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Cancer: 50 Shades of F-cked Up?

Posted Oct 27 2012 9:51pm
Galena Officinalis (French lilac or Goat's Rue)
Ancient remedy for polyuria (sign of diabetes mellitus, sugar in the urine)

Original source of chemical that
was tweaked and patented into drug known as
metformin, a diabetes now emerging as 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). Stay away from Crestor (rosuvastatin) and other statins which may cause diabetes, higher blood glucoses (BG) and insulin resistance . Photo credit: modified [17].



Hyperinsulinemia? Insulin resistance?

How to recognize 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)

--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





Prevalence of Refined Monsanto-grains, the S.A.D. and Other Nonsense


For many decades, like heart disease and stroke, cancer had high rates of association of diabetes and obese individuals. 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 intestinal pertubation from GMO Bt crops has a subtle but immense bearing on the growing rates of excessive insulin resistance and hyperinsulinemia.

Prior Animal Pharm: Pesticides Cause Insulin Resistance and Obesity


This is concerning...Before embolic dieseases were #1 and #3 for mortality in the U.S.A. (heart disease, strokes, respectively) however, only 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)?

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 hyperinsulinemia and hypothyroidism)...? Is our diet and lifestyles more devoid of nutrients and vitamins (choline, n-3 pufa, methyl donors like animal sourced-folates, magnesium, zinc, selenium, animal sourced-retinol, etc)?

Why has the cancer rate suddenly changed? 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 and metabolic syndrome, I think it's 50 shades of f-cked up... [ref Twilight fan fiction]

Cancers 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), and broken sun-dark circadian rhythms merely add to these metabolic disturbances.

* 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).)





Insulin and AMPK

Most cancer takes years to initiate and progress to amass to recognizable sizes in the prostate, breast, colon, or abdominal areas. 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.

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 is 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 fluxes on and off depending on fasting v. feeding states. Certain situations such as excess and overnutrition shut off a metabolic switch known as AMPK chronically and excessively instead of following a pattern of intermittent flux. AMPK is among many pathways known to regulate whole organism and single cell energetics [2]. Metformin, a diabetes drug, that works to improve BG control and reduce diabetic complications; it is a stimulator of AMPK. 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. Photo credit [9].



Metformin Appears to Desist Cancer Growth

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 [3]. 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. Other observational studies show significant relative risk reduction of colorectal, liver, pancreatic, breast 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 sulfonylureas (mechanism: increase endogenous insulin secretion) are associated SIGNIFICANTLY with MORE cancer  over other therapies or metformin. Really? Yes.

More research is coming... since there are no 'textbook' neoplasm solutions (besides hack, radiate and chemo) as in treatment and therapeutics of clinical hypertension, obesity, metabolic syndrome, heart disease and other insulin-related sequelae [4,5,6].





Metformin: Drug That Lowers Insulin and Insulin Resistance (But Prevents Exercise-induced Muscle Gains and 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 agonists (Actos, Avandia) have a mild reduction n heart disease and mortality but this is negated or even trumped by the associated increased incidences of sudden death, heart disease heart failure/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 e.g. epicardial adipose depots (heart)].


Until recently the mechanism of action of metformin was unknown. Recent studies suggest that metformin improves mitochondrial electronic charge in the liver which activates and increases AMPK. 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 auto-immunity, and more importantly, spontaneous weight loss.  Unlike starvation and exercise, typically hunger subsides. Metformin apparently has no hypothalamus AMPK effects, and this is perhaps why hunger does not ensue despite weight loss associated with metformin.  Other notabe effects of metformin are -- nausea, diarrhea, unpredicted 'explosive' diarrhea (as several patients have complained to me), abdominal cramping, intestinal dysbiosis leading to clinical vitamin B12 deficienty and related cognitive deficits over time.

New research from Braun et al however show that metformin actually does mimic exercise but when combined with exercise, metformin appears to negate the skeletal muscle benefits of exercise [7,8]. Unlike exercise or periodic starvation which typically leads to muscle gains and growth upon refeeding, when metformin is added to an exercise program, the muscle gains and other benefits are BLUNTED. Why? 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 energy-sucking processes, like making muscles grow nice and hypertrophy [16]. Makes sense, no? Braun and his lab have done phenomenal work on elucidating more of the how our bodies utilize macronutrients and to tease this part of the metabolic picture IMHO. But it is actually no surprise that exercise trumps metformin drug use in cases where insulin resistance may be reversible, as it appears. Photo credit: modified [16].

Other negatives of metformin use are higher lactate (build up from aerobic fatty acid metabolism). One (fatal) risk with metformin use is lactic acidosis from toxic accumulation of lactate; it is approximately 50% fatal. The risk is higher in kidney- and liver-compromised states such as dehydration, binge/chronic alcohol use, kidney disease, liver disease, heart failure and elderly, and 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. At Crossfit and RobbWolf.com, numerous stories of *cough cough* unintended pregnancies 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 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 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.

This experiment was indeed short. Most of us in the evo/ancestral/paleo 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 old DNA and optimal expression of insulin?



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 anti-inflammatory, fasted energetic state and when physical training is fat burning (50-65% max heart rate).

The brain runs naturally well on ketones (granted the adrenals are healthy). We are built to intermittently fast and run on ketones when required (postnatal, extended chronic aerobic exercise, intermittent or chronic starvation) [10,11,12].

Several studies show the surprisingly positive benefits of MCT oil, ketotic diets or infusion of ketones for treating cancer. Why? Ketones are the opposite of insulin-promoting, high-carb, grain-based 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 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 (synthetic progestin) over toxicity experienced for 18 months, I tried frequent IF but found it further deteriorated adrenal function. So I'd caution anyone with frail, marginal or un-compensated adrenal function to consider the value of avoidance of IF and consider the value of the varied, low glycemic index carbs in adrenal exhaustion protocols (100 - 150 grams daily) like Dr. Lam's  adrenal optimization protocol.




Ketones and Metformin are HDAC-Inhibitors


Bioactive components of our food have epigenetic influence on our 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, stops and grammar that give words life and context. Researchers Shaw and Mihaylova studied the effects of metformin and AMPK and elucidated out one of the core mechanisms of metformin and AMPK's action for reversing chronic insulin resistance defects [13]. AMPK lead to inhibition an enzyme that blocks punctuation, or in other words, normal DNA editing, known as histone deacetylase (HDAC).  By inhibiting this enzyme HDAC, antioxidant pathways were turned on and DNA chromatin form and function resumed to normal.

It turns out that ketones and metformin have epigenetic similarities; both are HDAC inhibitors [13,14]. Like many spices, herbs and food, there are bioactive components in food that behave on editing and modifying our DNA blueprint[15]. Photo credit [15].



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. Cancer treatment monetary costs 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 grains, 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 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'  [11]

Dr. Eades: Metabolism and Ketones






References:

1. Obesity related hyperinsulinaemia and hyperglycaemia and cancer development.
Becker S, Dossus L, Kaaks R.
Arch Physiol Biochem. 2009 May;115(2):86-96.

2. An energetic tale of AMPK-independent effects of metformin.
Miller RA, Birnbaum MJ.
J Clin Invest. 2010 Jul 1;120(7):2267-70.

3.  Effect of metformin on survival outcomes in diabetic patients with triple receptor-negative breast cancer.
Bayraktar S, Hernadez-Aya LF, Lei X, Meric-Bernstam F, Litton JK, Hsu L, Hortobagyi GN, Gonzalez-Angulo AM.
Cancer. 2012 Mar 1;118(5):1202-11.

4. Metformin induces unique biological and molecular responses in triple negative breast cancer cells .
Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, Thor AD.
Cell Cycle. 2009 Jul 1;8(13):2031-40.

5. Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy .
Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP. Breast Cancer Res Treat. 2009 Nov 22.

6. Expanding the arsenal: metformin for the treatment of triple-negative breast cancer?
Jiralerspong S, Gonzalez-Angulo AM, Hung MC.Cell Cycle. 2009 Sep 1;8(17):2681.

7. Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes .
Malin SK, Gerber R, Chipkin SR, Braun B.
Diabetes Care. 2012 Jan;35(1):131-6.

8. Combining short-term metformin treatment and one bout of exercise does not increase insulin action in insulin-resistant individuals.
Sharoff CG, Hagobian TA, Malin SK, Chipkin SR, Yu H, Hirshman MF, Goodyear LJ, Braun B.
Am J Physiol Endocrinol Metab. 2010 Apr;298(4):E815-23.

9. AMPK: a metabolic gauge regulating whole-body energy homeostasis.
Lage R, Diéguez C, Vidal-Puig A, López M.
Trends Mol Med. 2008 Dec;14(12):539-49.

10.  Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports.
Nebeling LC, Miraldi F, Shurin SB, Lerner E.
J Am Coll Nutr. 1995 Apr;14(2):202-8.

11. Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet.
Seyfried BT, Kiebish M, Marsh J, Mukherjee P.
J Cancer Res Ther. 2009 Sep;5 Suppl 1:S7-15. Review.

12. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides.
Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, Wittig R, Voelker HU, Thiede A, Coy JF.
BMC Cancer. 2008 Apr 30;8:122.

13. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism.
Mihaylova MM, Shaw RJ.
Nat Cell Biol. 2011 Sep 2;13(9):1016-23.

14. From natural products to small molecule ketone histone deacetylase inhibitors: development of new class specific agents.
Jones P, Steinkühler C.
Curr Pharm Des. 2008;14(6):545-61.

15. Epigenetic impact of dietary polyphenols in cancer chemoprevention: lifelong remodeling of our epigenomes.
Vanden Berghe W.
Pharmacol Res. 2012 Jun;65(6):565-76.

16. Understanding the benefit of metformin use in cancer treatment.
Dowling RJ, Goodwin PJ, Stambolic V.
BMC Med. 2011 Apr 6;9:33.

17. AMPK and the biochemistry of exercise: implications for human health and disease .
Richter EA, Ruderman NB.
Biochem J. 2009 Mar 1;418(2):261-75.


[Re-tweaked old Nephropal(eo) post]
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