Pancreatic cancer and diabetes – a cellular case of chicken and egg

We’ve all heard the age-old question about the chicken and the egg.

Well scientists studying the link between diabetes (a condition where the amount of glucose in your blood is too high because the body cannot use it properly) and pancreatic cancer are facing a similar conundrum. It seems there’s a link between the two conditions, but it’s not clear which one comes first.

While the majority of people with diabetes will never develop pancreatic cancer, the question of whether diabetes could be a cause or a consequence of pancreatic cancer is an important one.

Answering this could help scientists better understand the biology of these two conditions, and might help spot people at higher risk of pancreatic cancer.

So, as it’s pancreatic cancer awareness month, we’ve dug into the evidence to see what is known about these links, and which questions remain unanswered.

We know there’s a link

Doctors first started exploring the possibility of a link between diabetes and pancreatic cancer in the 1940s and 1950s.

Several reports had come out saying that patients with pancreatic cancer were more likely to also have diabetes than other people. This has been shown for type 2 diabetes as well as type 1 and young onset diabetes.

Since then, many studies have shown a link between the two conditions. Overall, it seems that people with diabetes are around twice as likely to be diagnosed with pancreatic cancer than the general population.

And this makes sense, given that diabetes and pancreatic cancer are diseases that both affect the pancreas.

The next big question is: how does this work? Does diabetes increase a person’s risk of pancreatic cancer or is it the cancer that causes diabetes? Or is there something else increasing the risk of both conditions?

How pancreatic cancer could cause diabetes

8 in 10 people with pancreatic cancer have some level of intolerance to sugar, and up to 5 in 10 have diabetes.

In cancer patients who do have diabetes, the condition is often diagnosed shortly before, or after, their cancer diagnosis, suggesting that the diabetes is a symptom of the developing cancer, rather than its cause.

As the cancer may affect the insulin producing cells, or cause the insulin to be less effective, diabetes can sometimes be the first symptom [of pancreatic cancer]

– Dan Howarth, Diabetes UK

Dan Howarth, head of care at Diabetes UK, says that while it’s not yet known to what extent the diseases are linked, there is clearly a link.

“Although the evidence is mixed in terms of numbers, there are many studies which suggest that a small proportion of people with type 2 diabetes develop cancer of the pancreas within a year following their diabetes diagnosis.”

In 2015, the National Institute of Health and Care Excellence (NICE) added newly diagnosed diabetes together with weight loss in a person over 60 to the list of ‘red flags’ that should lead to a doctor sending that patient for a scan to look for pancreatic cancer.

But exactly how a growing cancer could result in sugar intolerance and diabetes is still a matter of debate.

The pancreas is responsible for producing hormones such as insulin, which regulate the amount of sugar in our blood. One theory is that changes in the pancreas caused by a growing tumour may affect the levels of insulin in the body, because the normal functions of the cells in the pancreas are disrupted.

“As the cancer may affect the insulin producing cells, or cause the insulin to be less effective, diabetes can sometimes be the first symptom [of pancreatic cancer],” says Howarth.

An interesting finding that supports the theory that diabetes could be a symptom of pancreatic cancer is the fact that in some cases the diabetes symptoms disappear, or at least improve, once the cancer is removed.

But there are other bits of research that tell a different story.

The other side of the story

Studies have shown that people with diabetes remain at a higher risk of pancreatic cancer, even many years after their diabetes is first diagnosed.

And there’s also some evidence of an increased risk of pancreatic cancer in people with type 1 and young onset diabetes, who’ve had diabetes almost all their life.

This suggests that the diabetes may not be a symptom of cancer. So could it be a cause?

Some of the hallmarks of diabetes are changes in how cells make and process energy (metabolism), increases in certain hormones, and persistent inflammation. All of these can have cancer-promoting effects, stimulating cells to grow and divide, which could in some cases increase the risk of pancreatic cancer developing.

So what comes first?

At this moment in time we do not have a definitive answer to the question of what comes first – diabetes or pancreatic cancer. Much like the chicken and egg debate, there is evidence for either side.

In fact, some researchers are now suggesting that the answer may actually be both.

In some people, diabetes may develop as a result of pancreatic cancer interfering with how the pancreas works. This is probably the case for patients who are diagnosed with pancreatic cancer shortly before or after being told they have diabetes.

In a small number of other cases, diabetes may eventually lead to pancreatic cancer. This could be the case in those who have lived with diabetes for a longer time and are diagnosed with pancreatic cancer many years after finding out they have diabetes.

One of the biggest challenges scientists are facing now is how to design the best study to answer these questions.

Both conditions are difficult to spot early and can go undiagnosed for many years. So studies that look at which was diagnosed first, before making links between the two, will have pitfalls.

And that’s not the whole story

Diabetes and pancreatic cancer also share several common risk factors. For example, both are more common in older age, both are linked to being overweight or obese, and the risk of both is affected by smoking and by how much alcohol we drink. This makes it harder for scientists to study how the two conditions are linked.

And the whole thing is further complicated by the fact that different drugs people take to control their diabetes also seem to affect their risk of pancreatic cancer. Different diabetes drugs, for example, may lower or raise the risk of this cancer.

Research suggests that metformin (Glucophage) and statins can reduce the chances of developing pancreatic cancer, while sulphonylureas may increase the risk.

There is not enough evidence to suggest that diabetes medications cause pancreatic cancer

– Dan Howarth, Diabetes UK

Evidence for the effects of drugs such as sitagliptin (Januvia) and vildagliptin (Galvus) on pancreatic cancer risk is still growing, as these drugs are relatively new. So far most studies show that these drugs seem to have no effect on pancreatic cancer risk, but studies that follow patients for longer periods of time are needed to confirm this.

Insulin – another medication used to control diabetes – also appears to increase the risk of pancreatic cancer, at least in the short term.

In the long term there is some conflicting evidence that seems to point to a protective effect, meaning it seems to reduce the risk.

But all these studies need to be interpreted with care, as they have flaws that could reduce the strength of their findings.

“There is not enough evidence to suggest that diabetes medications cause pancreatic cancer,” explains Howarth. “Previous studies have linked this, however there were many limitations to these studies and this area of research continues.”

And importantly, all these medications are vital for patients to manage their diabetes, with a recent study suggesting that those who control their blood sugar levels well may be at lower risk of pancreatic cancer than those who don’t.

So even if a medication could increase pancreatic cancer risk, the benefits of taking it are likely to outweigh any harms.

“Patients should not stop their medication, unless advised by their doctor,” says Howarth.

“If not managed, diabetes can lead to serious complications such as kidney disease, blindness, nerve damage and amputations. As well as heart attacks and strokes.

“For this reason taking care of diabetes and continuing medications is highly important and is likely to prove more beneficial than stopping them due to a small risk of cancer of the pancreas.

“At the same time, vigilance is required of patients on such therapies, for any side effects suggestive of pancreatic disease.”

What should we make of all this?

The conclusion is that it’s still not clear yet whether diabetes is a cause, or consequence, of pancreatic cancer. It seems likely that it can actually be either, depending on each individual case.

What’s important is that people affected by diabetes don’t panic. Someone who has diabetes won’t necessarily also develop pancreatic cancer.

In fact, less than 2 in 100 people with diabetes are diagnosed with pancreatic cancer in the 3 years after being told about their diabetes. And the more time that elapses after the diabetes diagnosis, the less likely it is that someone will develop pancreatic cancer – although their risk is still a little higher than that of someone who doesn’t have diabetes.

“The number of pancreatic cancer cases is small, which means although a higher risk than the general population, a relatively small risk for people with diabetes,” confirms Howarth.

And there could be benefits

There are also some benefits to knowing that there’s a link. For example, spotting a new case of diabetes could be used as a way to identify people at higher risk of pancreatic cancer so they can be monitored for changes that could be signs of the disease.

And due to its cancer risk reducing effects, the anti-diabetic drug metformin is being trialled as a possible cancer treatment, together with chemotherapy, to manage pancreatic cancer.

While the chicken and egg question hasn’t been resolved yet, in time the link between diabetes and pancreatic cancer will be understood more clearly.

And this will open up new ways to help those affected by these conditions.

In the meantime, our researchers are also working hard to find new ways to treat pancreatic cancer.

Jana Witt is a health information officer at Cancer Research UK