Glycemic Index and Colorectal Carcinogenesis

Misciagna et al. [1] report the results of an interesting study of fasting serum fructosamine, glucose, insulin, and triglycerides in relation to risk of colorectal adenoma in this issue of the journal. The results are suggestive of an elevated adenoma risk with higher fructosamine and triglyceride levels and with lower fasting insulin level. The authors address some potential methodologic limitations, including selection, measurement bias and confounding. Thus, these issues will not be dealt with in this commentary. Instead, this will focus instead on the contributions of this study to our understanding of colorectal carcinogenesis. The insulin resistance or metabolic syndrome is characterized by a number of abnormalities, including dyslipidemia (low concentrations of HDL cholesterol, and elevated concentrations of triglycerides, VLDL, and small dense LDL), hypertension, chronic inflammation, procoagulation, and impaired fibrinolysis [2]. Obesity, in particular visceral adiposity, physical inactivity and a Western dietary pattern are involved in the etiology of this syndrome. The similarity of risk factors for colon cancer and for factors related to the insulin resistance syndrome was first described in detail about a decade ago [3, 4]. Since that time, an impressive body of epidemiologic data has accumulated indicating that colon cancer risk is associated with the insulin resistance syndrome. This evidence is strong from studies based on determinants of the insulin resistance syndrome (obesity, abdominal distribution of adiposity, physical inactivity), and on the major disease consequence of this syndrome, type 2 diabetes [5]. Studies of hypertriglyceridemia, hyperglycemia, and hyperinsulinemia in relation to colon cancer risk are suggestive, but not definitive at this point. For colorectal or colon cancer [6-10], and for adenoma [11, 12], a number of studies have shown a significant or borderline significant increased risk associated with hyperglycemia. Higher level of glycosylated hemoglobin (HbA1e), a marker of average glycemia over the previous 2 months, was associated with an elevated risk of colorectal cancer in one cohort study [13], but not in a smaller cohort study [14]. A novel feature of the study by Misciagna et al. is the use of fructosamine, which is an indicator of total glycated proteins in the serum, and which correlates with average blood glucose over a period of several weeks. Although HbAI is generally considered as the gold standard for measurement of glycemic control in diabetic patients, the authors suggest some potential theoretical advantages of fructosamine over HbAlc in the context of studying colorectal carcinogenesis. They cite evidence that fructosamine is glycated more rapidly than hemoglobin [15], and thus might better indicate a peak in blood glucose following a meal with high glycemic load. They also cite a study that fou d that in non-diabetics, 6 weeks of a high glycemic diet increased levels of fructosamine but not of HbA1c [16]. In addition, in a recent meta-analysis of randomized studies of low-glycemic index diets in the management of diabetes, results were stronger for a reduction of fructosamine than of HbA1~ if the duration of the study was less than 6 weeks [17]. HbA1~ measures non-enzymatic glycosylation of hemoglobin in erythrocytes, whereas fructosamine measures non-enzymatic glycation of proteins in the same compartment of plasma glucose; thus, fructosamine might better reflect plasma glucose fluctuations. A recent study indicated that the discordance between HbAjc and fructosamine in an individual is stable over time, and may possibly have some pathophysiologic relevance and not merely reflect differences in turnover of the affected proteins [18]. Clearly more study is required to better understand what physiologic aspects HbAIc and fructosamine are measuring, how they differ, and how they relate to colorectal carcinogenesis. Although HbAI is considered the gold standard for assessing glycemic control for diabetics, HbA1c may not necessarily be the superior measure of postprandial spikes from a high glycemic diet in non-diabetics, which could possibly be most relevant for the study of colorectal cancer. Because many studies of HbAIc and fructosamine have been done in diabetics, it is critical to get more information in non-diabetics. The findings from the study by Misciagni et al., while requiring confirmation, suggest that an indicator of level of glucose in the blood sensitive to foods with a high glycemic index influences colorectal carcinogenesis. A recent prospective study found that diets with a high glycemic index and load were associated with an increased risk of colon cancer [19]. However, not all studies are supportive [20]. If insulinemic rather than glycemic spikes are most etiologically relevant, the inconsistent findings for dietary glycemic index would not be surprising because the glycemia response explains only about 23% of the variability in insulinemia [21]. Besides glycemic index,