This thread is linked to Metformin, a caloric restriction simulator and Insulin growth factor regulator. See also Boron, Resveratrol, Vitamin D
Take-Home Messages From The 2011 Nutrition & Metabolism Society Symposium In Baltimore
http://asbp.org/siterun_data/news/do...305215314.html
Quote:
Dr. Thomas Seyfried–“Ketone Bodies and Cancer”
- Most brain tumors are untreatable and patients die from the pressure build-up
- Calorie restriction is necessary for treating brain tumors
- The mitochondria are dysfunctional in human brain tumors
- Otto Warburg noted that cancer leads to irreversible damage
- Tumor cells are unable to shift from feeding on glucose to ketones
- Cancer is more of a metabolic disease than a genetic one
- There’s an 80% reduction in tumor weight when calorie-restricted
- Calorie-restriction one of the most powerful therapies for killing cancer cells
- As glucose is decreased, cancer cells reduce as well
- A low-carb, calorie-restricted diet is better than the best drug therapy for cancer
- Ketogenic calorie-restricted diets have reduced brain tumors in mice and humans
- Blood glucose remains too high on an unlimited calories low-carb diet to treat cancer
- Calorie-restricted low-carb diets create adequate ketones for treating brain tumors
- Ketogenic, calorie-restricted diets don’t cure cancer, but they come close
- Tumors can’t grow when calories are cut to create ketones
- Limiting carbs and calories puts you in the zone of managing tumor growth
- Brain cancer in children can be treated with ketogenic diets by reducing glucose
- Avoid radiation therapy if all all possible–ketogenic, calorie-restricted diet is best for cancer
Dr. Eugene Fine–“Reduced Carbohydrates in Aggressive Resistant Tumors (RECHARGE Trial)”
- Not all cancers are dependent on glucose for growth, including prostate cancer
- Hyperinsulinemia is a major cancer risk factor–that’s why reducing insulin in paramount
- It’s plausible that reducing insulin secretion could inhibit cancer growth
- The typical American diet contains 300-400g carbs daily–spiking insulin
- Cut the carbs and you’ll cut the insulin and reduce your cancer risk
- You don’t want an insulin knockout (Type 1 diabetes), but rather an insulin knockdown
- A low-carb diet provides the proper control of insulin without eliminating the good it does
- Reduced carb diets have not demonstrated adverse effects up to 2 years as a medical therapy
- Humans were built as hunter-gatherers to be in a ketotic state most of the time
- Fasting is in our ancestral biochemistry with no ill effects
- There is no known dietary requirement for carbohydrate in your diet
- Grains and vegetables are only a relatively recent addition to the human diet
- A very low-carb diet changes the metabolic environment where cancer would grow
- Too many people are living outside of a sustained ketogenic state leading to more cancer
- RECHARGE Trial used very low-carb diet on 10 patients who failed on chemotherapy
- The study placed the participants on a very low-carb ketogenic diet for 28 days
- Average daily intake consumed by study patients was 27g carbs and 1236 daily
- All of the study participants were ketotic
- Future direction of research will be a larger study using ketogenic diets–funding needed
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http://www.sciencedaily.com/releases...0806094822.htm Study Links High Carbohydrate Diet To Increased Breast Cancer Risk
ScienceDaily (Aug. 6, 2004) — PHILADELPHIA – Carb-conscious dieters may be lowering their risk of breast cancer while they’re shedding pounds, based on the findings of research published in this month’s edition of the journal Cancer Epidemiology, Biomarkers & Prevention.
In a case-control study of 1,866 women in Mexico, those who derived 57 or more percent of their total energy intake from carbohydrates incurred a risk of breast cancer 2.2 times higher than women with more balanced diets. Dietary patterns in Mexico are characterized by higher consumption of carbohydrates and lower intake of fat and animal protein than those in more affluent western countries.
The team of researchers from the Instituto de Salud Pública in Cuernavaca, Mexico, and the Harvard School of Public Health in Boston, suggests that
the association between carbohydrates and breast cancer may be related to elevated levels of insulin and insulin-like growth factor binding proteins in the blood.
“Scientists have long suspected that diet was among the factors contributing to breast cancer,” said study co-author Walter Willett, M.D., M.P.H., Dr.P.H, the Fredrick John Stare Professor of Epidemiology and Nutrition at the Harvard School of Public Health. “Now, with studies like ours, we are beginning gradually to understand what elements of diet specifically are associated with the disease, and to grasp the chemical and biological processes that contribute to it at the cellular level.”
Of all the carbohydrate compounds, sucrose and fructose demonstrated the strongest association with breast cancer risk in the study. Sucrose is derived from sugar cane, sorghum and the sugar beet; it is most commonly found in table sugar and sweetened prepared foods and beverages. Fructose is a component of sucrose and is also found in fruit.
Eating sweets and starches causes a rapid rise in the body’s blood sugar levels, which in turn cues the production of insulin and triggers a biological process that ultimately can influence carcinogenesis by causing cells to proliferate.
Insulin and an insulin-like growth factor also may contribute to higher circulating levels of biologically active estrogens, a risk factor for breast cancer in pre-menopausal women. Ninety percent of breast tumors are insulin-receptor positive and over-express the insulin-like growth factor.
The prevalence of type 2 diabetes, often associated with obesity, reflects an underlying insulin resistance in the Mexican population generally. Among urban Mexicans, nearly one-third of women between the ages of 12 and 49 are overweight. Yet when the research team took into account body mass index and other such potentially confounding factors as socioeconomic status, age at first birth, number of children, and family history of breast cancer, the relationship between carbohydrate intake and breast cancer remained the same.
Dietary fat – certainly a contributor to obesity – fared well in the research, showing no significant association with breast cancer risk overall. Willett noted, however, that the intake of polyunsaturated fat by the women in the study group was only about half that of the United States population.
Insoluble fiber intake was associated with lower risk of breast cancer, possibly because fiber may modulate the absorption of carbohydrates and thus affect the glycemic response.
“This study raises important questions about high carbohydrate diets, particularly among populations or individuals prone to insulin resistance. However, one study is not enough to make major changes in diet, and more work on this topic is urgently needed,” Willett said.
Explore carb/glycemic issues here:
LINK
2009
A new report from Duke University ads further evidence to the theory that carbohydrates fuel cancer growth. While previous studies showed that carbohydrate restriction could slow prostate cancer in an animal study, they were not sure if it was the weight loss these animals experienced that was slowing the tumors, or if was the carbohydrate restriction that was responsible.
This new study was designed to keep the weight of the test subjects the same.
When mice on a no-carbohydrate/very high fat diet were compared to mice on a low fat/high carb diet or a high fat/high carb diet, the no-carb mice fared much better.
According to Stephen Freedland, M.D., Duke Prostate Center urologist and lead investigator on this study,
"The mice that were fed a no-carbohydrate diet experienced a 40 to 50 percent prolonged survival over the other mice." (full report)
Clinical trials in humans are scheduled to start within a few weeks. I do not expect the results to be any different in people than they found in the mice.
With the small mountain of other evidence (1, 2, 3, 4) showing that high blood sugar and/or high insulin levels fuel cancer growth, this is just additional confirmation that the standard high carbohydrate diet recommended by diet experts, medical professionals and government agencies is making people sick.
It also shows that obesity and a high fat diet ARE NOT the cause of cancer. Obesity is just another side effect of a bigger problem... impaired glucose metabolism and/or elevated blood sugar and insulin levels. As for dietary fat, it has been a part of the human diet for millions of years. To blame it for cancer and obesity that have only been epidemic in very recent history shows a level of intellectual dishonesty I just can't begin to understand.
http://www.examiner.com/x-798-Denver-Low-Carb-Examiner~y2009m5d26-More-evidence-carbs-fuel-cancer
Cancer Prev Res (Phila Pa). 2009 Jun;2(6):557-65. Epub 2009 May 26.
The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model.
Mavropoulos JC,
Buschemeyer WC 3rd,
Tewari AK,
Rokhfeld D,
Pollak M,
Zhao Y,
Febbo PG,
Cohen P,
Hwang D,
Devi G,
Demark-Wahnefried W,
Westman EC,
Peterson BL,
Pizzo SV,
Freedland SJ.
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
PURPOSE:
Numerous dietary factors elevate serum levels of insulin and insulin-like growth factor I (IGF-I), both potent prostate cancer mitogens. We tested whether varying dietary carbohydrate and fat, without energy restriction relative to comparison diets, would slow tumor growth and reduce serum insulin, IGF-I, and other molecular mediators of prostate cancer in a xenograft model. EXPERIMENTAL DESIGN: Individually caged male severe combined immunodeficient
mice (n = 130) were randomly assigned to one of three diets (described as percent total calories): very high-fat/no-carbohydrate ketogenic diet (NCKD: 83% fat, 0% carbohydrate, 17% protein), low-fat/high-carbohydrate diet (LFD: 12% fat, 71% carbohydrate, 17% protein), or high-fat/moderate-carbohydrate diet (MCD: 40% fat, 43% carbohydrate, 17% protein). Mice were fed to maintain similar average body weights among groups. Following a preliminary feeding period, mice were injected with 1 x 10(6) LNCaP cells (day 0) and sacrificed when tumors were >or=1,000 mm(3). RESULTS: Two days before tumor injection, median NCKD body weight was 2.4 g (10%) and 2.1 g (8%) greater than the LFD and MCD groups, respectively (P < 0.0001).
Diet was significantly associated with overall survival (log-rank P = 0.004). Relative to MCD, survival was significantly prolonged for the LFD (hazard ratio, 0.49; 95% confidence interval, 0.29-0.79; P = 0.004) and NCKD groups (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.02). Median serum insulin, IGF-I, IGF-I/IGF binding protein-1 ratio, and IGF-I/IGF binding protein-3 ratio were significantly reduced in NCKD relative to MCD mice. Phospho-AKT/total AKT ratio and pathways associated with antiapoptosis, inflammation, insulin resistance, and obesity were also significantly reduced in NCKD relative to MCD tumors. CONCLUSIONS:
These results support further preclinical exploration of carbohydrate restriction in prostate cancer and possibly warrant pilot or feasibility testing in humans.
PMID: 19470786 [PubMed - indexed for MEDLINE]
Prostate. 2008 Jan 1;68(1):11-9.
Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis.
Freedland SJ,
Mavropoulos J,
Wang A,
Darshan M,
Demark-Wahnefried W,
Aronson WJ,
Cohen P,
Hwang D,
Peterson B,
Fields T,
Pizzo SV,
Isaacs WB.
Department of Surgery, Durham VA Medical Center, Durham, North Carolina 27710, USA.
steve.freedland@duke.edu
BACKGROUND: Recent evidence suggests carbohydrate intake may influence prostate cancer biology.
We tested whether a no-carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low-fat diets in a xenograft model. METHODS: Seventy-five male SCID mice were fed a NCKD (84% fat-0% carbohydrate-16% protein kcal), low-fat (12% fat-72% carbohydrate-16% protein kcal), or Western diet (40% fat-44% carbohydrate-16% protein kcal). Low-fat mice were fed ad libitum and the other arms fed via a modified-paired feeding protocol. After 24 days, all mice were injected with LAPC-4 cells and sacrificed when tumors approached 1,000 mm(3). RESULTS:
Despite consuming equal calories, NCKD-fed mice lost weight (up to 15% body weight) relative to low-fat and Western diet-fed mice and required additional kcal to equalize body weight. Fifty-one days after injection, NCKD mice tumor volumes were 33% smaller than Western mice (rank-sum, P = 0.009). There were no differences in tumor volume between low-fat and NCKD mice.
Dietary treatment was significantly associated with survival (log-rank, P = 0.006), with the longest survival among the NCKD mice, followed by the low-fat mice. Serum IGFBP-3 was highest and IGF-1:IGFBP-3 ratio was lowest among NCKD mice while serum insulin and IGF-1 levels were highest in Western mice. NCKD mice had significantly decreased hepatic fatty infiltration relative to the other arms. CONCLUSIONS: In this xenograft model,
despite consuming more calories, NCKD-fed mice had significantly reduced tumor growth and prolonged survival relative to Western mice and was associated with favorable changes in serum insulin and IGF axis hormones relative to low-fat or Western diet. (c) 2007 Wiley-Liss, Inc.
PMID: 17999389 [PubMed - indexed for MEDLINE]
J Nutr Health Aging. 1999;3(2):92-101.
Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction.
Kari FW,
Dunn SE,
French JE,
Barrett JC.
Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
This paper focuses on the role of insulin-like growth factor-1 (IGF-1) and its associated regulatory apparatus as a key endocrine, autocrine, and paracrine signalling system involved in mediating the anti-carcinogenic activity of dietary restriction. Literature is reviewed showing that
the inhibitory action of dietary restriction on carcinogenesis is global and pervasive--it is effective in several laboratory species, for a variety of tumor types, and for both spontaneous tumors and tumors caused by different types of tumor-inducing agents. Evidence is presented showing the IGF-1 pathway responds appropriately to nutritional interventions including diet restriction. Recent evidence points to an obligatory role for the IGF-1 receptor in the establishment and maintenance of the transformed phenotype and reveals that IGF-1 in concert with insulin-like binding protein 3 and p53 is involved in autocrine/paracrine growth signaling pathways as adaptive responses to environmental stimuli. Considered together these works show that
the IGF-1 pathway is uniquely poised to influence cellular transformation leading to the malignant phenotype by modulating the balance of cellular proliferation and cell death (apoptosis) in precancerous and cancerous cells and by influencing metastasis of nascent tumors. We evaluated these hypotheses directly using animal models of mononuclear cell leukemia, bladder transitional cell carcinogenesis, and breast cancer. Our studies demonstrate that
manipulation of IGF-1 level through dietary intervention influences tumor growth and metastasis. Upregulation of this pathway demonstrated that increased IGF-1 stimulates tumor proliferation, progression and metastasis. Conversely, downregulation of this pathway in vivo as a consequence of dietary restriction results in antitumorigenic activity. We found that the functional disruption of IGF-1R markedly influences breast cancer metastasis in nude mice by suppressing cellular adhesion, invasion, and metastasis of breast cancer cells to the lung, lymph nodes, and lymph vessels. Epidemiological observations and clinical oncology results support the involvement of IGF-1 in carcinogenesis and anticarcinogenesis. This leads to the hypothesis that factors such as IGF-1 which regulate body size and composition may be related to human cancer incidence or prognosis. Additional understanding of this pathway and its interactions with other signaling pathways will advance our ability to develop new interventions towards decreased cancer risk in humans.
PMID: 10885804 [PubMed - indexed for MEDLINE]
Monday, Sep. 17, 2007
Can a High-Fat Diet Beat Cancer?
By Richard Friebe
http://www.time.com/time/health/arti...662484,00.html
Quote:
What sounds like yet another version of the Atkins craze is actually based on scientific evidence that dates back more than 80 years. In 1924, the German Nobel laureate Otto Warburg first published his observations of a common feature he saw in fast-growing tumors: unlike healthy cells, which generate energy by metabolizing sugar in their mitochondria, cancer cells appeared to fuel themselves exclusively through glycolysis, a less-efficient means of creating energy through the fermentation of sugar in the cytoplasm. Warburg believed that this metabolic switch was the primary cause of cancer, a theory that he strove, unsuccessfully, to establish until his death in 1970.
To the two researchers in Würzburg, the theoretical debate about what is now known as the Warburg effect — whether it is the primary cause of cancer or a mere metabolic side effect — is irrelevant. What they believe is that it can be therapeutically exploited. The theory is simple: If most aggressive cancers rely on the fermentation of sugar for growing and dividing, then take away the sugar and they should stop spreading. Meanwhile, normal body and brain cells should be able to handle the sugar starvation; they can switch to generating energy from fatty molecules called ketone bodies — the body's main source of energy on a fat-rich diet — an ability that some or most fast-growing and invasive cancers seem to lack.
The Würzburg trial, funded by the Otzberg, Germany–based diet food company Tavartis, which supplies the researchers with food packages, is still in its early, difficult stages. "One big problem we have," says Schmidt, sitting uncomfortably on a small, wooden chair in the crammed tea kitchen of Kämmerer's lab, "is that we are only allowed to enroll patients who have completely run out of all other therapeutic options." That means that most people in the study are faring very badly to begin with. All have exhausted traditional treatments, such as surgery, radiation and chemo, and even some alternative ones like hyperthermia and autohemotherapy. Patients in the study have pancreatic tumors and aggressive brain tumors called glioblastomas, among other cancers; participants are recruited primarily because their tumors show high glucose metabolism in PET scans.
Four of the patients were so ill, they died within the first week of the study. Others, says Schmidt, dropped out because they found it hard to stick to the no-sweets diet: "We didn't expect this to be such a big problem, but a considerable number of patients left the study because they were unable or unwilling to renounce soft drinks, chocolate and so on."
The good news is that for five patients who were able to endure three months of carb-free eating, the results were positive: the patients stayed alive, their physical condition stabilized or improved and their tumors slowed or stopped growing, or shrunk.
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The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer.
FULL PDF
Weihua Zhou, Purna Mukherjee, Michael A Kiebish, William T Markis, John G Mantis and Thomas N Seyfried*
Address: Department of Biology, Boston College, Chestnut Hill, USA
Email: Weihua Zhou - zhouwb@bc.edu; Purna Mukherjee - mukherjp@bc.edu; Michael A Kiebish - kiebish@bc.edu; William T Markis - markisw@bc.edu; John G Mantis - mantisjo@bc.edu; Thomas N Seyfried* - thomas.seyfried@bc.edu * Corresponding author
Abstract
Background: Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain
cells.
In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal®, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG).
Methods: Adult mice were implanted orthotopically with the malignant brain tumors and KetoCal® was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal® on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet.
Results: KetoCal® administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal® diet reduced plasma
glucose levels while elevating plasma ketone body (β-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal® groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, β-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy.
Conclusion: The results indicate that
KetoCal® has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal® for brain cancer management was due largely to the reduction of total caloric content, which reduces circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet.
Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal® is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.
Published: 21 February 2007
Nutrition & Metabolism 2007, 4:5 doi:10.1186/1743-7075-4-5
Received: 29 November 2006
Accepted: 21 February 2007
This article is available from:
http://www.nutritionandmetabolism.com/content/4/1/5
© 2007 Zhou et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
http://creativecommons.org/licenses/by/2.0),
"Glycemic load" of diet tied to breast cancer risk
http://www.reuters.com/article/healt...ame=healthNews
Sat Jul 11, 2009 12:48am EDT
NEW YORK (Reuters Health) - The amount of carbohydrates a woman eats, as well as the overall "glycemic load" of her diet, impact her chances of developing breast cancer, Swedish researchers report.
The concept of glycemic load is based on the fact that different carbohydrates have different effects on blood sugar. White bread and potatoes, for example, have a high glycemic index, which means they tend to cause a rapid surge in blood sugar. Other carbs, such as high-fiber cereals or beans, create a more gradual change and are considered to have a low glycemic index.
Dr. Susanna C. Larsson of Karolinska Institute in Stockholm and colleagues analyzed data on 61,433 women who completed "food frequency" questionnaires in the late 1980s.
Over the course of about 17 years, 2952 women developed breast cancer and, according to the investigators,
glycemic load "was significantly positively associated with risk of overall breast cancer." Women with higher glycemic load diets were more apt to develop breast cancer.
In addition, carbohydrate intake, glycemic index and glycemic load were all positively associated with risk of a certain type of breast tumor - namely, estrogen receptor (ER)-positive/progesterone receptor (PR)-negative breast cancer.
Women with the highest "glycemic index diet" had a 44% increased risk of developing ER+/PR- breast cancer compared to women with the lowest glycemic index diet.
Women in the highest category of "glycemic load" had an 81% increased risk of ER+/PR- tumors, and those with the highest carbohydrate intake had a 34% increased risk, compared to those in the lowest groups.
The investigators speculate that high-glycemic load diets may boost breast cancer risk by increasing concentrations of insulin and sex hormones in the body, which may contribute to the development and spread of breast cancer cells.
The findings support the benefits on breast health of a diet high in healthy "low glycemic index" foods.
SOURCE: International Journal of Cancer, July 2009.
http://external.doyma.es/pdf/12/12v5...6356pdf001.pdf (In Spanish)
J. PÉREZ-GUISADO
Google Translate version
CARBOHYDRATES, GLUCOSE
METABOLISM AND CANCER
Many epidemiological studies have linked a high intake of animal products with the genesis of cancer. However, when
collecting and analyzing data, these studies do not take into account the possible effects of dietary carbohydrates and
glucose metabolism abnormalities, which are important confounding variables that could be important diases. Factors related to carbohydrates and glucose metabolism,
such as the energetic contribution of carbohydrates, the glycemic index and glycemic load, fasting glycemia and
insulinemia, as well as glucose and insulin levels after oral glucose load, are associated with the risk of developing many types of cancer. Therefore, these factors should be kept in mind when collecting and interpreting epidemiologic information.
Arguments In Favor Of Ketogenic Diets
Abstract
http://www.ispub.com/ostia/index.php...ol4n2/diet.xml
Many negative comments have been made about the use of ketogenic diets (KDs) and experts today believe that the best way to lose weight is by cutting back on calories, chiefly in the form of fat. The international consensus is that carbohydrates are the basis of the food pyramid for a healthy diet. However, this review will clarify that low-carbohydrate diets are, from a practical and physiological point of view, a much more effective way of losing weight. It is also argued that such diets provide metabolic advantages, for example: they help to preserve muscle mass, reduce appetite, diminish metabolic efficiency, induce metabolic activation of thermogenesis and favor increased fat loss and even a greater reduction in calories. These diets are also healthier because they promote a non-atherogenic lipid profile, lower blood pressure and decrease resistance to insulin with an improvement in blood levels of glucose and insulin. Low-carbohydrate diets should therefore be used to prevent and treat type II diabetes and cardiovascular problems. Such diets also have neurological and antineoplastic benefits and diet-induced ketosis is not associated with metabolic acidosis, nor do such diets alter kidney, liver or heart functions.
Quote:
Carbohydrate neoplastic effects versus ketogenic diet antineoplastic effects
Many scientists believe that the healthiest diets contain 55-70% carbohydrates and that KDs may be potentially cancerous since many epidemiological studies have linked a high intake of animal products with the genesis of cancer. However, when collecting and analyzing data, these studies fail to take into account the possible effects of dietary carbohydrates and glucose metabolism abnormalities, which are important confounding variables. Factors related to the carbohydrate and glucose metabolism, such as the energetic contribution of carbohydrates, glycemic index and glycemic load, fasting glycemia and insulinemia, as well as glucose and insulin levels after oral glucose load, are associated with the risk of developing many types of cancer. Therefore, these factors should be borne in mind when collecting and interpreting epidemiologic information. Moreover, many studies have reported tumor-inhibitory effects in KDs 132.
A direct link has been identified between the risk of endometrial cancer and the glycemic index 133] or glycemic load 133,134. Augustin et al. 135 found a connection between carbohydrate intake and the risk of gastric cancer. Augustin et al 136 also found a direct link between glycemic index and glycemic load and the risk of ovarian cancer and, consequently, a possible role of hyperinsulinemia/insulin resistance in the development of ovarian cancer. Borugian et al. 137 reported that increased non-fiber (“effective”) carbohydrate and total carbohydrate consumption are both associated with the increased risk of colorectal cancer in both sexes. In women, relative risk is higher for the right colon, whereas in men the relative risk is higher for the rectum. Franceschi et al. 138 found a positive link between the glycemic index and glycemic load and colorectal cancer. It has been suggested that this association is caused by insulin resistance; insulin resistance therefore leads to colorectal cancer 139,140 through the lesion-promoting effect of elevated levels of insulin, glucose or triglycerides 139]. The most important carbohydrates associated with the risk of colorectal cancer are bread, cereal dishes, potatoes, cakes and desserts, and refined sugar intake. In contrast, fish, raw and cooked vegetables and fruit displayed a negative association with the risk. Consumption of eggs and meat (white, red or processed meats) appeared to be non-influential 141. In relation to the risk of developing breast cancer, Holmes et al. 142 discovered no evidence linking meat or fish intake during mid-life and later with the risk of breast cancer. Nevertheless, carbohydrates provided by starch were the most frequently found component contributing to the positive association with breast cancer. Starch food sources included food such as white bread, pasta, rice, crackers and cookies were particularly linked 143; this is due to the proven association between the glycemic index or glycemic load and the risk of breast cancer, possibly due to the role of hyperinsulinemia/insulin resistance in breast cancer development 144. Franceschi et al. 143 found that high intakes of polyunsaturated and unsaturated fatty acids were associated with a lower risk of breast cancer and that saturated fatty acids, protein and fiber were not significantly associated with breast-cancer risks. Romieu et al. 145 also found a positive connection between carbohydrate intake and breast cancer risk but not with fat intake.
KDs have shown to be efficient in reducing the size of tumors and avoiding the loss of muscle mass associated with disease in humans 146,69 and mice 147.
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Arch Latinoam Nutr. 2008 Dec;58(4):323-9.
[Ketogenic diets: additional benefits to the weight loss and unfounded secondary effects]
[Article in Spanish]
Pérez-Guisado J.
Departamento de Medicina, Facultad de Medicina, Universidad de Córdoba, Córdoba, España.
It is also necessary to emphasize that
as well as the weight loss, ketogenic diets are healthier because they promote a non-atherogenic lipid profile, lower blood pressure and diminish resistance to insulin with an improvement in blood levels of glucose and insulin. Such diets also have antineoplastic benefits, do not alter renal or liver functions, do not produce metabolic acidosis by Ketosis, have many neurological benefits in central nervous system, do not produce osteoporosis and could increase the perfomance in aerobic sports.
PMID: 19368291 [PubMed - indexed for MEDLINE]
J Am Coll Nutr. 1995 Apr;14(2):202-8.
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. Nutrition Department, Case Western Reserve University, School of Medicine, Cleveland, Ohio, USA.
OBJECTIVE: Establish dietary-induced ketosis in pediatric oncology patients to determine if a ketogenic state would decrease glucose availability to certain tumors, thereby potentially impairing tumor metabolism without adversely affecting the patient's overall nutritional status.
DESIGN: Case report.
SETTING: University Hospitals of Cleveland.
SUBJECTS: Two female pediatric patients with advanced stage malignant Astrocytoma tumors.
INTERVENTIONS: Patients were followed as outpatients for 8 weeks. Ketosis was maintained by consuming a 60% medium chain triglyceride oil-based diet. MAIN
OUTCOME MEASURES: Tumor glucose metabolism was assessed by Positron Emission Tomography (PET), comparing [Fluorine-18] 2-deoxy-2-fluoro-D-glucose (FDG) uptake at the tumor site before and following the trial period.
RESULTS:
Within 7 days of initiating the ketogenic diet, blood glucose levels declined to low-normal levels and blood ketones were elevated twenty to thirty fold. Results of PET scans indicated a 21.8% average decrease in glucose uptake at the tumor site in both subjects. One patient exhibited significant clinical improvements in mood and new skill development during the study. She continued the ketogenic diet for an additional twelve months, remaining free of disease progression.
CONCLUSION: While this diet does not replace conventional antineoplastic treatments, these preliminary results suggest a potential for clinical application which merits further research. PMID: 7790697 [PubMed - indexed for MEDLINE]
http://healthbeatnews.com/news/archives/431
Dietary Ketosis In The Treatment of Solid Tissue Malignancy
By Dr. Dana Myatt
Many believe that cancer cells, damaged by mutation, are more resilient than normal cells. However,
malignant cells are largely incapable of the metabolic flexibility displayed by normal cells, and therein lies their weakness and the potential for a gentle but highly effective point of attack.
Nutritional and botanical factors can have profound positive effects in cancer treatment, but
the single most potent anti-cancer strategy documented in the medical literature strikes at the core of cancer’s metabolism: glycolysis, especially anaerobic glycolysis, and impaired mitochondrial function.
Numerous animal and human studies have demonstrated that the glycolytic pathway of cancer cells can be confounded by metabolic ketosis, often with profound apoptotic effects on cancer cells but without negative consequence — and in fact with
protective effects — to normal cells.
(1-6)
Metabolic ketosis curtails cancer growth by a variety of mechanisms including:
I.
Decreasing the glucose substrate required for cancer cell metabolism. Most tumors express abnormalities in the number and function of their mitochondria.
(7-12) Such abnormalities prevent the bioenergetic utilization of ketone bodies, which require functional mitochondria for their oxidation.
II.
Decreasing insulin, a secondary growth factor for cancer cells.
(13-14)
III.
Decreasing inflammation. Inflammation acts to promote cancer by altering cell-to-cell communication and delaying local detoxification.
(15-25) Metabolic ketosis has significant anti-inflammatory effects.
(9, 26-29)
IV.
Decreasing ROS production. Reactive Oxygen Species are known to promote
cancer
(30-33) ; metabolic ketosis decreases ROS production.
(34-37)
V.
Reversing cachexia while simultaneously decreasing tumor weight.
(38-40)
VI.
Decreasing angiogenesis.
(29, 41-42)
VII.
Inducing apoptosis.
(11,29, 38)
VIII.
Suppressing the p53 oncogene, the most common point mutation observed in human cancer; more than 50% of all human tumors examined to date have identifiable p53 gene point mutations or deletions. A ketogenic diet has been shown to suppress the p53 oncogene in animal models.
(43)
IX.
Acting synergistically with chemotherapy and/or specific nutritional supplementation. (44-45)
In spite of improved availability of foods containing anti-carcinogenic phytonutrients and vitamins, most types of cancer have not declined as expected. This correlates to the overall calorie increase and overweight condition of our society, a condition which puts us in "constant feast" mode instead of the periodic fasting our ancestors previously experienced. (46) Some observers feel that our previous occasional fasts, which would induce ketosis, were beneficial for cancer control. It has also been hypothesized that alternative "cancer diets" such as juice fasting, calorie restriction or the use of Coley’s toxins are effective primarily because they induce metabolic ketosis.
This presentation will serve as a review of the nature and behavior of characteristics common to all solid tissue cancer cells. It will offer a novel but well-documented clinical nutritional treatment strategy which targets multiple cancer cell vulnerabilities while simultaneously protecting and enhancing the function of normal cells and tissues.
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23.) Stewart JW, Koehler K, Jackson W, Hawley J, Wang W, Au A, Myers R, Birt DF: Prevention of mouse skin tumor promotion by dietary energy restriction requires an intact adrenal gland and glucocorticoid supplementation restores inhibition.
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24.) Zhu Z, Jiang W, Thompson HJ: Mechanisms by which energy restriction inhibits rat mammary carcinogenesis: in vivo effects of corticosterone on cell cycle machinery in mammary carcinomas.
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35.) Veech RL: Metabolic control analysis of ketone and insulin action: Implications for phenotyping of disease and design of therapy. Lecture:The Dynamic and Energetic Basis of Health and Aging Monday, Nov 11 - Wednesday, Nov 13, 2002, The Cloister’s, NIH, Bethesda MD.
36.) Masuda R, Monahan JW, Kashiwaya Y: D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures.
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37.) Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet.
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http://esciencenews.com/articles/200...er.development
UAB researchers link calorie intake to cell lifespan, cancer development
Published: Thursday, December 17, 2009 - 17:39 in
Health & Medicine
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Jamie Cottle/UAB
Researchers from the University of Alabama at Birmingham (UAB) have discovered that restricting consumption of glucose, the most common dietary sugar, can extend the life of healthy human-lung cells and speed the death of precancerous human-lung cells, reducing cancer's spread and growth rate. The research has wide-ranging potential in age-related science, including ways in which calorie-intake restriction can benefit longevity and help prevent diseases like cancer that have been linked to aging, said principal investigator Trygve Tollefsbol, Ph.D., D.O., a professor in the Department of Biology.
"These results further verify the potential health benefits of controlling calorie intake." Tollefsbol said. "Our research indicates that calorie reduction extends the lifespan of healthy human cells and aids the body's natural ability to kill off cancer-forming cells."
The UAB team conducted its tests by growing both healthy human-lung cells and precancerous human-lung cells in laboratory flasks. The flasks were provided either normal levels of glucose or significantly reduced amounts of the sugar compound, and the cells then were allowed to grow for a period of weeks.
"In that time, we were able to track the cells' ability to divide while also monitoring the number of surviving cells. The pattern that was revealed to us showed that restricted glucose levels led the healthy cells to grow longer than is typical and caused the precancerous cells to die off in large numbers," Tollefsbol said.
In particular, the researchers found that two key genes were affected in the cellular response to decreased glucose consumption. The first gene, telomerase, encodes an important enzyme that allows cells to divide indefinitely. The second gene, p16, encodes a well known anti-cancer protein.
"Opposite effects were found for these genes in healthy cells versus precancerous cells. The healthy cells saw their telomerase rise and p16 decrease, which would explain the boost in healthy cell growth," Tollefsbol said. "The gene reactions flipped in the precancerous cells with telomerase decreasing and the anti-cancer protein p16 increasing, which would explain why these cancer-forming cells died off in large numbers."
The UAB research into the links between calorie intake, aging and the onset of diseases related to aging is thought to be a first of its kind given that it used the unique approach of testing human cells versus laboratory animals.
"Our results not only support previous findings from the feeding of animals but also reveal that human longevity can be achieved at the cellular level through caloric restriction," Tollefsbol said.
"The hope is that this UAB breakthrough will lead to further discoveries in different cell types and facilitate the development of novel approaches to extend the lifespan of humans," he added.
11/16/09
Targets 09 Episode 3: Listen to
David Sabatini, M.D., Ph.D., a member of the Whitehead Institute and associate professor of biology at MIT, speak about his work on
dietary restriction and tumor response.
http://media.libsyn.com/media/aacr/A...odcastsEp3.mp3
Some notes:
History of dietary/caloric restriction theory: restriction by 30% thought to reduce incidence and growth amongst all cancers.
Current research found disparities in response
divided cancers into responsive/unresponsive
Resistant cancers, when cell analyzed didn't care about insulin growth factors. Responsive cancers followed insulin levels tightly which implicated PI3 kinase pathway, one of the major systems of response to insulin levels.
Looked at the two types of cells and found Pi3 kinase pathways differed, resistant cells had mutated PI3 kinase pathways. Manipulation of pathway could induce resistance or responsiveness showing causation and identified PI3K as pivotal.
Mimetics (metformin?) of caloric restriction could prove helpful. However findings suggest need to identify which tumors will respond.
Despite prevalent thinking that restriction worked on all tumors, closer look at data from the 30's actually does show disparities.
Identification of main pathway/response determination is biggest finding. Simplifies what was thought to be a complex process. Insulin levels drop when you calorically restrict. But here's a (mutated) pathway that lets the cells think there's always insulin.
If caloric restriction important the reverse is implicated. Obesity may be biggest driver of increased cancer. Need to find out role of mutated pathway in obese patients.
Suggests organism/metabolism focus is warranted.
Study demonstrated advancement in mouse models that showed same results of human xenograft models.
Interesting Ketogenic diet discussion:
http://stan-heretic.blogspot.com/200...re-cancer.html
J Am Diet Assoc. 1995 Jun;95(6):693-7.
Implementing a ketogenic diet based on medium-chain triglyceride oil in pediatric patients with cancer.
Nebeling LC, Lerner E. Nutrition Department, Case Western Reserve University, Cleveland, Ohio 44106-4906, USA.
Traditionally, a ketogenic diet is given to drug-resistant children with epilepsy to improve seizure control. Inducing a ketogenic state in patients with cancer may be a useful adjunct to cancer treatment by affecting tumor glucose metabolism and growth while maintaining the patient's nutritional status. A ketogenic diet consisting of 60% medium-chain triglyceride (MCT) oil, 20% protein, 10% carbohydrate, and 10% other dietary fats was provided to a select group of pediatric patients with advanced-stage cancer to test the effects of dietary-induced ketosis on tumor glucose metabolism. Issues of tolerance and compliance for patients consuming an oral diet (consisting of normal table foods and daily MCT oil "shakes") and for patients receiving an enteral formula are reviewed. Preliminary use of the MCT oil-based diet suggests a potential in pediatric patients with cancer. PMID: 7759747 [PubMed - indexed for MEDLINE]
http://www.baldwincountynow.com/arti...e083396309.txt
USA Mitchell Cancer Institute researchers make discovery.
Find could be effective strategy against breast cancer
By Curt Chapman
Staff Writer
(Created: Thursday, August 27, 2009 10:05 AM CDT)
FAIRHOPE, Ala. — Researchers at the University of South Alabama Mitchell Cancer Institute (MCI) have discovered that
the growth of breast cancer cells can be slowed by thwarting an enzyme pathway that produces cellular energy needed by the disease. The findings have been published online by the leading cancer research journal, Oncogene.
 | | Dr. Ming Tan |
|
Otto Warburg, a German scientist and Nobel laureate, discovered nearly 80 years ago that
normal cells depend on a process that consumes oxygen and glucose to make energy. Cancer cells, however, are more reliant on sugar metabolism, known as glycolysis.
Cancer cells consume far more sugar than normal cells to maintain sufficient energy supplies, according to researchers, and
they become addicted to glycolysis.
Recent studies found this unique property is an Achille’s heel for cancer cells. By understanding the unique energy demands of cancer cells, the MCI scientists believe drugs may be designed to target this weakness.
It all seems like a relatively simple solution to a rather complicated problem.
“Actually,
cutting off the energy supply to living cells is not difficult,” said Dr. Ming Tan, assistant professor of oncologic sciences, Vincent F. Kilborn Jr. Cancer Research Scholar and leader of the MCI research team that made the discovery. The real difficulty is to selectively cut off the energy supply of cancer cells and to spare the normal cells.”
He explained that Warburg’s initial discovery would have borne significant fruit years ago, but because of the lack of knowledge of molecular biology and a technology limitation at the time of the German’s research, the mechanism of glycolysis was unknown, and there was no good method to block the specific enzyme pathways of glycolysis.
Tan said,
“Recently researchers have found that cancer cells benefit from the switch of energy supply to glycolysis, and molecular advances in this area have revealed that we may exploit the cancer cell’s ‘sweet tooth’ for cancer therapy.”
 |
| Studies being conducted at the USA Mitchell Cancer Institute by a team of researchers led by Dr. Ming Tan could one day produce a silver bullet that could target breast cancer cells, as well as other types of malignancies. Photo courtesy of the University of South Alabama. |
It’s too soon to tell how long it might take for the new discoveries to produce a silver bullet that helps fight all forms of breast cancer, but they hold promise.
“Recent studies found that the activation of tumor-promoting genes is one of the reasons for the switch of energy supply of cancer cells,” Tan said. “In our study we used an experimental model that has activation of tumor promoting gene ErbB2, which happens frequently in breast cancer cells. This is why our findings are particularly meaningful for breast cancer.
He added,
“Warburg effect is a common feature of most cancer cells. Although we used a breast cancer model with activation of tumor-promoting gene ErbB2, the insight we gained through studying this model system should also have implications to other tumor promoting genes-mediated glycolysis.”
Tan said the research is still in early pre-clinical study stage. It was conducted in the laboratory using cancer cells.
Animal studies and human sample tests are needed before it can be put into practical use in patients, and that stage is expected to begin soon.
“Cancer metabolism has emerged as one of the most exciting areas of cancer research that may open a new therapeutic avenue and may bring new hope for cancer patients,” Tan said. “The pre-clinical studies may lead to translation into clinical trial and may ultimately benefit many cancer patients in the future.”
He said
there are currently a few sugar metabolism inhibitors under pre-clinical study, such as 2-DG, which are given to animals orally. Other forms of the treatment may be developed depending on the individual properties of the specific therapeutic agents.
Others working alongside Tan on the research are Drs. Yuhua Zhao, Ming Zhou, Hao Liu, Yan Ding, Hung Khong and Oystein Fodstad.
This MCI study was funded through the Vincent F. Kilborn Jr. Cancer Research Foundation at USA and the Radiumhospitalets Legater of the University of Oslo in Norway. Tan said the team is grateful for the generous support.
Tan came to the University of South Alabama two years ago, and began working on the research project after completing studying literature on cancer metabolism for two years.
Asked what is next on his radar, he said, “The emphasis of our research is on signal transduction pathways regulating the malignant behavior of tumor cells. Currently we focus on growth factor receptors, such as HER-2/ErbB2, mediated signal transduction, cancer metabolism, metastasis, resistance to therapeutic agents and targeted therapy for cancer using human breast cancer as a model system. Our ultimate goal is to translate the knowledge acquired in the laboratory into future novel therapeutics.”
Cancer Cell Int. 2009 May 29;9:14.
Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Fine EJ, Miller A, Quadros EV, Sequeira JM, Feinman RD. Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
efine@aecom.yu.edu.
ABSTRACT:
BACKGROUND: Recent evidence suggests that several human cancers are capable of uncoupling of mitochondrial ATP generation in the presence of intact tricarboxylic acid (TCA) enzymes.
The goal of the current study was to test the hypothesis that ketone bodies can inhibit cell growth in aggressive cancers and that expression of uncoupling protein 2 is a contributing factor. The proposed mechanism involves inhibition of glycolytic ATP production via a Randle-like cycle while increased uncoupling renders cancers unable to produce compensatory ATP from respiration. METHODS: Seven aggressive human cancer cell lines, and three control fibroblast lines were grown in vitro in either 10 mM glucose medium (GM), or in glucose plus 10 mM acetoacetate [G+AcA]. The cells were assayed for cell growth, ATP production and expression of UCP2. RESULTS: There was a high correlation of cell growth with ATP concentration (r = 0.948) in a continuum across all cell lines. Controls demonstrated normal cell growth and ATP with the lowest density of mitochondrial UCP2 staining while all cancer lines demonstrated proportionally inhibited growth and ATP, and over-expression of UCP2 (p < 0.05). CONCLUSION: Seven human cancer cell lines grown in glucose plus acetoacetate medium showed tightly coupled reduction of growth and ATP concentration. The findings were not observed in control fibroblasts.
The observed over-expression of UCP2 in cancer lines, but not in controls, provides a plausible molecular mechanism by which acetoacetate spares normal cells but suppresses growth in cancer lines. The results bear on the hypothesized potential for ketogenic diets as therapeutic strategies. PMID: 19480693 [PubMed - in process]
Nutr Metab (Lond). 2010 Apr 22;7:33.
Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report.
Zuccoli G,
Marcello N,
Pisanello A,
Servadei F,
Vaccaro S,
Mukherjee P,
Seyfried TN.
Source
Radiology Department, Arcispedale Santa Maria Nuova, Reggio E, 42100, Italy.
giulio.zuccoli@gmail.com.
FREE TEXT
Abstract
ABSTRACT:
BACKGROUND:
Management of glioblastoma multiforme (GBM) has been difficult using standard therapy (radiation with temozolomide chemotherapy). The ketogenic diet is used commonly to treat refractory epilepsy in children and, when administered in restricted amounts, can also target energy metabolism in brain tumors.
We report the case of a 65-year-old woman who presented with progressive memory loss, chronic headaches, nausea, and a right hemisphere multi-centric tumor seen with magnetic resonance imaging (MRI). Following incomplete surgical resection, the patient was diagnosed with
glioblastoma multiforme expressing hypermethylation of the MGMT gene promoter.
METHODS:
Prior to initiation of the standard therapy, the patient conducted water-only therapeutic fasting and a restricted 4:1 (fat: carbohydrate + protein) ketogenic diet that delivered about 600 kcal/day. The patient also received the restricted ketogenic diet concomitantly during the standard treatment period. The diet was supplemented with vitamins and minerals. Steroid medication (dexamethasone) was removed during the course of the treatment. The patient was followed using MRI and positron emission tomography with fluoro-deoxy-glucose (FDG-PET).
RESULTS:
After two months treatment, the patient's body weight was reduced by about 20% and no discernable brain tumor tissue was detected using either FDG-PET or MRI imaging. Biomarker changes showed reduced levels of blood glucose and elevated levels of urinary ketones. MRI evidence of tumor recurrence was found 10 weeks after suspension of strict diet therapy.
CONCLUSION:
This is the
first report of confirmed GBM treated with standard therapy together with a restricted ketogenic diet. As rapid regression of GBM is rare in older patients following incomplete surgical resection and standard therapy alone, the response observed in this case could result in part from the action of the calorie restricted ketogenic diet. Further studies are needed to evaluate the efficacy of restricted ketogenic diets, administered alone or together with standard treatment, as a therapy for GBM and possibly other malignant brain tumors.
- PMID:
- 20412570
- [PubMed - in process]
- PMCID: PMC2874558
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