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How Diabetes Can Increase Cancer Risk



  Diabetes
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For years scientists have been trying to solve a medical puzzle: Why do people with Type 1 or Type 2 diabetes have an increased risk of developing certain cancers? Researchers today report a possible explanation for this double stroke. They found that DNA suffers more damage and is repaired less frequently when blood sugar levels are high than normal, healthy blood sugar, which increases the risk of cancer.

Researchers will present their findings at the National Meeting & Exposition of the American Chemical Society (ACS) in the fall of 201

9.

"It has long been known that people with diabetes are up to 2.5 times more likely to have certain types of cancer," says John Termini, Ph.D., who presented the work at the meeting. These cancers include ovarian cancer, breast cancer, kidney cancer and others. "As the incidence of diabetes continues to increase, the cancer rate is also likely to increase."

Scientists have suggested that the increased cancer risk for diabetics is due to hormonal dysregulation. "In people with type 2 diabetes, their insulin does not effectively transfer glucose into the cells," explains Termini. "So the pancreas is producing more and more insulin and getting what's called hyperinsulinemia." In addition to controlling blood sugar levels, the hormone insulin may stimulate cell growth and potentially lead to cancer. In addition, most people with type 2 diabetes are overweight and their excess adipose tissue produces more adipokines than those with a healthy weight. These hormones promote chronic inflammation associated with cancer. "The most common idea is that the increased cancer risk has to do with hormones," says Termini. "That's probably part of it, but there was not much solid evidence."

Terms of City of Hope, a cancer and diabetes research and treatment center, had a different idea. He wondered if high blood sugar levels in diabetes could damage the DNA and make the genome unstable, which could lead to cancer. Termini and colleagues therefore looked for a specific type of damage in the form of chemically modified DNA bases, so-called adducts, in tissue culture and rodent models for diabetes. In fact, they found a DNA adduct named N 2- (1-carboxyethyl) -2'-deoxyguanosine or CEdG that was more prevalent in diabetic models than in normal cells or mice. In addition, high glucose levels affected the process of cell fixation. "Exposure to high glucose levels leads to both DNA adducts and their repair suppression, which, when combined, can lead to genome instability and cancer," says Termini.

Recently, Termini and colleagues completed a clinical trial measuring CEdG levels and its counterpart in RNA (CEG) in people with type 2 diabetes. As in mice, people with diabetes had significantly higher CEdG and CEG levels than people without the disease.

But the team did not stop here. They wanted to find out the molecular reasons why the adducts were not properly fixed by the cells. They identified two proteins that appear to be involved: the transcription factor HIF1α and the signaling protein mTORC1, both of which are less active in diabetes. HIF1α activates several genes involved in the repair process. "We have found that stabilizing HIF1α in a high-glucose environment will increase DNA repair and reduce DNA damage," says Termini. "And mTORC1 actually controls HIF1α, so if you're stimulating mTORC1, you're stimulating HIF1α."

According to the terms, there are already several drugs that stimulate HIF1α or mTORC1. The researchers want to find out if these drugs reduce the risk of cancer in animal models for diabetics and if so, test them on humans. Termini states that metformin, a widely used anti-diabetes drug that helps lower blood sugar levels, also stimulates DNA repair. "We are trying to test metformin in combination with drugs that specifically stabilize HIF1α or enhance mTORC1 signaling in diabetic animal models," he says. In the meantime, better control of blood sugar for diabetics could be a more immediate way to reduce their cancer risk. "That sounds like a simple solution, but for most people it's extremely difficult to maintain glycemic control," says Termini.


High blood sugar increases the pancreatic cancer rate


Further information:
Hyperglycemia-induced DNA damage and inhibition of DNA repair – a possible mechanistic link between diabetes and increased cancer risk, according to the National Meeting & Exposition of the American Chemical Society (ACS) of the fall of 2019. ACS.

Summary

Diabetes (type 1 and type 2) is significantly associated with an increase in cancers at all sites, with incomplete understanding of how diabetes affects cancer susceptibility. Mechanistic hypotheses linking diabetes and cancer have elicited the mitogenic and anti-apoptotic effects of excess insulin and insulin-like growth factor 1 (IGF-1), increased adipokine secretion from adipose tissue, and steroid hormone dysregulation. However, as genomic instability plays an important role in triggering and promoting cancer, we have focused on defining the mechanisms by which diabetes-related metabolic dysfunction contributes to DNA damage and decreased DNA repair. We suggest that hyperglycemia-induced DNA damage and the inhibition of DNA repair are major pathological complications of diabetes that exacerbate genomic instability. Using tissue culture and diabetic animal models, we show that increased glucose levels significantly increase the levels of the DNA adduct N2- (1-carboxyethyl) -2'-deoxyguanosine (CEdG) and its RNA-analogous CEG and that these adducts are significant associated with this are diabetes and diabetic complications. Chronic exposure to elevated glucose also increases DNA strand breaks and inhibits the nucleotide excision repair (NER) required to remove CEdG from the DNA. Inhibition of NER occurs at the gene expression level due to metabolism-induced destabilization of HIF1α, since many NER signaling pathway genes can be induced by this transcription factor. Inhibition also occurs at the level of mTORC1-regulated translation of HIF1α, as DNA damage induces REDD1 (Regulated in Development and DNA Damage Responses 1), which dephosphorylates Akt and attenuates mTOR signals. Since pharmacological agents have been described which stabilize HIF1α or increase translation through mTOR, this increases the potential for therapeutic intervention to improve DNA repair, limit genomic instability, and possibly reduce diabetes-related cancer risk.

Provided by
American Chemical Society




Quote :
How Diabetes Can Increase Cancer Risk (2019, Aug 25)
26th August 2019 retrieved
from https://medicalxpress.com/news/2019-08-diabetes-cancer.html

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