Many people with cancer have type 2 diabetes, and many people with diabetes develop cancer. Researchers now have a clearer idea of how these two diseases are linked.
People who are obese or have type 2 diabetes have an increased risk of developing cancer. But people with cancer also have a greater risk of developing type 2 diabetes.
New Danish research shows that poor regulation of lipolysis – how the body metabolizes fat – and how this affects glucose metabolism are probably what links the two diseases.
More precisely, the research shows that cancer takes over various functions of the body and induces several metabolic perturbations, including reducing insulin sensitivity and increasing the production of glucose in the liver. Both can lead to developing type 2 diabetes.
“We initially thought that cancer-induced inflammation might have caused the reduced insulin sensitivity in our study, but this turned out not to be the case. Instead, cancer appears to cause the body to secrete more fat into the blood, which can lead to insulin resistance. This benefits a cancer cell but not the person with cancer,” explains author Lykke Sylow, Associate Professor, Department of Exercise, Nutrition and Sports, University of Copenhagen.
The research has been published in Metabolism.
Insulin and glucose fuel cancer cells
Several previous studies have suggested that insulin and glucose may promote the growth of cancer.
Insulin is a growth hormone, and cell studies have shown that high levels of insulin and glucose cause cancer cells to grow faster.
Elevated levels of insulin establish better conditions for cancer cells to grow. This applies to people with prediabetes because high blood glucose creates a need for more insulin.
In addition, the rapidly growing cancer cells need lots of glucose to grow.
“Our goal was to investigate whether there is a mechanism that enables cancer cells to affect metabolic function throughout the body,” explains Lykke Sylow.
Cancer destroyed the metabolic functioning of mice
The researchers gave mice lung cancer and subsequently observed whether they developed various metabolic disorders, such as ones affecting the liver’s glucose production and insulin sensitivity in the adipose tissue and skeletal muscles. These disorders are common among people with prediabetes or obesity.
The researchers did this by giving the mice insulin and investigating how it lowers blood glucose, which happens when insulin causes fat and skeletal muscles to absorb glucose.
In mice with cancer, however, the intake of glucose was markedly reduced, and the liver also produced more sugar.
“We measured the metabolism of the mice using seven parameters and found perturbations on six metabolically essential functions when the mice had cancer,” says Lykke Sylow.
Cancer shuts off the blood flow to muscles
The researchers also found that some capillaries in the muscles did not open in the cancer-affected mice, which they usually do after a meal when the insulin is circulating in the blood.
The capillaries open during a meal to ensure that muscle and fat tissue have access to the nutrients in the bloodstream.
This is an important process for absorbing glucose into the muscles.
But the researchers examined the cancer-affected mice and found that this did not happen.
“This does not happen when the mice have cancer. This is very noticeable and typical for people who are very insulin resistant,” explains Lykke Sylow.
Cancer regulates fat metabolism
Lykke Sylow believes that cancer probably even regulates all the metabolic processes to create as favourable conditions for itself as possible.
The more insulin and sugar that circulates throughout the body, the better the conditions for the rapidly growing cancer cells.
The question is how they do this.
Both mice and people with cancer have elevated circulating fatty acids in the body, so they release more fat from adipose tissue into the blood than healthy people.
The researchers inhibited the lipolysis of adipose tissue in the mice and prevented them from becoming insulin resistant.
“We believe that this may be the mechanism the cancer cells use. They influence fat metabolism, which affects insulin sensitivity, which affects the glucose levels in the body. For the cancer cells, this is smart because the glucose bypasses the muscle and fat and the cancer cells then get more for themselves,” explains Lykke Sylow, who also emphasizes that this is the first step towards understanding the link between cancer and metabolic perturbations and that further research is required.
Applying experiments to people
The next step in the research is to investigate whether the findings in mice can be replicated among people.
Lykke Sylow would also like to investigate whether the discovery is only relevant for lung cancer or whether other types of cancer also regulate metabolic function to benefit themselves.
Breast cancer and colorectal cancer have also previously been linked to impaired metabolism.
The researchers from the University of Copenhagen are currently examining women who have been diagnosed with breast cancer and are looking for changes in fat metabolism after chemotherapy.
“Determining whether the results also apply to people is very important. Mice end up with a tumour so large that people would never experience anything similar. We must therefore determine whether our findings are also clinically relevant,” says Lykke Sylow.
Metabolic treatment might become cancer treatment
According to Lykke Sylow, the perspective in the new research is that the discovery can be rapidly implemented clinically, so doctors immediately screen people with cancer for metabolic syndrome, a precursor of type 2 diabetes.
“People with metabolic syndrome can be given glucose-lowering medication and be advised to exercise more. Improving their metabolic function may benefit cancer treatment,” says Lykke Sylow.
She elaborates that 10–50% of women who have been treated for breast cancer experience relapse. The risk of relapse is three times greater for women who have metabolic syndrome than for women who do not have it.
“This is very relevant clinically for improving people’s outcomes. People have a greater risk of dying from cancer if they also have metabolic syndrome. In the future, we might be able to test whether increasing the insulin sensitivity among people with cancer can prevent relapse after initial treatment,” says Lykke Sylow.
“Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion” has been published in Metabolism. In 2018, the Novo Nordisk Foundation awarded a grant to Lykke Sylow for the project Identifying Key Orchestrators of Pathways in the Interactions between Metabolism, Insulin Sensitivity and Muscle Wasting.
