According to the American Cancer Society, prostate cancer is the second most common cancer in American men, with about 174,650 new cases estimated for 2019 and a death toll expected to exceed 31,000 for the year. (Skin cancer occupies the number one spot for incidence, while lung cancer is the leading cause of cancer death in American men.) Overall, the statistics translate to 1 in 9 men being diagnosed with this condition during his lifetime and 1 in 41 dying from it. While these statistics are alarming, most men who are diagnosed with prostate cancer do not die from it, particularly if it is discovered early and the cancer is slow-growing. Since early detection may play a significant role in the prognosis and ultimate outcome, let’s take a closer look at something that may be contributing to increased risk, and that may be detectable even before cancer develops: chronically elevated insulin.

Chronic hyperinsulinemia is associated with benign prostatic hyperplasia (BPH). While this is “benign” enlargement of the prostate gland, it might nevertheless provide clues into the possible relationship between elevated insulin and prostate cancer, particularly keeping in mind that, as stated in a meta-analysis published last month in Current Diabetes Reviews, “Insulin is known to have direct and indirect effects on cell cycle progression, proliferation and metastatic activities.”

Insulin is best known for its role in lowering blood sugar, but this is actually one of the hormone’s least significant properties. In fact, insulin is not even required for glucose uptake or utilization in humans—glucose uptake is never truly insulin dependent. Insulin is an anabolic hormone; it stimulates or at the very least facilitates growth of tissue—an observation anyone who’s struggled to lose body fat on a high-carbohydrate diet can attest to. Insulin facilitates storage of fat in adipose tissue; it also appears to facilitate prostate enlargement: “in insulin-resistant individuals, the increased level of circulating insulin directly and/or indirectly affects different molecular signaling and can promote prostatic growth.”

This is not a mere association; hyperinsulinemia may be causal in BPH. Men with high fasting insulin levels have a greater annual growth rate of the prostate gland. One study went so far as to say that fasting insulin and the ratio of insulin-like growth factor binding protein-3 (IGFBP-3) to prostate specific antigen (PSA) predict prostate size in men with BPH: higher insulin along with a lower IGFBP-3/PSA ratio predict a larger prostate. One researcher wrote that hyperinsulinemia is a “driving force” behind BPH.

Returning to cancer, the meta-analysis mentioned above found a significant direct association between fasting insulin level and cancer mortality in men. (The analysis was not limited to prostate cancer, however.) This may be especially apparent in men over age 65, who are more likely than younger men to develop prostate cancer in the first place. A meta-analysis from earlier this year found that fasting insulin levels and HOMA-IR were significantly higher in men with prostate cancer compared to healthy controls, but that this was limited to older men. Other research confirms that hyperinsulinemia is associated with development, progression and aggressiveness of prostate cancer.

A paper in the Journal of the National Cancer Institute found that elevated fasting insulin and higher HOMA-IR were positively and significantly associated with increased risk for prostate cancer. In the lowest quartile of fasting insulin, prostate cancer incidence was 154 cases per 100,000 person-years. This more than doubled to 394 cases per 100,000 person-years in the highest insulin quartile. Compared to the lowest quartile, the odds ratio of developing prostate cancer in the second, third and fourth quartiles were 1.50 (95% confidence interval [CI] = 0.75 to 3.03); 1.75 (CI = 0.86 to 3.56); and 2.55 (CI = 1.18 to 5.51), respectively.

It’s worth noting that insulin, but not glucose, was correlated with the increased cancer incidence. As we’ve written about previously, untold numbers of patients are living with hyperinsulinemia but normoglycemia—blood glucose that remains normal owing to pathologically elevated insulin, and this chronically high insulin is a major driver of cardiometabolic disease even while the blood sugar is normal. The scope of this under-recognized issue is staggering.

The hyperinsulinemia that often results from androgen deprivation therapy (ADT)—a standard prostate cancer treatment—is “associated with increased tumor aggressiveness and faster treatment failure.” A study published this summer looking at prostate cancer cells in vitro reported for the first time some potential mechanisms by which insulin makes these cells more invasive and mobile and proposes that a greater understanding of strategies to lower insulin levels—such as through diet and/or drugs could “improve both quality of life and overall survival” and may also have direct anti-cancer effects by inhibiting prostate cancer cell proliferation.

It’s reasonable to speculate that hyperinsulinemia—however it’s induced, be it via ADT or through a poor diet and other lifestyle factors—may have the same negative effects on cellular signaling. The ADT issue aside, this is not unique to prostate cancer. Metabolic syndrome—essentially, chronically elevated insulin—is strongly associated with breast cancer recurrence and worse outcomes after treatment, which has led researchers to question the conventional dietary advice for cancer patients, particularly when they’re undergoing or are recovering from treatment, which may include suggestions to consume anything that will help maintain or restore body weight without regard for the sugar or carbohydrate content or the effect of this on insulin levels. Insulin also appears to make pancreatic cancer more aggressive and invasive, and may contribute to development of colon cancer and greater mortality from liver cancer. 

As mentioned earlier, many people have normal blood glucose in the presence of chronically high insulin. Moving from blood glucose to body weight, insulin resistance is often associated with obesity, but excess body fat is not a prerequisite for developing hyperinsulinemia (in fact, it’s often the result, not the cause). A prospective cohort analysis published in the International Journal of Cancer determined that among all study participants (nearly 10,000 people with no previous history of cancer or diabetes), cancer mortality was significantly higher in those with hyperinsulinemia compared to those without hyperinsulinemia (hazard ratio 2.04, 95% CI 1.24–3.34). Looking specifically at subjects who were not obese, those with hyperinsulinemia also had significantly higher cancer mortality (HR 1.89, 95% CI 1.07–3.35). The study authors were so bold as to say, “…improvement of hyperinsulinemia may be an important approach for preventing cancer regardless of the presence or absence of obesity.”

It’s clinically relevant to understand that while certain cancers appear to be driven by obesity, the fact that hyperinsulinemia brings higher cancer mortality in non­-obese individuals suggests that it may not be the obesity, per se, but rather, the hyperinsulinemia that’s the pathological factor. Researchers note that insulin has direct oncogenic effects on cancer cells. Many individuals with hyperinsulinemia have obesity, but many do not, so rather than targeting obesity, perhaps cancer treatment should set its sights on chronically elevated insulin regardless of a patient’s body weight.

It’s telling that metformin and other diabetes drugs are being studied for use in cancer patients. If drugs that help control blood sugar and improve insulin sensitivity have a potential role in fighting unregulated cell division and metastasis, perhaps other strategies that have similar metabolic effects could be investigated as well. For example, ketogenic diets are being studied as adjuvants to conventional therapies. This area of research is in its early stages and while the approach is mechanistically sound, findings are mixed so far and no clear conclusions can yet be drawn.

Whether or not diets that limit insulin excursions may have a therapeutic role in cancer treatment once someone is already afflicted, it appears that remaining insulin sensitive is one piece in the very complex puzzle of reducing risk for cancer or potentially improving outcomes after treatment.