The epidemiological link between insulin and cancer incidence is that of hyperinsulinemia. This probably accounts for most of the increase in cancer incidence in obese or previously obese subjects. In addition to the fact that high insulin levels are associated with increased cancer incidence, it has other effects. For example, women with high insulin levels at the time of breast cancer diagnosis have a poorer long-term outcome. Insulin is a powerful mitogen and when insulin levels are increased because of insulin-resitance its activity can spill over onto IGF-1 receptors. Like IGF-1 the insulin receptor pathway is also linked to growth via the ERK pathway. Since insulin resistance involves the PI3 kinase pathway this primarily effects the immediate metabolic effects of insulin, such as glucose uptake, rather than the growth effects.

Yes thats very good question. Insulin enhance IGF1 production in the liver metabolism. IGF1 is mitogenic and could be the reason why high carbohydrate costs will triggar development of cancer. My suggestion is also that this possible connection between high carbohydrate intake and cancer should be more elucidated.

Thanks Hans. Mentionig the IGF-1 brought me to another question: I have read that also high meat consumption, or proteins in general (but more from animal sources), also increase IGF-1. I guess that while the IGF-1 is needed during adolescence, adult humans do not need high levels of it. What would be your comment on that? From my point of view: we need proteins for the obvious metabolic needs, but we do not need processed carbohydrates. The reason why I am asking is the current debates of the vegetarian/vegan advocates versus low-carbohydrate/high meat promoters. While the high glycaemic (or GL) diet has been linked with a range of metabolic diseases, which can be corrected (at least temporarily) with cutting down on carbohydrates, the low-carb advocates put the high meat and animal products diet as superior to treat these diseases, including the obesity. But it seems they tend to forget about the cancer, which takes more time to develop and is more difficult to study in relation to dietary intervention. So therefore I am trying to find out where the high GI (GL) and low-carb diets stand in relation to cancer.

Yes thats correct that protein also enhance levels of IGF1 in blood. When you eat meat the levels of aminoacids in blood increase and induce insulin release which in turn elevate proteinsyntesis. As a second effect IGF1 increase from the liver. IGF1 is needed in adults for the metabolic action of insulin in vascular smooth muscle and other types of smooth muscle. There is not enough with insulin receptors in vascular smooth muscle while IGF1 receptors is common. High intake of protein and GI diet will in that way trigger unphysiological levels of IGF1 in blood and maybe enhance the mitogenic effect of IGF1 in different kind of tissues.

Thanks for a deeper insight. So, it can be said that high GI (GL) diet not only promotes weight gain, insulin resistance, atherosclerosis, but also plays a role in cancer development via IGF1. This was only an introduction to what I am trying to find out in a simplistic way. What I was interested to uncover was whether high intake of meat and low carbohydrate (most of the carbohydrates, not only high GL, but also resistant starch, beneficial for the colon) can actually increase the chances for colorectal cancer (at least). I am not talking about strict Atkins diet, leaving probably most other food groups out whereas the low-carb promoters try to implement some low-carb vegetables and fruits along the high intake of proteins. As I said, the cancer takes longer to develop whereas monitoring the indicators of cardiovascular diseases, diabetes and similar metabolic abnormalities require few weeks to see whether a diet is improving or worsening them. With the cancer it is not so easy. I understand there are many types of cancer and they are specific so not one dietary factor affects all forms of cancer the same way. For now I am primarily interested in the colorectal cancer and if possible, other forms. I have looked at the WCRF, Cancer Research UK, some EPIC sources and few individual observational studies linking meat consumption to various forms of metabolic diseases. While I might agree to some extend that we got it wrong with the fat and cardiovascular disease, I do not like the aggressive critique of such studies in terms of link between the red meat and several forms of cancer, saying that the observational studies are not a science as I had a chance to read from Gary Taubes, for example. He is promoting a weight loss, diabetes and CVD solution via low-carb, high meat and animal products consumption (for non-vegetarians), even at the price of going on zero carbs in obese people that cannot get rid of the weight 'they do not like' with even very low-carb approach. This seems to be promoted for a pretty long time 'while they do not like their weight', completely ignoring a cancer potential of such diet. Therefore instead of creating the unphysiological levels of IGF1 by grouping high protein and high GL diet, I would be interested in finding the risks of the meat based diet in a long term, since the insulin part seems to be sorted for now and protein does not trigger such high insulin response as glucose does. To me it appears that even lowering the glucose levels does not make the population healthy (as Gary hopes and promotes so passionately).

Please go through one our recent findings, I hope it will help you in different prescriptive

http://www.molecular-cancer.com/content/12/1/72

Insulin have metabolic as well as mitogenic effects. Insulin and Insulin like growth factor-1 have structural similarity. Because of this they can bind to the each other receptor, which brings more aggressive signalling in the cancer cells.

CH metabolism may have influences on tumor growth by ways different to IGF, for example, Krebs cycle products and energy metabolism are not exactly the same in cancer and normal cells, this has been the subject of therapy-focused research.

For sure, things such as a high red meat intake does increase cancer risk, as well as weight gain, all of this has an influence in the Insulin complex of metabolic regulation, but some proposed recently that the noxious effect of /BQs can be mitigated by cooking meat with beer (an effect of the folates and Vit B complex content in beer, coming from yeasts, or a reduction in carcinogen production induced by fire?)

The unexpected beneficial results of the so called 'Paleolitic diet', with most calory intake coming from fat and proteins having an origin in animals (then the product of hunting, the proposal that humans initially competed with vultures for carcasses is far from being proven)

However, probably the same as Hypoxia, effects of diet and diet-related hormone environment on different tumors and on different cells within the same tumors can't never be extrapolated to 100% of tumors of an individual type and to 100% of cells in an individual tumor, the concept of 'alternating' or 'rotating' therapies, that consider that in metastatic cancer, any therapy will select cell clones resistant to the therapy, and thus, it would be wise changing to a drug with a different mechanism of action after, let us say, just 4 courses of therapy, in the usual Schedule of every 21-28 days.

The concepts coming from the libraries of tumor cells used for development of new anti-cancer drugs, markers exist that indicate which type of cell will be resistant to a certain line of drugs, could perhaps also be of help in assessing the complex interactions between energy metabolism, metabolic condition, and growth promoting signaling and pathways in cancer cells. Have a good academic year. Salut †

Dear Dagmar, the exact mechanisms for this association are unknown, but Insulin and insulin-like growth factor (IGF), acting through their tyrosine kinase growth factor cascade and enhancing tumor cell proliferation. This can be considering as a describing for association of obesity and cancer. it has been hypothesized that cells with accelerated rates of division and proliferation are predisposed to the development of cancer and high circulating levels of a potent mitogen such as insulin-like growth factor (IGF)-I, which is produced by insulin order, are associated with increased risk for several common cancers.

Thank you guys.

The epidemiological link between insulin and cancer incidence is that of hyperinsulinemia. This probably accounts for most of the increase in cancer incidence in obese or previously obese subjects. In addition to the fact that high insulin levels are associated with increased cancer incidence, it has other effects. For example, women with high insulin levels at the time of breast cancer diagnosis have a poorer long-term outcome. Insulin is a powerful mitogen and when insulin levels are increased because of insulin-resitance its activity can spill over onto IGF-1 receptors. Like IGF-1 the insulin receptor pathway is also linked to growth via the ERK pathway. Since insulin resistance involves the PI3 kinase pathway this primarily effects the immediate metabolic effects of insulin, such as glucose uptake, rather than the growth effects.

I wonder if, as Insulin levels do have a connection to BMI and total fat tissue in the body, as Fat tissue has the power to metabolize Steroids into more active Sexual-Steroid Hormones, and Hormonal environment has been shown having an influence in the development and outcome of Tumors from tissues that don't have a known relationship in its growth to Sexual Steroid Hormones, if more complex endocrine pathways added to IGFR can be considered in the influence of Insuline in Tumor Promotion and Growth. Thanks. Salut †

Lots of relevant Info:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949481/pdf/nihms218163.pdf

http://erc.endocrinology-journals.org/content/20/1/R1.full.pdf+html

http://cancerres.aacrjournals.org/content/71/13/4484.full.pdf+html

http://www.nutritionandmetabolism.com/content/pdf/1743-7075-8-75.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1819381/pdf/1743-7075-4-5.pdf

file:///C:/Users/Michael%20J/Downloads/Poff_KD_and_HBOT_metastatic_cancer_PLOS1_2013-libre.pdf

I think the role of insulin in tumors/cancer development is purely increases the transport of glucose into the tumor/cancer cells to meet the high demand of energy, as they need a lot of energy for their anaerobic growth.(not aerobic growth).To meet the increased anaerobic needs of enhanced proliferation, cancer cells require both sufficient energy and biosynthetic precursors as cellular building blocks to fuel cell growth. In cancer cells, metabolic pathways are rewired in order to divert nutrients, such as glucose and glutamine, into anaerobic pathways to satisfy the demand for cellular building blocks (Vander Heiden et al., 2009). Accumulating evidence indicates that the reprogramming of tumor metabolism is under the control of various oncogenic signals (Levine and Puzio-Kuter, 2010). The Ras oncogene in particular has been shown to promote glycolysis (Racker et al., 1985; Yun et al., 2009). Constitutive KrasG12D signaling drives uncontrolled proliferation and enhances survival of cancer cells through the activation of its downstream signaling pathways, such as the MAPK and PI3K-mTOR pathways (Gysin et al., 2011). Integrated transcriptomic, biochemical, and metabolomic analyses reveal a fundamental role of the Kras oncogene in reprogramming tumor metabolism by selectively activating biosynthetic pathways to maintain tumor growth. To increase acetylation of KrasG12D may block its functions

of rewiring and diverting nutrients and enables cells going back to the aerobic pathway of healthy cells.

See "Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism" Haoqiang Ying, et al, Cell. Apr 27, 2012; 149(3): 656–670.

This is an excellent discussion. Keep in mind that there are also insulin receptors on tumor cells and some form hybrid receptors with IGF1Rs. The net effect is more anti-apoptotic signaling rather than pro-mitogenic signaling. Local autocrine and paracrine IGF1 and IGF2 secretion are important regulators. This activity synergies with other growth factors and cytokines to enhance tumorigenesis.

Yes, thank you for pointing out some other events also happening with modified insulin receptors. But, as to the question of the role of insulin (not the receptors) in tumors/ cancer development, I did not put these into my answer.

Actually, many factors potentially contribute to the role of  insulin in the development and progression of cancer. These include hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, inflammatory and angiogenic adipokines and cytokines, and the gut microbiome Epidemiological studies have shown that hyperinsulinemia and hyperglycemia associated with type 2 DM are linked to an increased risk of several types of cancer, especially the liver and pancreas.  Hyperinsulinemia and the exposure of the liver to high insulin concentrations in the portal circulation plays the major role. This is because insulin binds to and activates the related insulin-like growth factor-I (IGF-I) receptor (80% homology with insulin receptor. This leads to more potent mitogenic and transforming activities. moreover, insulin decreases IGF-I-binding proteins (IGF-BP1) resulting in increased free IGF-I, the biologically active form of the growth factor. Besides, The action of insulin in malignant cells is favored by mechanisms acting at both the receptor and post-receptor level. Insulin receptors are overexpressed in cancer cells. The IR may be expressed in two different isoforms, A and B. In malignant cells, IR isoform A (IR-A) expression is predominant and its activation, in contrast to the IR-B isoform, causes more mitogenic than metabolic effects. By binding to the overexpressed IR-A, insulin may favor cancer progression and facilitates the growth of tumors by increasing cell proliferation. 

One has to be aware of the many signaling pathways  altered by hyperinsulinemia that are in favor with cancer progression.

Thanks for your insight Samira. What is the differential role of the IR-A and -B isoforms in activating downstream signaling/mitogenic pathways, such as Akt, mTOR and alike? Thanks.

Thank you Paulo for your interest in my comment. As for the activation of downstream signaling/mitogenic pathways, such as Akt, mTOR, it is known that the metabolic actions of insulin are mediated by the PI3 kinase route and the growth actions by MAP kinase. The PI 3-kinase route is predominantly affected in insulin resistance;  hyperinsulinemia produces greater activity via the MAP-kinase route. Many observations indicate that the indirect effects of insulin mediated by IGF-I are likely to be more important than its direct effects.

Accordingly, the IGF signaling pathway plays a leading role in the development and progression of cancers. It has been implicated in carcinogenesis and cancer risk in many studies. The Insulin-like Growth Factor 1 (IGF-1) signaling pathway activates several downstream signals important to cancer development and survival. Once insulin is bound to these receptors it activates downstream targets to promote cell growth and proliferation (Ras/Raf/MEK pathway) and cell survival and cell cycle progression (PI3K/AKT/mTOR pathway). Moreover, IGF signaling has been implicated in regulation of angiogenesis, as this pathway can activate HIF-1α expression and VEGF secretion.  

This is a very interesting discussion. It is important to bear in mind that that insulin and family of insulin like growth factors act on homolgous receptors though their metabolic roles are different. IGFs are mitogens that regulate cell proliferation, differentiation and apoptosis, transformation. Their pathway involves family of IGF binding proteins and proteases for regulation of singalling. When receptor binding activates receptors tyrosine kinase activity, leads to cascade of events leading to activation of downstream signalling through , either PI3K or ras-raf-MAPK signalling ultimately leading to gene-expression. And insulin and IGF1 have been shown to use identical portals for gene expression in a ligand specific manner. And both receptors are now being studied as targets for anti-cancertherapy. So the effect of insulin may also mimic the effect of IGF1 in transformation, proliferations and growth of the tumours besides those discussed above. Ref. below may help.

http://www.ncbi.nlm.nih.gov/pubmed/20360006

http://www.ncbi.nlm.nih.gov/pubmed/24338270

http://jnci.oxfordjournals.org/content/92/18/1472.full