DIABETES AND CANCER Part 1

A diagnosis of either diabetes or cancer causes significant stress. Although cancer is not a typical complication of diabetes, there is an increase in the occurrence of cancer in people living with diabetes (PLWD).

In 2009 the American Diabetes Association and the American Cancer Society developed a consensus document to look at the following questions:

1. Is there an association between diabetes and cancer?
2. What risk factors are common to both diabetes and cancer?
3. What are the biologic links between diabetes and cancer risk?
4. Do diabetes treatments influence risk of cancer?

WHAT IS THE ASSOCIATION BETWEEN DIABETES AND CANCER?

The diagnosis of both conditions in the same person occurs more frequently than would be expected by chance. Some cancers occur more commonly in the presence of diabetes (cancer of liver, pancreas and endometrium) and some cancers are less common in the presence of diabetes (prostate). Still other cancers have not been conclusively shown to have an association with diabetes (lung, kidney, non-Hodgkin lymphoma). Currently the association of cancer and Type 1 diabetes is not confirmed. In addition to seeing an increase in the incidence of cancer in PLWD, it seems that diabetes increases the risk of complications and mortality from cancer.

WHAT BIOLOGICAL ASSOCIATION IS THERE BETWEEN DIABETES AND CANCER?

1. Hyperglycaemia. In the 1920’s scientist Otto Warburg observed that cancer cells consume large amounts of glucose as they rapidly divide and proliferate. This is now called the Warburg effect.
2. Hyperinsulinaemia and insulin resistance. Certain cancers possess insulin receptors and stimulation of these by high levels of circulating insulin can directly affect the metabolism of cancer cells, promoting their growth. Insulin also stimulates insulin like growth factor 1 (IGF-1) which promotes cancer cell growth and inhibits cancer cell death. Insulin increases the levels of oestrogen that the body is exposed to which in turn increases the risk of certain cancers such as breast cancer.
3. Inflammation. Many proinflammatory substances (interleukin-6; tumour necrosis factor alpha) can induce malignant changes in cells and cancer progression. Both hyperglycaemia and hyperinsulinaemia cause oxidative stress which in turn causes inflammation. The most common cause of chronic low-grade inflammation is obesity.

WHAT ARE COMMON RISK FACTORS BETWEEN DIABETES AND CANCER?

1. Most people living with Type 2 diabetes are overweight or obese. As mentioned, obesity is a state of low-grade inflammation. The longer overweight or obesity is present, the greater the risk of developing cancer. The Centre for Disease Control (CDC) in America lists 13 cancers more commonly seen in people living with obesity: oesophageal, breast in post-menopausal women, colon and rectum, uterus, liver, stomach, kidneys, gallbladder, ovaries, pancreas, thyroid, multiple myeloma and a type of brain cancer called meningioma.
2. The incidence of most cancers increases with age with an estimated 78% of all newly diagnosed cancer occurring in people over the age of 55 years.
3. In general men are slightly more at risk of developing cancer than women and in turn have a higher incidence of type 2 diabetes.
4. Statistics show that in the USA, African Americans develop and die from cancer more than other racial groups. This may be due to a variety of factors such as socioeconomic status as well as genetic factors.
5. Tobacco smoking causes over 70% of all respiratory cancers and is a strong risk factor in many other cancers. In addition, studies suggest that smoking is an independent risk factor for developing Type 2 diabetes and we know smoking will always worsen the complications of diabetes.
6. Even if alcohol is consumed moderately it is associated with an increased risk of cancers such as mouth, throat, gastrointestinal and breast. Moderate alcohol consumption may be protective against the development of diabetes, but excess alcohol is a diabetes risk.
7. Sedentary lifestyle. There is a definite link between lack of physical activity and the risk of type 2 diabetes and cancer.

DO DIABETES TREATMENTS INFLUENCE THE INCIDENCE OF CANCER AND CANCER PROGNOSIS?

Good glucose control lowers the risk of complications and possibly cancer too. The influence of the various drug treatments are as follows:

1. Metformin. At diagnosis all people with Type 2 diabetes are prescribed metformin and this continues lifelong unless it cannot be tolerated, or kidney function drops below a certain threshold. Metformin reduces circulating levels of glucose and insulin by reducing the production of glucose in the liver. Studies have shown that metformin inhibits the growth and proliferation of cancer cell lines. Other research has demonstrated that metformin can selectively kill certain cancer stem cells, improving the effectiveness of the anticancer regimen. This has been particularly described in breast cancer. There is significant evidence to show that PLWD who are on metformin are less likely to get cancer than PLWD that do not take metformin. Additional observational data also suggests that PLWD taking metformin who do develop cancer are more likely to go into remission. Metformin is sometimes used as an adjuvant treatment in a cancer regimen even in people without diabetes, particularly with breast cancer therapy.
2. Thiazelidiones. These are medications that work in the liver to treat insulin resistance. Pioglitazone is the only one available in South Africa. Results of studies are conflicting whether these drugs decrease, increase or do not affect cancer risk.
3. Sulphonyureas. There is very little data to suggest any benefit or risk in this group of medications.
4. Incretins. These are medications such as the injectables liraglutide, semaglutide and dulaglutide. They bind to the GLP1 (glucagon like peptide-1) receptor which results in lower glucose levels and weight loss. Liraglutide showed an increased risk of medullary thyroid cancer in rats. The risk of this cancer remains a black box warning. A study published in the British Medical Journal in April 2024 calculated that there was very little increase in risk for thyroid cancer in patients using GLP1 receptor agonists. However, if there is a history of thyroid cancer or a family history of thyroid cancer the PLWD may still be advised not to use this therapy.
5. Insulin. As mentioned above, we know that high levels of insulin can be implicated in causing cancer. Naturally, PLWD who must inject insulin to treat their diabetes will be concerned. To date there is no definite proof that insulin as a therapy causes cancer.