Washington: The researchers have identified the reason why people with Type 1 or Type 2 diabetes have an increased risk of developing some forms of cancer. The study to be presented at the 'American Chemical Society Fall 2019 National Meeting' has found that DNA sustains more damage and gets fixed less often when blood sugar levels are high compared to when blood sugar is at a normal, healthy level, thereby increasing one's cancer risk.
"It's been known for a long time that people with diabetes have as much as 2.5-fold increased risk for certain cancers," said John Termini, who is presenting the work at the meeting. These cancers include ovarian, breast, kidney and others. Scientists have suspected that the elevated cancer risk for diabetics arises from hormonal dysregulation.
"In people with Type 2 diabetes, their insulin is not effectively carrying glucose into cells," Termini explained. "So the pancreas makes more and more insulin, and they get what's called hyperinsulinemia."
In addition to controlling blood glucose levels, the hormone insulin can stimulate cell growth, possibly leading to cancer. Also, most people with Type 2 diabetes are overweight, and their excess fat tissue produces higher levels of adipokines than those at a healthy weight.
Termini and his colleagues looked for a specific type of damage in the form of chemically modified DNA bases, known as adducts, in tissue culture and rodent models of diabetes. Indeed, they found a DNA adduct, called N2-(1-carboxyethyl)-2'-deoxyguanosine, or CEdG, that occurred more frequently in the diabetic models than in normal cells or mice.
"Exposure to high glucose levels leads to both DNA adducts and the suppression of their repair, which in combination could cause genome instability and cancer," Termini added. The researchers also wanted to determine the molecular reasons why the adducts weren't being fixed properly by the cells.
They identified two proteins that appear to be involved: the transcription factor HIF1a and the signalling protein mTORC1, which both show less activity in diabetes. According to Termini, several drugs that stimulate HIF1a or mTORC1 already exist. The researchers plan to see if these drugs decrease cancer risk in diabetic animal models and if so, they will test them in humans.