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The Relationship Between Insulin and Cancer

Issue 26 Winter/Spring 2016

Study couldn’t find benefit for prostate cancer, but other factors may be at play

Howard Strickler, MD, MPH

Howard Strickler, MD, MPH
Harold and Muriel Block Chair in Epidemiology
Professor, Department of Epidemiology & Population Health
Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
Bronx, NY

Obesity is endemic in the United States, with more than one-third of U.S. adults reported to be obese and another one-third considered overweight.1,2 While it is widely known that obesity is a major cause of adult onset diabetes, cardiovascular disease, and stroke, there is less awareness that obesity is also associated with the risks of several of the most common forms of malignancy and causes of cancer-related death, including tumors of the colon, kidney, pancreas, uterus, and post-menopausal breast cancer.3,4

The molecular factors that may explain the obesity–cancer relationship are the focus of extensive ongoing research, since this information may be helpful in identifying individuals who are at high risk of cancer, and identifying novel targets for prevention or treatment.

Several sources of evidence suggest that the hormone insulin and insulin signaling – the ways in which cells react to the hormone – play a role in the development and progression of at least some of these obesity-related cancers.

In addition to insulin’s well known role in blood sugar metabolism, the hormone can also stimulate cells to proliferate. Insulin also has what is known as “anti-apoptotic” activity, meaning that it inhibits cells from initiating steps leading to cell death. Both of these properties are linked with an increased risk for malignancy.

couple looks at device measuring insulin level

High insulin levels are common in obese individuals, and tumor cells have been reported to disproportionately express high levels of a particular form of insulin receptor (IR), the IR-A isoform, related to insulin’s anti-apoptotic activity.5,6

Furthermore, several large prospective studies of insulin levels have reported strong, highly significant associations with obesity-related cancers.

For example, one study was based in the Women’s Health Initiative (WHI) observational cohort, a study that enrolled more than 93,000 women during the 1990s. After adjustment for insulin levels, body mass index (a measure used to assess obesity), was no longer significantly associated with breast cancer risk. Instead they found that women with the highest blood levels of insulin had more than double the risk of breast cancer years later as those with the lowest levels, and they also had double the risk of uterine cancer.

While not all studies found similar results, relatively few large studies used blood specimens collected after an overnight fast, as the WHI did – important to the accuracy of the results. In additional follow-up studies in WHI, it was further shown that the associations of fasting insulin levels with risk of uterine and postmenopausal breast cancer were unaffected by adjustment for multiple markers of inflammation7 and that the obesity–breast cancer relationship was more greatly affected by insulin rather than estradiol (an important estrogen).8

All of these analyses controlled for exercise, family history, and multiple additional possible risk factor variables.

Most recently, the investigators working in WHI examined the concept of “metabolically healthy obesity” and its relationship with postmenopausal breast cancer risk.9 Metabolically healthy obese individuals are obese but have normal insulin and blood sugar levels.

As hypothesized, the metabolically healthy obese women had similar low risk of breast cancer as normal-weight women who were metabolically healthy, whereas women with insulin resistance (a failure of cells to respond normally to insulin) had significantly increased relative risk, regardless of whether they were overweight, obese or normal weight.

close up of a man's sizable gut

Collectively, these data suggest that insulin levels, rather than overweight or obesity per se, may be useful in gauging the cancer risk of postmenopausal women. It also suggests that insulin signaling cellular pathways – related to the cancer-promoting activity of insulin – may be targets for novel prevention and treatment strategies.

However, more research is needed. In particular, there appears to be an unexplained difference between the effects of insulin levels occurring naturally in the body (endogenous insulin), which are associated with cancer risk, versus injected insulin, which was found not to be associated with cancer risk in a randomized clinical trial.10

Notably, a recent study of uterine cancer using a different research approach has further bolstered the evidence of a direct role of endogenous insulin levels in cancer development.11

Specifically, in a study of approximately 1,300 uterine cancer cases and 8,000 healthy women, the researchers correlated cancer risk with genetic variants known to affect levels of blood sugar and insulin.

The results showed that genetically predicted higher fasting insulin levels were associated with a more than doubling of uterine cancer risk. This represents important new data, and strongly suggests a direct causal role of insulin levels in cancer development; ie, since the genetic research approach helped allay concerns that other risk factors, such as unhealthy behaviors, might explain the association.

Future studies of cancer that build upon this recent research and involve both genetic analysis and direct measurement of fasting insulin as well as other molecular factors that may contribute to the obesity–cancer relationship are warranted.

Given the high prevalence of obesity in this country, and throughout the world, this is likely to be a highly productive and helpful area of investigation for some time to come.

References:

  1. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 2012;307:491-7.
  2. Ogden CL, Yanovski SZ, Carroll MD, Flegal KM. The epidemiology of obesity. Gastroenterology 2007;132:2087-102.
  3. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569-78.
  4. Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon DA, Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet 2014;384:755-65.
  5. Belfiore A, Frasca F. IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 2008;13:381-406.
  6. Rajapaksha H, Forbes BE. Ligand-Binding Affinity at the Insulin Receptor Isoform-A and Subsequent IR-A Tyrosine Phosphorylation Kinetics are Important Determinants of Mitogenic Biological Outcomes. Front Endocrinol (Lausanne) 2015;6:107.
  7. Hvidtfeldt UA, Gunter MJ, Lange T, Chlebowski RT, Lane D, Farhat GN, Freiberg MS, Keiding N, Lee JS, Prentice R, Tjonneland A, Vitolins MZ, et al. Quantifying mediating effects of endogenous estrogen and insulin in the relation between obesity, alcohol consumption, and breast cancer. Cancer Epidemiol Biomarkers Prev 2012;21:1203-12.
  8. Gunter MJ, Xie X, Xue X, Kabat GC, Rohan TE, Wassertheil-Smoller S, Ho GY, Wylie-Rosett J, Greco T, Yu H, Beasley J, Strickler HD. Breast cancer risk in metabolically healthy but overweight postmenopausal women. Cancer Res 2015;75:270-4.
  9. Badrick E, Renehan AG. Diabetes and cancer: 5 years into the recent controversy. Eur J Cancer 2014;50:2119-25.
  10. Nead KT, Sharp SJ, Thompson DJ, Painter JN, Savage DB, Semple RK, Barker A, Perry JR, Attia J, Dunning AM, Easton DF, Holliday E, et al. Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. J Natl Cancer Inst 2015;107.