Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers1,2. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis3. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy3–6. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K–mTOR signalling axis in tumours, thereby compromising treatment effectiveness7,8. Here we show, in several model tumours in mice, that systemic glucose–insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.
Abstract Growth factors, such as insulin, can induce both acute and long-term glucose uptake into cells. Apart from the rapid, insulin-induced fusion of glucose transporter (GLUT)4 storage vesicles with the cell surface that occurs in muscle and adipose tissues, the mechanism behind acute induction has been unclear in other systems. Thioredoxin interacting protein (TXNIP) has been shown to be a negative regulator of cellular glucose uptake. TXNIP is transcriptionally induced by glucose and reduces glucose influx by promoting GLUT1 endocytosis. Here, we report that TXNIP is a direct substrate of protein kinase B (AKT) and is responsible for mediating AKT-dependent acute glucose influx after growth factor stimulation. Furthermore, TXNIP functions as an adaptor for the basal endocytosis of GLUT4 in vivo, its absence allows excess glucose uptake in muscle and adipose tissues, causing hypoglycemia during fasting. Altogether, TXNIP serves as a key node of signal regulation and response for modulating glucose influx through GLUT1 and GLUT4.
Cancer is considered by many to not be a single disease but a wide array of diseases with, so far as we know, different causes. Viruses are a well-known cause of certain cancers, so it is safe to say that there is no single causal agent of cancer, however appealing that prospect would be.
Much of the pathological behavior of cancer cells can be explained by the effects of oxidative stress (OxStr): mitochondrial dysfunction, genetic damage, and a shift to glycolysis despite the presence of oxygen. 4-hydroxynonenal (HNE) damages and impairs the function of pyruvate dehydrogenase, the enzyme that allows substrates produced by glycolysis to enter the mitochondria .
This loss, combined with malfunctioning mitochondria emitting high rates of ROS and oxidized linoleic acid metabolites (OxLAMs), may explain the metabolic dysregulation and anti-oxidant upregulation often seen in cancer cells.
Epidemiological work has shown low rates of cancer in populations eating traditional diets. In Asians, migration to industrialized countries increases breast cancer rates many-fold to the point where they reach Western levels .
Linoleic Acid (LA) in the diet is in fact required to induce cancer in animals experimentally. The cancer-promoting effects of LA increase as it increases in the diet. This effect plateaus at around 4.4% of total energy, well below levels of consumptions seen in industrial civilizations .
One of the hallmark traits of cancer cells is the seemingly random mutations pervading unstable and disorganized nuclear genomes. There can be tens of thousands of mutations, much fewer than that  and sometimes none at all . For many cancers, the theory of it resulting from a single mutation doesn’t hold for most cancers. HNE and malondialdehyde (MDA) both damage DNA in vivo and HNE preferentially damages the p53 gene. The latter is part of the body’s natural cancer-control mechanism and is defective in colorectal and hepatocellular cancers [62, 63].
Vegans like to cite that insulin resistance is because of low carb or because of high fat. LOL. Yes, low carb dieters can get glucose intolerance and have high blood glucose, but in the context of low carb this is entirely different than insulin resistance in a high carb eater. This study from Oxford delves into BMI and fasting insulin (which goes high when a high carb dieter is “insulin resistant”) contributing to the etiology of pancreatic cancer.
Some are pointing at TMAO as a potential mechanism for meat to cause cancer, but it actually seems that insulin plays as part, and gut bacteria are also a major factor. See this
It is also shown that there are specific gut bacteria in the gut that cause TMAO accumulation doesn’t happen in mice that are simply given an antibiotic… With the other gut bacteria die off that seems to be implied with the low fiber content of a carnivorous diet, it just might be that these gut bacteria die off and become irrelevant when we are pointing the finger regarding heart disease.
From the first article linked here about TMAO, initial questions immediately rise:
“…the gut flora is a much better predictor of blood TMAO levels than whether someone eats meat. Those with high Prevotella, low Bacteroides averaged about triple the TMAO levels of those with low Prevotella, high Bacteroides flora.”
In this one they replaced saturated fat and cholesterol with veg oils and cancer went up.
In fact, the study that originally connected nitrates with cancer risk and caused the scare in the first place has since been discredited after being subjected to a peer review. From Chris Kresser’s, “The Nitrate Myth”:
“When it comes to food, vegetables are the primary source of nitrites. On average, about 93% of nitrites we get from food come from vegetables. It may shock you to learn that one serving of arugula, two servings of butter lettuce, and four servings of celery or beets all have more nitrite than 467 hot dogs. (2) And your own saliva has more nitrites than all of them! So before you eliminate cured meats from your diet, you might want to address your celery intake. And try not to swallow so frequently.”
“Whereas glucose favors overall growth kinetics, fructose enhances protein synthesis and appears to promote a more aggressive cancer phenotype”
“If you overfeed someone with fat, you don’t increase their cancer risk at all. If you overfeed someone with carbohydrates, you dramatically increase their cancer risk. Protein is half way in between.”
Conclusions: Patients with resected stage III colon cancer who consumed a high-insulinogenic diet were at increased risk of recurrence and mortality. These findings support the importance of dietary management following resection of colon cancer, and future research into underlying mechanisms of action is warranted.
“What I discovered was that THE WHO REPORT IS NOT A SCIENTIFIC DOCUMENT. IT IS A POLITICAL DOCUMENT.”
So I will just drop this here again:
This one speaks on the faulty evidence used, and the RCT’s dismissed, in the decision for the WHO to name meat a carcinogen. Seems as though perhaps the WHO has a bias? Lol. Of course we knew that after the whole announcement to team up with 7th Day Adventists.
“these prospective data do not support a positive association between higher red meat and fat intake and colorectal cancer risk. Higher intake of poultry and fish may be associated with a lower risk of colorectal cancer.” –Harvard.
Walter Willett admitted this long ago about the Framingham study. Does no one else find it funny that this quote shows that he recognizes something as a scientist but then is involved in championing the crusade against this healthy option by sponsoring bad science? QUACK.
Created by Travis Statham - @travis_statham January 14, 2019