Diverting a Common Pathway for Type 2 Diabetes and Cancer Risk

Type 2 diabetes and cancer both have a tremendous impact on human health, and both share a common pathway known as PI3K, a complex chain of signals that regulates cell growth and plays a critical role in human cancers. “Patients with pre-diabetes (also called insulin resistance) or with early stage type 2 diabetes typically have insulin levels that are much higher than normal,” says Lewis Cantley, PhD, Director of the Sandra and Edward Meyer Cancer Center at NewYork-Presbyterian/Weill Cornell Medical Center.   “This increase in insulin in the blood  triggers the PI3K pathway in early stage cancers and accelerates cancer growth. The good news is that it is possible to reduce the risk of both type 2 diabetes and certain cancers by getting more exercise and eating less sugar.”

Dr. Cantley was recently awarded the prestigious 2020 Dr. Paul Janssen Award for Biomedical Research for his landmark discovery of the enzyme phosphoinositide-3-kinase, or PI3K.

Dr. Cantley was recently awarded the prestigious 2020 Dr. Paul Janssen Award for Biomedical Research for his landmark discovery of the enzyme phosphoinositide-3-kinase, or PI3K. Around 30 years ago, Dr. Cantley found that PI3K stimulates cells to take up glucose in response to insulin. If this pathway is too slow, the body becomes insulin resistant and cells fail to take up enough glucose, which results in type 2 diabetes.  If the pathway is too fast, cells receive an overabundance of glucose, which spurs the growth of cancer.

“With type 2 diabetes, your body doesn’t respond normally to insulin, a hormone that regulates the movement of sugar into your cells,” explains Dr. Cantley, who holds a PhD in biophysical chemistry.  “We now know that type 2 diabetes is a consequence of the inability of PI3K to be activated in muscle, fat and liver in the presence of insulin. Like muscle, fat and liver cells, cancer cells also have insulin receptors and use insulin to grow.”

In his pioneering research, Dr. Cantley discovered that human cancers frequently have mutations that increase the activity of PI3K. Some of these mutations increase the ability of insulin to activate PI3K. Over the past three decades, Dr. Cantley has identified new treatments for cancers that result from defects in the PI3K pathway. “We now know that the gene that encodes PI3K is one of the most frequently mutated cancer-promoting genes in humans,” he says. “As many as 80 percent of cancers, including those of the breast, colon, pancreas, brain, bladder and many cancers of the blood have mutations that facilitate the activation of PI3K.” 

At Weill Cornell Medicine, Dr. Cantley has been investigating the role of the PI3K pathway, which serves as a target for new drugs including the breakthrough lymphoma and leukemia drug idelalisib, which in 2014 became the first PI3K inhibitor to be approved by the FDA, and duvelisib and copanlisib, which are used to treat subsets of blood cancers. Another drug, alpelisib, approved in 2019, is used to treat ER positive, HER2 negative breast cancers that have mutations in the gene encoding PI3K (PIK3CA). 

“Several women’s cancers strongly correlate with obesity, particularly endometrial cancer,” says Dr. Cantley. “Patients with endometrial cancer almost always have a PI3K kinase pathway mutation. The mutations in this pathway can occur independent of obesity, so we are exploring whether women with elevated insulin levels, whether or not they are overweight, are at greater risk for endometrial cancer.” 

With type 2 diabetes inexorably tied to cancer risk, the importance of maintaining a healthy lifestyle is paramount. “The Mediterranean diet is used by epidemiologists more than any other diet to control diabetes and prevent heart disease and cancer,” says Dr. Cantley. “This diet emphasizes eating foods like fish, fruits, vegetables, beans, high-fiber breads and whole grains, nuts, and olive oil. Patients on the Mediterranean diet tend to be healthier and live longer than those who are not.”

“I always recommend that people try to eat as little sugar and starch as possible, because these foods quickly convert into glucose and cause your insulin levels to spike,” he says. “Think about what cavemen ate 100,000 years ago. Fruits were available only one month out of the year, and for the rest of the year they were only eating protein and fat and slow-release carbohydrates from uncooked roots.”

“Studies have consistently shown a strong association between obesity and both insulin resistance and type 2 diabetes incidence,” adds Dr. Cantley. “Not only is eating well important, getting regular exercise is key because exercise consumes glucose in the muscle and keeps insulin levels low.”

Additionally, Dr. Cantley recommends that patients with type 2 diabetes work with their endocrinologists to determine ways to minimize or avoid drugs that will raise their insulin levels. “Drugs such as SGLT2 inhibitors, which include canagliflozin, dapagliflozin, and empagliflozin, lower blood sugar and insulin levels in adults with type 2 diabetes, though they have some side effects” he says. 

Patients with type 2 diabetes should also undergo appropriate cancer screenings as recommended for their age, gender and family history.

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