Cancer: 50 Shades of F-cked Up?

Galena Officinalis (French Lilac or Goat's Rue)
Ancient remedy for polyuria
(sign of diabetes mellitus, frequent urine and sugar in the urine)

Original source of chemical that
was tweaked and patented into diabetes drug known as
metformin, which is emerging as the newest cancer drug
Photo Credit: Agro Semena

Hyperinsulinemia and Insulin Resistance: New Metabolic Markers for Cancer ?

I've talked a lot about insulin as it relates to disease but recently it is being discussed as a marker for cancer [1].  Though elevated blood insulin and insulin resistance (calculated HOMA) are emerging as new correlated factors for cancer and tumour progression, modern conventional medicine still has little solutions for either 'identifying' or 'treating' hyperinsulinemia other than two classes of drugs (PPAR agonists and biguanides/metformin). BTW be aware Crestor (rosuvastatin) and other statins can cause diabetes, higher blood glucoses (BG) and insulin resistance. Photo credit: modified [2].



Hyperinsulinemia? Insulin resistance (IR)?

How to recognize signs of hyperinsulinemia and IR?

Hyperinsulinemia and insulin resistance are associated with the initiation and growth of:

--central abdominal adiposity

--intraorgan adiposity (fatty liver, fatty pancreas, fatty gallbladder, fatty heart, fatty coronary/renal/peripheral arteries, fatty ovaries (e.g. PCOS and ensuing infertility), fatty muscles/sarcopenia)

--fatty liver (on ultrasound or reliable predictor: elevated liver test, ALT)

--skin tags

--warts

--acanthosis nigricans (darkening in armpits, behind knees, neck)

--melasma (skin darkening from insulin resistance induced by hormone imbalance by birth control, pregnancy, menopause, hormone replacement therapy)

--benign tumours

--malignant cancers, leukemias and lymphomas

--fatty brain degeneration, Alzheimer's ('Type 3 Diabetes Mellitus')




Pervasive Refined, Pesticide-Coated Monsanto-Grains, the S.A.D. and Other Nonsense

For many decades, like heart disease and stroke, cancer had high rates of association with diabetes and obesity. But recently the stats changed. I can agree with higher rates of insulin-related problems being secondary to macronutrient overnutrition of carbohydrates derived from refined sources (wheat, cereals, sugar, white monospecies potatoes, etc) however with the advent of pesticide technology since the Vietnam War and introduction of GMO crops in the 1990s, I believe that our burden of toxicants and insidious intestinal perturbation from GMO Bt crops are having subtle but immense influences on the growing rates of excessive insulin resistance and hyperinsulinemia.

Prior Animal Pharm: Pesticides Cause Insulin Resistance and Obesity

Photo credit: Oberlin Thesis [3]

This is concerning...Before embolic diseases were #1 and #3 for mortality in the U.S.A. (heart disease, strokes, respectively) however, a few years ago, mortality from cancer eclipsed heart disease death as the #1 killer for the first time. Are Americans smoking more (no)? Is the GMO Bt corn/wheat(gluten) based Food Pyramid more engrained than ever in dietary, medical and public school education (yes YES and yes...)?

What are Americans doing differently compared to 5-10 yrs ago? Are they getting more influenza, swine flu, whooping cough, HPV and other mercury-laden or aluminum-laden vaccines (metals can contribute to insulin resistance and hypothyroidism)...? Is our diet and lifestyles more devoid of nutrients, saturated fat, and vitamins (choline, n-3 pufa, methyl donors like animal sourced-folates, magnesium, zinc, selenium, and animal sourced-retinol, etc)?

Why has the cancer rate suddenly jumped? What other factors are behind the story? Is it toxin related, lifestyle related, stress related, epigenetic related?  I believe all have a factor... and like hypertension, heart disease, obesity, metabolic syndrome, migraines, and autism, I think it's 50 shades of f-cked up... [ref Twilight fan fiction]

* 2.6-fold increase prostate CA at highest insulin quartiles (J Natl Cancer Inst. 2009 Sep 16;101(18):1272-9. Serum insulin, glucose, indices of insulin resistance, and risk of prostate cancer.)

* 2.2-fold increase breast CA at highest waist-to-hip ratio (Cancer Causes Control. 2000 Sep;11(8):721-30. Markers of insulin resistance and sex steroid hormone activity in relation to breast cancer risk: a prospective analysis of abdominal adiposity, sebum production, and hirsutism (Italy).)

* Higher quartiles of insulin were predictive in non-diabetic breast CA women of 'poorer outcomes, consistent with the existence of a prognostic effect of insulin across broad categories of body weight.' Goodwin et al. J Clin Oncol 2001;20:42-51.




Aging, Cancer, IR -- AMPK Downregulated and NFkB/Inflammation Ramped Up

Tumor cells can initiate and grow with neolithic, post-agriculture, high/refined carbohydrate, grain-dominant diets as a result of constant and incessant switching to glucose-burning cell metabolism instead of energy efficient fat-burning fluxes. Environmental and food toxicants, stress, lack of exercise, 'iSolation' (excess electronics, less face-to-face contact), deficiency of micronutrients and vitamins (including choline and methyl donors from liver, organ meats and egg yolks) and broken sun-dark circadian rhythms merely add to these heavy metabolic disturbances.

Photo credit: [4]

Insulin and AMPK

Most cancers may take 10-20 years to initiate, progress and amass to recognizable sizes in the prostate, breast, colon, brain, abdominal or other areas [4]. What triggers oncogenes and mutations to occur? To promote diversity of our genes and accelerated evolution to climactic changes in ecological microniches, it is natural for our genes to accumulate DNA mutations and changes. Just as developing abdominal fat and a 'summer mode' of adiposity is protective short term, humans and other lifeforms are built for these changes. Plasticity of DNA expression gives us the benefit of longevity and reverting to forms more adaptable to diverse conditions, environments and shifting situations. Photo credit: modified [5].

Insulin is an ancient growth hormone and mitogenic; its function is to grow tissue. It's essential for life. Type 1 Diabetes individuals have none and, without insulin, may go into diabetic comas within 24-36 hours. Often Type 1 Diabetes patients have a sarcopenic, low muscle phenotype because adequate and correctly timed insulin spikes with meals are necessary for appropriate muscle growth and maintenance. All animals require low basal amounts of insulin for metabolism and energy however the consequences of high, constant and postprandial (aftermeal) insulin levels are activation of mTOR to grow tissues, inflammation, increased ROS and the inability of the mitochondria to phosphorylate ATP for metabolic energy.

AMPK is among many networked pathways known to regulate whole organism and single cell energetics [2, 4-8]. AMPK is found in all eukaryotes and is considered a highly conserved, master metabolic switch by some to coordinate growth, metabolism, food intake, body weight, autophagy, mitophagy, mitochondrial biogenesis and inflammation. AMPK fluxes on and off depending on fasting v. feeding states and energetic demands.  In mammals, AMPK is turned on under situations of perceived low cellular energy, e.g. low ATP which occur whilst exercise demands increase, periodic starvation and long-term starvation. Feeding, hyperglycemia (high BG), insulin spikes and other situations temporarily shut off AMPK. This makes sense, no? The body is accumulating energy, storing for the future, and replenishing depleted reserves. Under normal situations, the pattern is intermittent.  Unfortunately, AMPK can be shut off chronically instead of following a pattern of periodic flux. This is associated and observed in conditions such as clinical hyperinsulinemia, obesity, metabolic syndrome, aging and cancer [5-8]. Metformin  is an indirect stimulator of AMPK.  It is a diabetes drug, that can improve BG control, insulin resistance and shown to reduce both diabetic microvascular complications and cardiac events (macrovascular). Photo credit [7].



Metformin Appears to Desist Cancer Growth

Apparently in triple-negative breast cancer (TNBC; negative for estrogen, progesterone, and the type II tyrosine kinase (RTK) HER-2 receptor), effects of metformin are showing promise in vitro and human prospective studies are underway.  In a 2012 retrospective chart review, metformin combined with adjuvant chemotherapy in triple negative breast cancer was associated with reduced incidence of distant metastatic disease (p=0.06), however no significant differences in survival rates were observed [10].

Other observational studies show significant 25-62% relative risk reduction of colorectal, liver, pancreatic, breast, endometrial/uterine, and other cancers in metformin users versus non-users in Type 2 Diabetes trials. By the way, research shows that diabetes treatments with insulin and/or sulfonylureas (mechanism: increase endogenous insulin secretion) are associated with 500% and 250% SIGNIFICANTLY MORE CANCER, respectively, over other therapies or metformin in a comprehensive, non-industry funded U of T M.D. Anderson retrospective study that shook up the the Big Pharma world [11]. Really?

Yes. Again, many many many shades of f-cked up...

Hold your breath. More exciting research is coming... since there are no 'textbook' neoplasm solutions (besides hack, irradiate, chemo).  Treatment and therapeutics are lacking IMHO just as prevention and treatment for clinical hypertension, obesity, metabolic syndrome, heart disease and other insulin-related consequences are woefully inadequate [12,13].





Metformin: Drug That Lowers Insulin and Insulin Resistance (But Prevents Exercise-induced Muscle Growth and VO2 Max Benefits)

The effectiveness of metformin goes without fanfare. It is the #1 firstline medication for diabetes and the only diabetic drug that has been shown to lower cardiac mortality.  Other diabetic medications like PPAR-gamma agonists (Actos, Avandia) display marginal reductions in mortality but this is negated or even trumped by the associated increased prevalence of drug-associated sudden death, heart disease, heart failure, peripheral edema and heart failure mortality in the published clinical trials [Why? PPAR-gamma increases insulin sensitivity in the brown and subcutaneous white fat, exactly WHERE WE DO NOT WANT IT i.e. epicardial adipose depots ('fatty heart')].

Until recently the mechanism of action of metformin was unknown. Recent studies suggest that metformin affects LKB1 which activates and increases AMPK activity. We have discussed earlier AMPK as it's role is important in conserving proliferation and growth per demand and for the purpose of energy production. Simply put, AMPK increases fat uptake into peripheral cells, fat burning, and mitochondrial biogenesis in muscles upon energetic demands (e.g. when ATP goes down at the cellular level). When I used to counsel patients on metformin, I added sometimes that metformin is like 'exercise in a pill' -- it results in lower glucoses, lower insulin resistance, reduction in adiposity, lowering of inflammation, and weight loss.  Unlike starvation and exercise, however, metformin generally does not induce eventual hunger (in fact it can induce nausea and anorexia). Metformin apparently has no hypothalamus AMPK effects,  and this is perhaps why hunger does not ensue despite weight loss associated with metformin.  Other notable effects of metformin are -- GI upset, nausea, diarrhea, unpredicted 'explosive' diarrhea (as several patients have complained to me), abdominal cramping, intestinal dysbiosis leading to clinical vitamin B12 deficiency and related cognitive deficits over time. Photo credit: [9].

New research from Braun and his brainiac research group showed that metformin actually does mimic exercise yet when combined with exercise, metformin (2000 mg/day) appears to negate the complete, skeletal muscle benefits of exercise in prediabetic individuals [14,15]. Braun and his lab have done fantastic work on elucidating how our bodies utilize varied macronutrient substrates, handle energy deficits/surpluses and teasing out how metformin fits into the metabolic picture IMHO.  Unlike exercise or periodic starvation which typically leads to muscle gains and growth (e.g. protein synthesis) upon refeeding, when the synthetic drug, metformin, is added to an exercise program, the lean mass growth and increases of expected VO2 max benefits are BLUNTED. The exercise program was 12 weeks, 3 times weekly, of 60-75 cycling (45 min, 70% of pretraining max) and progressive resistance training including chest press, leg press, and latissimus pull-downs. Protein synthesis appeared blocked -- the FFM (fat-free mass, proxy for lean body mass) decreased significantly in the span of the 12-week experiment in both drug groups: metformin alone (M-alone, lost 1.7 kg) and metformin+exercise (EM, lost 0.5 kg), whereas the pure exercise group significantly gained 2.0 kg of lean, fat-free mass.

AMPK activation which may be devoid of natural on-off fluxes appears to be ultimately associated with sacrifice of protein and muscle construction post-exercise stimulus. When AMPK is turned-on, the function is to increase net energy (ATP). The metabolic pathways are shunted toward producing energy for IMMEDIATE demands and shunted toward eliminating short-term energy-sucking processes, like pancreatic insulin secretion, liver gluconeogenesis, and growing nice musculature, physiques and hot bodies. Makes sense, no? Yes, it does improve the metrics of conventional diabetes medicine (BG, HgbA1c), but at what cost? Is 'metabolic flexibility' over-compensated and lost without natural AMPK rhythms [16]?  Exercise obviously improves the balance between dysfunctional carbohydrate oxidation and lipid oxidation, yet synthetically knocking out carbohydrate oxidation via constant AMPK appears to induce sarcopenia and hinder the full insulin-sensitizing, anti-inflammatory benefits of exercise. Actually it is no surprise that exercise trumps metformin drug use in cases where insulin resistance may be reversible, as it seems.

Other negatives of metformin are that higher blood lactate may result (build up from anaerobic or hypoxic glucose/carb metabolism). One risk with metformin use is lactic acidosis from toxic accumulation of lactate which can be ~~50% fatal. The danger for this adverse effect is higher in kidney- and liver-compromised states such as dehydration, binge/chronic alcohol use, kidney disease, liver disease, heart failure, elderly, and co-adminstration with kidney-toxic drugs -- therefore use is contraindicated.



Controlling Insulin and Insulin Resistance With Paleo-Ancestral Eating: Frasetto et al

In PCOS women, metformin has some success at improving fertility. What about diet and exercise? At Crossfit and RobbWolf.com, numerous stories of *cough cough* unintended pregnancies in (previously) infertile couples abound! Exercise +paleo/ancestral eating reverse infertility more effectively than pharmaceuticals and current reproductive technology IMHO as it appears from stories in paleo-land.

Frasetto et al (EJCN 2009) 68% Decrease Insulin and 72% Improvement on Insulin Resistance on Hunter-Gatherer 7-Day Paleolithic Diet

In the 10-day experiment, Frasetto et al demonstrated that basal insulin in overweight men and women age 18 to 50 could be lowered by 68% from 69 mol/L to 21 pmol/L on a grain-free, legume-free, dairy-free (~220 grams carbs/day, Low Glycemic Index) diet that simulated our evolutionary roots. Additionally, HOMA, a measure of insulin resistance, dramatically decreased from 3.2 to 1.0 by 72%. Elevated blood pressure and weight naturally decreased. The study aimed for neutral weight (no change) and required higher caloric intake to offset the weight loss in the Paleo group.

This experiment was indeed short. Most of us in the evo/ancestral/paleo/primal community hear of similar success stories of health reversal on this type of timeline all the time.

Why? Because perhaps the evolutionary-based diet is aligned with older DNA and optimal expression of insulin sensitivity?



Ketones Appear to Desist Cancer Growth

Ketones are generated by either consuming MCT oil/coconut oil or a low or no carbohydrate diet. Ketones are the metabolic currency of the (a)  fasting or starving energetic state and (b) when physical training is fat burning (25-70% max heart rate) and extended.

The brain runs naturally well on ketones (granted the adrenals are healthy; ketone generation requires cortisol and adrenaline). We are built to intermittently fast and run on ketones when required (postnatal, extended chronic aerobic exercise, intermittent or chronic starvation).

Several studies show the surprisingly positive benefits of MCT oil, ketotic diets or infusion of ketones for treating cancer [17,18,19]. Why? Ketones are the opposite of IR-promoting, refined, high-carb, grain-intensive diets.

In our evolutionary fitness and paleo communities, it is popular to practice periodic starvation of 18-36 hours several times during a month (granted healthy adrenals and good deep rest/sleep). The practice elicits many health promoting effects as it increases ketone bodies to utilize as fuel for the brain and muscles, synthesized from visceral and subcutaneous fat stores.

[**  FYI... I rarely do intermittent fasting (IF) now since my adrenal glands are borderline-frail. As an individual experiment to combat body fat increases (15 lbs) due to the Mirena IUD (18 months of synthetic progestin toxicity), I did try frequent IF but found it further deteriorated adrenal function. So I'd caution anyone with  un-compensated, frail or marginal adrenal function to consider the value of avoidance of IF and consider the merit of varied, low glycemic index carbs in adrenal exhaustion protocols (100 - 150 grams daily --nonallergenic starches and whole foods) like Dr. Lam's adrenal optimization protocol. **]




Ketones and Metformin are Epigenetic HDAC-Inhibitors

Bioactive components of our food have epigenetic influence on potentical cancer profiles and insulin/IR signatures. We live now in the post-genomic DNA world. DNA may be the text and chromatin, the words, of our chapters, but epigenetic modifications are the punctuation, paragraphs and grammar that give words life and context. Researchers Shaw and Mihaylova at the Salk Institute in San Diego studied the effects of metformin and AMPK and elucidated one of the core mechanisms of metformin and AMPK's action for reversing chronic insulin resistance defects [8]. AMPK activation stimulates downstream inhibition of an enzyme, histone deacetylase (HDAC), that blocks 'punctuation', or in other words, normal chromatin DNA 'editing.'  HDAC inhibition leads to activation of intracellular antioxidant pathways and resumption of normal DNA chromatin form and function.

It turns out that ketones and metformin have similar epigenetic molecular mechanisms; both are HDAC inhibitors [8,20]. This is believed to be how they may elicit some of their powerful effects in insulin resistant conditions. Many spices, herbs, vegetables, animal products, fermented dairy products (phenylbutyrate), royal jelly (phenylbutyrate) and polyphenol-rich foods contain bioactive components that behave by editing and providing clarity/context to our DNA blueprint via inhibition of HDAC [21]. Photo credit [21].

How About An Evolutionary Medicine Based Approach to Cancer Treatment and Prevention?

Radiation, chemotherapy and treatment of cancer take a toll on pediatric, adult and elderly patients. Some of the long term effects including cardiotoxicity, nerve ending and brain damage and even increased risk for other cancers. Many cancer treatments fail with 5- and 10-year survival rates of 25-50% or less. The monetary costs of cancer treatment can add up and may eventually bankrupt Medicare and current health insurances provided by large and small businesses. Can we afford to continue and ignore the misalignment between government sanctioned dietary advice (whole unprocessed lectins, Rockefeller-wheat-gluten-galore, GMO-corn-soy-everything, low fat, high refined carbs, n-6 pufa overload) and the chronic and acute diseases including cancer? How best for modern conventional medicine to mutate, re-align, evolve and provide healthcare from the perspective of evolution?

I have no answers but would be interested in your thoughts...





Evolutionary Bloggers:

Robb Wolf: Sept 2007 post and his interview with Dr. Seyfried 'Cancer and ketosis' [18]

Dr. Eades: Metabolism and Ketones






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[Re-tweaked old Nephropal(eo) post]