by Megan L Norris
figures by Bradley Wierbowski
The emerging link between cancer and diabetes
In the early 2000s, observations that diabetics are more likely to get cancer than non-diabetics began piling up. Was this because diabetes and cancer share general risk factors such as diet, aging and obesity? Or was there a direct link between them, with cancer benefiting from the sugar-rich and inflamed environment brought on by diabetes? Making bad news worse, it became apparent that cancer thrives in the presence of excess insulin, like that injected by many diabetics as therapy. Thus, one of the ways to treat diabetes could be making the cancer risk even worse.
Almost as soon as this dark cloud began to loom, rays of light broke through from an unexpected source. Research on a popular type II diabetes treatment called metformin revealed that metformin actually seemed to lower the risk for colorectal and other cancers in diabetics. Though it may seem paradoxical that metformin and insulin injections, two treatments for the same disease, could have such opposite effects on cancer, years of research in both the clinic and the laboratory has begun to pull back the curtain on this mystery. Broadly speaking, metformin makes the body more sensitive to the insulin it already is. For type II diabetics, not only does this increased insulin sensitivity treat diabetes, but it drains the fuel on which some cancers may thrive.
Diabetes is a pervasive disease
Diabetes is the 7th leading cause of death in the US and is on the rise. More than 10% of Americans over 20 years old have diabetes, with type II diabetes accounting for 95% of those cases. Untreated, diabetes leads to excessive amounts of glucose in the blood, a state called hyperglycemia, which can damage organs such as the heart, kidney and nerves.
In a non-diabetic individual following a meal, sugars and starches break down into glucose, which circulates in the blood. Beta-cells in the pancreas release insulin to trigger the movement of glucose out of the bloodstream and into cells where it can be used or stored. As shown in Figure 1, when no insulin is produced (type I diabetes) or is produced but not sensed correctly (type II diabetes), glucose amounts remain elevated in the blood causing dangerous hyperglycemia.
In addition to high blood glucose, diabetics also have a condition called hyperinsulinemia, which refers to excessively high amounts of insulin in their bloodstream. Since type I diabetes is marked by the body’s inability to produce insulin, a common treatment is insulin injection. Fine-tuning both the concentration and timing of these injections, and properly mimicking what a non-diabetic body can do, has proven a great challenge. As a result, these injections lead to significantly higher insulin levels than a non-diabetic would ever experience, resulting in hyperinsulinemia. Conversely, type II diabetics can make their own insulin, but their body isn’t sensitive to it. As a result, their bodies often pump out more and more insulin, resulting in a nearly constant state of hyperinsulinemia.
Additionally, this constant demand on the beta-cells can cause them to wear out and lose their ability to make insulin at all; patients who experience this are often given the insulin injections more common to type I diabetics, perpetuating their hyperinsulinemia through a different means. These elevated insulin levels are much less toxic to organs as compared to excess glucose, so the fact that treating hyperglycemia can lead to hyperinsulinemia, though not ideal, has been historically viewed as a considerably lesser evil.
Cancer runs on insulin
How could diabetes be affecting cancer? The simplest possibility is that what makes a person predisposed for diabetes is the same as what makes them predisposed for certain cancers, such as obesity and age. In this scenario, shown in Figure 2, one disease isn’t causing the other. Rather, both diseases simply capitalize on the same health situations. Though shared predispositions and risk factors may certainly explain some of the co-occurrence between diabetes and cancer, doctors and researchers are collecting mounting evidence that implicates diabetes as having a more direct role in increasing the risk of cancer. For one, cancer cells require a lot of energy to grow, divide, and spread. Importantly, one of cancer’s most vital energy sources is glucose, meaning that the high blood glucose levels in many diabetics could greatly benefit the growth and progression of cancer. More striking, however, is that insulin has been found to promote tumor growth and metastasis. Though this happens in diabetics and non-diabetics alike, people with diabetes have especially high levels of insulin in their blood, which could make for extra fertile grounds for cancer progression (Figure 2). As such, the insulin injections aimed at treating diabetes may also be increasing cancer risk.
Metformin treats diabetes without giving cancer a leg up
With the excess glucose and insulin present in diabetics and cancer potentially thriving off of both, must diabetics just live with an increased cancer risk? Enter metformin: the first-choice drug to treat type II diabetes. The exact way that metformin works is still being explored, but in the last two decades we have learned that metformin seems to have two important, and likely overlapping, methods of action. First, it sensitizes the body to insulin and, second, it coerces cells to make more energy (see Figure 3).
By increasing sensitivity to insulin, metformin helps type II diabetics start using the insulin already present in their bodies. This results in decreased insulin levels, which many researchers believe is how metformin is affecting cancer. This also means that metformin requires some insulin to be present in order to work best, so it alone may not be able to treat type I diabetics. However, it has recently been proposed to treat type I diabetes with a mix of insulin therapy and metformin, with the hope that lower concentrations of insulin would be required. In either case, after cells are treated with metformin and begin responding better to insulin, the cells can remove glucose from the blood to make cellular energy, thereby decreasing hyperglycemia and treating diabetes.
Cancer as a metabolic disease
Insulin and glucose are both metabolites, meaning that they are produced as byproducts of metabolism — the processes that all cells perform to obtain energy. The realization that cancer is tightly linked to metabolism only came to light in the early 2000s from unexpected, and seemingly unrelated, sources. While one group of researchers in Scotland was studying the basics of metabolism in yeast, separate groups across the world were studying cancer in rats, humans and frogs. Unexpectedly, the groups realized that they were all studying the same genes. Nearly simultaneously, one of the same genes was predicted to be the target of metformin. When all the pieces were put together, the idea that metformin could treat diabetes and cancer began to make sense.
Today, the data demonstrating the efficacy of metformin protecting against cancer is clear. A 2015 paper in the journal Cancer revealed metformin treatment decreased the chance of colorectal cancer in diabetics by 12%. Other studies demonstrated metformin selectively blocks tumor growth, can suppress cancer-promoting genes and provides a reduced risk of cancer in general. Intriguingly, some data suggests that, for certain cancers, this protective effect is only seen in diabetic settings. That is, cancers that are thriving from the hyperinsulinemic environment were treatable with metformin, while other cancers were not affected. Research into which cancers are likely to be susceptible to metformin is ongoing and relies heavily on understanding with more detail just how metformin is working. Ideally, we will soon know exactly how metformin is impacting insulin, metabolism and cancer.
Basic science makes big discoveries
The case of metformin is not unique. The more scientists follow the rabbit hole of basic research, which is research targeted at fundamental biology as opposed to medicine or disease, the more we equip our researchers in the clinic to make important, perhaps startling, medical advancements. Though possibly a pervasive idea, it is inaccurate to think we would be better off if we focused all our research efforts on disease. We have certainly come a long way, but with each decade of basic research, we uncover things cells do that we could have never predicted the decade before. Though aiming research directly at a disease is of course useful, persevering in our understanding of the foundations of biology is both crucial and expedient to making meaningful medical discoveries.
Megan L Norris is a 5th year PhD student in the department of Molecules, Cells and Organisms at Harvard University.