Insulin Concerns and Promises

DIABETES, INSULIN, AND CANCER—At a symposium discussing controversies pertaining to relationships between diabetes and cancer, Jeffrey A. Johnson (Edmonton, Canada) reviewed epidemiologic data, beginning with a meta-analysis showing that diabetes is associated with increased rates of cancers of the pancreas, colon and rectum, bladder, liver, and breast; endometrial cancer; and non-Hodgkin’s lymphoma. Prostate cancer rates are decreased, perhaps as a consequence of a subtle form of hypogonadism, but prostate cancer mortality is increased among diabetic men who do develop prostate cancer. Obesity increases the development of cancers as well, to a greater degree with greater levels of obesity, particularly for cancers of the esophagus and thyroid and, among women, cancers of the endometrium, gallbladder, colon, and kidney. Cancer mortality increases by ;50% in both sexes in association with obesity (1). The interesting exception to the generally adverse association of obesity with malignancy is its negative relationship with lung cancer, with cigarette use the presumed confounder by its weight-reducing effect (2). The mechanism of the relationship between diabetes and cancer has not been defined in clinical studies. Johnson’s meta-analysis of trials of glycemic control did not show an effect on the risk of developing malignancy (3). Hyperglycemia was, however, associated with cancer mortality in 10-year studies of.1 million Korean (4) and .500,000 European (5) men and women, with the studies controlling for obesity though possibly reflecting a role of hyperinsulinemia. A role of hyperinsulinemia is further suggested by studies showing association of C-peptide with colorectal cancer risk (6,7). Reduced cancer survival seen in individuals with diabetes (8)may be, at least to an extent, due to diabetes-related diseases other than the malignancy itself (9) or to diabetic individuals having a lower likelihood of undergoing mammography, resulting in presentation with later-stage tumors (10). Lower rates of Pap test screening for cervical cancer have been reported in obese white women (11)—further evidence for the latter explanation. An important group of studies suggests that sulfonylureas and insulin are associated with greater likelihood of malignancy than that seen with metformin (12,13). Longer duration of insulin treatment is associated with greater likelihood of malignancy (14). Whether there is a specific effect of metformin or a general effect of improved insulin sensitivity is not clear, as greater levels of physical fitness are also associated with lower cancer mortality in diabetic and pre-diabetic individuals (15). Derek LeRoith (New York, NY) discussed the mechanisms of increased risk of cancer in obesity and in type 2 diabetes, reviewing studies of an insulin-resistant animal model to ask whether the breast cancer progression and increased prominence of metastases associated with hyperinsulinemia were caused by effects at the insulin receptor (IR) or the insulinlike growth factor (IGF)1 receptor. There are two subtypes of the IR. IR-B is the metabolic receptor. IR-A may be stimulated either by insulin or by IGF2 and is found in both fetal tissues and in cancers; IR-A appeared in LeRoith’s studies to explain insulin’s trophic effects on malignancy. The more aggressive tumor behavior and more rapid rate of growth associated with hyperinsulinemia also may reflect cross-talk between the IR/IGF1R and an oncogene. Treatment strategies blocking the IR reduce tumor growth but worsen hyperinsulinemia, as would be predicted from the model. Another approach is to reduce insulin levels. LeRoith described studies of a b-3 adrenergic receptor agonist decreasing adipose tissue mass; circulating insulin levels decreased with reduction in tumor growth. He concluded that endogenous hyperinsulinemia is an important risk factor for cancer progression, presumably working in conjunction with hyperglycemia, with dyslipidemia, with elevation in levels of a variety of nutrients, and with the proinflammatory state leading to elevations in IGF1, leptin, cytokines, and chemokines and reductions in adiponectin—all occurring as a consequence of insulin resistance. Hyperinsulinemia is, he concluded, one of many factors in the relationship between diabetes and malignancy, but he commented that it appears to explain the intersection of a number of related mechanisms of cancer growth. John Lachin (Rockville, MD) discussed what he termed “facts and fancies” in the understanding of whether there is a relationship between insulin glargine and cancer. He cited the Polish-born British mathematician Jacob Bronowski, who stated, “All information is imperfect . . . [and] errors are inextricably bound up with the nature of human knowledge” (16). The gold standard of medical research is the randomized controlled trial (RCT), which assures that treatment assignment is independent of patient characteristics, eliminating selection bias and confounding and allowing one to infer a causal relationship between the outcome and the experimental variable. In contrast, observational studies have no randomized control subjects and many potential biases of selection and confounding. Such studies are necessary in settings where a RCT is impossible, such as that of cigarette smoking and cancer, but make it difficult to establish causality. Thus, in analyzing such a set of observations, one must endeavor to understand the degree to which an association cannot be explained by other factors. Lachin cited as an example the association between coffee consumption and cancer, which has been shown to be confounded with cigarette smoking becausemore coffee drinkers smoke.Onemust in this case use a regression or stratification model, which requires correct model specification and knowledge of all confounders. Adjustment then is used to give the likelihood of adverse outcome if the confounder were imagined to be equally distributed between groups. Lachin pointed out, however, that c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c