation, metabolic endotoxemia, insulin resistance, hyperinsulinemia, obesity, and diabetes create the terrain, or environment, that favors cancer development, growth, and spread.

Some talk about the terrain. Some talk about the local tumor microenvironment. Both are correct. Neither terrain, nor local tumor microenvironment, can be addressed without consideration of diet, its impact on the gut microbiome, the resultant inflammatory cascade, and the associated metabolic derangement that I have spent the last many posts discussing. Any statement that diet has no effect on the initiation or progression of disease, including cancer, is one devoid of fact.

I have spent several posts connecting the metabolic dysfunction that results from poor diet, altered gut microbiome, increased LPS metabolic endotoxemia, systemic inflammation, and linking their connection to significant metabolic dysfunction that we call disease—type II diabetes. Is diabetes the result of purely sugar intake? No. But, is poor sugar control, defined as diabetes, the effect of poor diet-induced gut dysbiosis that leads to metabolic endotoxemia? Absolutely.

Not to complicate the issue further, but all LPS is not equal and leads to metabolic endotoxemia. Some LPS triggers metabolic endotoxemia, and other sources of LPS inhibit metabolic endotoxemia ^[lii]. But, that is a discussion to have at another time.

Why the need to be so complicated? As it relates to diabetes, it would be more straightforward if sugar intake did cause diabetes. Just as in cancer, it would be easier to believe that some alien implanted cancer in the body of some unsuspecting individual in a bad Sigourney Weaver Aliens sequel movie plot. Neither is true. Neither is as complicated as it might seem. But, it is imperative that we discuss the reality of the contributors to the metabolic dysfunction that leads to disease, not the sequential, oversimplified descriptions that lead to false truths. We must maintain a simultaneous view of the forest and the trees.

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