Insulin resistance has previously been overlooked but is now gaining recognition for how it can potentially affect health outcomes. A new study sheds light on the metabolic changes associated with cancer and suggests that insulin resistance could contribute to the development of other diseases among people with cancer. Exercise shows promise as a possible approach to improving insulin sensitivity and overall well-being.
In the 1990s, journals published a flurry of articles as researchers realised that people with cancer had higher insulin resistance than expected – in some cases, as severe as people with type 2 diabetes. At the time, scientists did not know what to make of these unusual readings, and their research appears to have been abandoned.
“They did not know this was actually a phenomenon that could have implications for patients at the time. The clinical relevance of these findings is only being recognised now,” says Lykke Sylow, Associate Professor of Biomedical Sciences at the University of Copenhagen, who studies molecular metabolism in cancer and ageing. Today, “we know that if you have type 2 diabetes and cancer, you are less likely to survive,” Sylow says. Could insulin resistance affect health outcomes?
A new article, published in February in Acta Oncologica, examines the research from the 1990s and more recently through the lens of current understanding of diabetes and cancer. This unexplained insulin resistance could be “an underlying reason why people with cancer develop so many other diseases,” Sylow says – and suggests avenues for potential treatment.
Cancer, a metabolic hijacker
Cancer dramatically rewires the body’s metabolism. Tumours – which are fundamentally areas of runaway cell division and growth – are energetic vampires, “and we know that the cancer takes up substantial glucose, its main fuel,” Sylow says. People with certain kinds of cancer, including lung, colorectal and pancreatic cancer, “have a monumental breakdown of tissues, a breakdown of muscle mass and fat mass”.
But Sylow and Joan Màrmol, a master’s student in her lab who researches the metabolic disturbances related to cancer, suspect that an unidentified metabolic change might be causing the insulin resistance identified in the 1990s.
Clouding the issue is the uncertainty surrounding how the metabolism of people with cancer might change since they are not routinely tested for insulin resistance. Normal glucose tests – through a blood draw or the finger-pricks so familiar to people with diabetes – cannot detect insulin resistance since glucose levels generally remain steady as long as the pancreas can compensate by releasing more and more insulin.
Like trying to keep the water in a bathtub
People with cancer are unlikely to suspect anything has changed since the symptoms of insulin resistance are quite subtle – “you do not notice it very much,” Sylow says. “You can go to the toilet often, you can be tired – and those can be ascribed to so many different things,” including cancer treatments.
Instead, the gold standard for detecting insulin resistance is the hyperinsulinaemic-euglycaemic clamp method, Màrmol explains. It is called a clamp because the key is holding blood sugar constant – and thus revealing sensitivity to insulin.
In a hyperinsulinaemic-euglycaemic clamp, the person’s system is flooded with insulin, which signals to the body to take glucose out of the bloodstream and store it in fat or skeletal muscle. But a second line into the body simultaneously pumps in additional glucose. The hyperinsulinaemic-euglycaemic clamp is like trying to keep the water in a bathtub at the same level – with both the stopper removed and the tap on.
If the body responds appropriately to insulin, lifting the stopper is easy and glucose is removed from the bloodstream like water going down the drain. A person with good insulin sensitivity needs considerable additional glucose to keep levels constant – a healthy pressure from the tap. Meanwhile, a person with insulin resistance – a sticky stopper – will need just a trickle from the glucose tap to keep levels constant.
As severe as diabetes
For their meta-analysis, the authors identified 15 studies from 1987 to 2018 that used the hyperinsulinaemic-euglycaemic clamp on people with many types of cancer, from pancreatic cancer to thyroid and lung cancer. They quickly realised that across the board, the people with cancer were more insulin resistant than would be expected for their age and weight.
Strikingly, the researchers found that the mean level of insulin resistance across the studies was “similar to or even higher” than people diagnosed with type 2 diabetes.
Why this would be is still very much unclear, Sylow explains. The tumour itself could produce insulin resistance, but it could equally be a product of cancer treatment – chemotherapy, radiation or glucocorticoids. Unfortunately, the studies included in the meta-analysis did not track the treatments or even how much time had elapsed since diagnosis.
It could also be a chicken and egg situation, Sylow points out – “we do not know whether they actually had insulin resistance before they got cancer,” she says. “Insulin resistance and all other types of metabolic dysfunction are clear risk factors for later developing cancer.”
A potential avenue for treatment
Sylow says she does not want people with cancer to see this new information and despair – insulin resistance might only affect a small minority.
The first order of business for researchers will be to better define who is at risk for cancer-related insulin resistance, the authors say – what types of cancer are most strongly associated and what types of people might be most vulnerable. “There is no quick, cheap measure of insulin resistance at the moment,” Sylow says, so screening everyone with cancer is not feasible.
Another area for future study is whether the insulin resistance developed during cancer and treatment is lasting. “A lot of evidence in mice shows that the treatment of cancer causes insulin resistance,” Sylow says. “This insulin resistance is reversible.”
And of course, the key will be determining whether treating the insulin resistance improves health outcomes.
There is already one promising avenue of treatment, although it can be a big ask for people with cancer. Exercise can improve the body’s response to insulin and is already recommended to people undergoing or recovering from cancer treatment because of other health benefits. Sylow says you do not have to be training for a marathon – “any level you can get away with,” even very light exercise once a week, seems to make a meaningful difference.