Increased adiposity after menopause has been associated with an increase in breast cancer. One of the keys would be hyperinsulinism.
Diabetes/insulin resistance and breast cancer are well-differentiated pathologies, but the insulin pathway plays a central and typical role in both. By identifying this metabolic alteration, we will act using our best weapons: diet, exercise, and metformin.
Insulin is a peptide hormone produced by the beta cells of the pancreas when plasma (blood) glucose rises.
This hormone stimulates glucose uptake by muscle and adipose tissue. Insulin inhibits gluconeogenesis (glucose formation) and glucose release in the liver.
High glucose levels cause the liver and muscles to store excess glucose.
In adipocytes, insulin promotes the transport of fatty acids from the bloodstream, their storage (lipogenesis) and inhibits lipolysis. In short, insulin facilitates energy storage to be mobilized when insulin levels are low (fasting).
Besides the organs, as mentioned earlier, insulin will also exert actions on neurons, endothelial cells (cells that line the vessels), and immune cells.
So as not to get lost in the concepts, let’s briefly review the insulin pathway.
Insulin binds to the insulin receptor and activates cell signaling pathways that are critical regulators of cellular homeostasis. These signaling pathways are altered in most biologically aggressive cancers.
Under nutrient-rich circumstances, insulin is released and binds to the insulin receptor. Insulin binding promotes tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS). The IRS, in turn, phosphorylates phosphatidyl inositol-3-kinase (PI3K) and activates AKT/mTOR signaling.
Insulin also activates insulin/IGF-1 signaling. IGF-1 binds to its receptor leading to phosphorylation cascades that activate the PI3K/AKT/mTOR pathway and the ras/RAF/ mitogen-activated protein kinase (MAPK) pathway.
Overfeeding alters energy storage and consumption balance, leading the individual to prediabetes ( insulin resistance ) and later to type 2 diabetes mellitus. Maintaining high insulin levels due to this over-intake produces desensitization at the skeletal muscle level. The pancreas is forced to produce insulin continuously, and eventually, those beta cells will die (phase in which the person with type 2 diabetes mellitus will require insulin).
Hyperinsulinism in the liver causes dyslipidemia (increased LDL cholesterol and triglycerides) and favors the development of fatty liver (hepatic steatosis).
The sustained increase in insulin stimulates appetite in the brain, favoring weight gain. In skeletal muscle, hyperinsulinism and insulin resistance means that the strength cannot take advantage of glucose. Thus the affected person will have less tolerance for physical exercise, also reporting fatigue.
In adipose tissue, hyperinsulinism increases lipid accumulation and causes inflammation.
In the blood vessels and kidneys, insulin promotes endothelial cell damage and kidney dysfunction due to increased synthesis of nitric oxide, reactive oxygen species, and decreased cell adhesion.
Insulin and cancer
Next, we will cite the mechanisms that relate to hyperinsulinism and tumorigenesis :
- Glycolysis: The PI3K/AKT/mTOR signaling pathway regulates glucose metabolism and aerobic glycolysis. Aggressive cancers are glucose-dependent and produce much energy through aerobic glycolysis (Warburg effect) and not through the Krebs cycle (mitochondrial oxidative phosphorylation).
- Oxidative stress: reactive oxygen species (ROS) are increased. These can damage DNA, initiate cancer or promote its progression.
- Cellular mobility: by activating the MAPK and PI3K/AKT pathways. Modulation of cytoskeletal proteins occurs, including vimentin and actin.
- Epithelial-mesenchymal transition (EMT).
- Inflammation: due to an increase in inflammatory cytokines, which, among other effects, can favor the formation of new vessels (angiogenesis). In addition, activation of M2 macrophages causes them to secrete epithelial growth factor (EGF) and tumor growth factor-beta (TGFbeta), both of which are involved in invasion, metastasis, and cell turnover. The activation of these pathways is related to a poor prognosis in triple-negative breast cancer.
- Angiogenesis: Insulin activates pathways that increase the production of vascular growth factors.
Prevention and treatment of insulin resistance, metformin you will take.
Metformin is a widely prescribed oral hypoglycemic drug. It is the first-line treatment in type 2 diabetes, and its use is also approved to treat polycystic ovary and gestational diabetes. Metformin is relatively well tolerated, although it can cause diarrhea, nausea, and epigastric pain in some people.
This drug inhibits hepatic glucose production, increases insulin sensitivity, and decreases intestinal glucose absorption, all of which favors the decrease in circulating insulin. Its anti-cancer potential would be explained precisely by that.
It is essential that, when insulin resistance, fasting hyperinsulinism, prediabetes, or type 2 diabetes mellitus is detected, we begin to act through dietary control, caloric restriction, physical activity, and, if necessary, the use of metformin.
The cited article focused on breast cancer, but these mechanisms would also be involved in other types of cancer. Oncologists should monitor this metabolic alteration closely as it could prevent the onset of cancers, improve patient outcomes, and prevent recurrences.