Diabetes Increases Cancer Risk: Here’s How

High blood sugar levels in diabetes predispose to DNA damage and decreased ability by the body to repair this DNA damage, compared to persons with normal blood sugar levels, thereby increasing the risk of cancer.

Highlights:

High blood sugar levels in diabetes predispose to DNA damage and also a reduced ability by the body to repair DNA damage, compared to persons with normal blood sugar levels, thereby increasing the risk of cancer
Increased levels of chemically damaged DNA in the form of a DNA adduct termed N2-(1-carboxyethyl)-2’-deoxyguanosine or CEdG, as well as decreased levels of protein HIF1α involved in the repair of damaged DNA
Better glycemic control and maintaining optimal blood sugar levels can reduce cancer risk in diabetics

High blood sugar levels in diabetes predispose to DNA damage and decreased ability by the body to repair DNA damage, compared to persons with normal blood sugar levels, thereby increasing the risk of cancer, finds recent study undertaken by scientists at City of Hope, a research and treatment center for cancer and diabetes.

The findings of the study were presented by John Termini, Ph.D at the American Chemical Society (ACS) Fall 2019. The ACS happens to be the world’s biggest scientific society and nearly 9500 presentations on wide-ranging topics in science will be featured during this conference.

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‘In diabetes, there are increased levels of chemically modified DNA known as adducts. A DNA adduct termed N2-(1-carboxyethyl)-2'-deoxyguanosine or CEdG was found to be elevated in diabetes. Additionally, the activity of a protein called HIF1α involved in the repair of damaged DNA was found to be reduced. This double whammy might explain why diabetics have increased cancer risk.’
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Elevated Blood Glucose and DNA Damage – Increases Cancer Risk

Currently, it is widely believed that hormonal dysregulation in diabetes increases cancer risk. However, Termini wanted to determine whether increased blood sugar levels found in diabetes could in some way damage DNA leading to instability of the genome and result in an increased risk.

"The most common idea is that the increased cancer risk has to do with hormones," Termini says.

"That’s probably part of it, but there hasn’t been a lot of solid evidence."

Termini and his colleagues checked for possible DNA damage in the form of chemically altered DNA bases, referred to as adducts, in mouse models and tissue cultures of diabetes.
Interestingly, they did find increased levels of a DNA adduct termed N2-(1-carboxyethyl)-2’-deoxyguanosine, or CEdG in diabetic mouse models compared to normal mice
Also, they found that the ability of the cell to fix the DNA damage was impaired
In a recent clinical study, the team also measured levels of CEdG, as well as its counterpart in RNA (CEG), in persons with type 2 diabetes and found raised levels of both compared to normal persons

The findings of the study, therefore, suggest that higher blood sugar levels in diabetes can cause increased DNA damage as well as a reduced ability to repair damaged DNA, thereby increasing cancer risk.

Metformin
Metformin is indicated for treatment of diabetes mellitus (type II) as monotherapy when hyperglycemia cannot be managed on diet alone. Metformin is substantially excreted by the kidney.

Why is DNA Repair Affected in Diabetes

The study team further wished to explore potential mechanisms that may be responsible for the reduced ability of the cells to repair damaged DNA. They found that the activity of two proteins involved in the DNA repair process, namely, HIF1α and the signaling protein mTORC1, was reduced in diabetes. HIF1α stimulates several genes that play a key role in DNA repair

"We found that if we stabilize HIF1α in a high-glucose environment, we increase DNA repair and reduce DNA damage," Termini says. "And mTORC1 actually controls HIF1α, so if you stimulate mTORC1, you stimulate HIF1α."

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Hormonal Dysregulation Theory and Increased Cancer Risk in Diabetes

It is a well-known fact that diabetes increases the risk of cancer nearly two and a half times compared to persons who are not diabetic.

Scientists currently believe that the increased risk of cancer in diabetes is due to hormonal dysfunction.
What happens is, in patients with type 2 diabetes, the activity of insulin is impaired and the pancreas secretes more insulin hormone trying to compensate resulting in hyperinsulinemia
Insulin hormone is also known to stimulate cell growth and proliferation, which if it becomes uncontrolled can cause cancer
Additionally, most people with type 2 diabetes are overweight, and excess fat tissue produces increased levels of chemicals called adipokines that stimulate inflammation, which if chronic can lead to cancer

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Future Plans

Currently, there are many drugs available that are known to stimulate HIF1α or mTORC1 already. The team plan to conduct further studies to check if these drugs may reduce cancer risk in animal models
If the tests are successful, they plan to test the drugs in humans
Metformin, a commonly prescribed anti-diabetic agent also stimulates DNA repair. The study team are also planning to test a combination of metformin and agents that stimulate HIF1α or mTORC1 in animal models

In summary, diabetes may increase cancer risk by increasing damage to DNA as well as impairing the ability of the body to repair the damaged DNA. The study authors recommend that an immediate way to reduce this risk is by achieving optimal glycemic control, although it may not always be easy.

Source-Medindia