Hyperglycemia, Insulin Resistance, and the Risk of Pancreatic Cancer

ABSTRACT & COMMENTARY

Financial Disclosure: Clinical Oncology Alert’s Editor, William Ershler, MD; nurse planner, Irene Q. Flores, RN, BSN OCN; peer reviewer, V.R. Veerapalli, MD; executive editor, Leslie Coplin; and managing editor, Neill Kimball report no financial relationships relevant to this field of study

Synopsis: There is a known association of obesity and glucose intolerance with pancreatic cancer but whether this is due to the effect of high glucose itself, insulin resistance, or pancreatic ß-cell dysfunction is unknown. In an epidemiological, nested, case-control analysis drawn from five large prospective cohorts, measures of insulin resistance were independently associated with pancreatic cancer risk, but this was not true for measures of hyperglycemia or ß-cell dysfunction alone.

Source: Wolpin BM, et al. Hyperglycemia, insulin resistance, imparired pancreatic ß-cell function, and risk of pancreatic cancer. J Natl Cancer Inst 2013;105:1027–1035.

Pancreatic cancer remains both a challenge to diagnose and an even greater challenge to effectively treat. In fact, only patients discovered early and with resectable disease have a chance for long-term survival. Unfortunately, the majority of patients (> 85%) have unresectable disease by the time disease-associated symptoms occur and a diagnosis is made.1 Patients who have the greatest chance for curative resection are those who have their tumors diagnosed when under evaluation for other problems and the pancreatic mass is discovered before symptoms occur. The timeline for progression of pancreatic cancer from resectable to unresectable is unknown. Glucose intolerance is known to occur in a substantial percentage of pancreatic cancer patients and it may occur earlier than other signs or symptoms of disease.2-5 Yet the relationship between glucose metabolism and pancreatic cancer remains unclear, and an observed associated risk could be secondary to consequences of peripheral insulin resistance, pancreatic ß-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance,6 and the proinsulin to insulin ratio marks pancreatic ß-cell dysfunction.7

Capitalizing on data from five prospective U.S. cohorts followed through 2008, Wolpin and colleagues performed a nested, case-control study of 449 pancreatic cancer patients and 982 control subjects, all of whom had prediagnostic blood samples but no prior diagnosis of diabetes. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression.

The data were analyzed in quintiles and it was found that the highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with an increased risk for pancreatic cancer (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.17-2.72 for HbA1c; OR, 1.57; 95% CI, 1.08-2.30 for insulin; and OR, 2.22; 95% CI, 1.50-3.29 for proinsulin). The proinsulin to insulin ratio was not associated with pancreatic cancer risk. To evaluate whether subclinical malignancy influenced results, the authors performed analyses with exclusion of patients whose tumor developed < 10 years after their samples were drawn. For those with cancers developing ≥ 10 years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile: OR, 2.77; 95% CI, 1.28-5.99 for insulin; and OR, 3.60; 95% CI, 1.68-7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant (highest vs lowest quintile, OR, 2.55; 95% CI, 1.54-4.21).

COMMENTARY

The association of obesity, diabetes, and pancreatic cancer has been well described but the mechanism accounting for this association has yet to be established. Although the current study does not definitively answer this, it is valuable in providing direction. The analysis demonstrated statistically significant positive associations between risk of pancreatic cancer and prediagnostic circulating markers of hyperglycemia (HbA1c) and peripheral insulin resistance (plasma insulin and proinsulin). However, the risk for pancreatic cancer was not associated with plasma proinsulin to insulin ratio (a marker of impaired ß-cell function). Furthermore, when evaluated in joint models, high levels of plasma proinsulin (a marker of peripheral insulin resistance) were associated with a nearly 2.5-fold increase in risk for pancreatic cancer, whereas HbA1c (a marker of hyperglycemia) was no longer associated with risk. Thus, insulin resistance existent over a decade or more was found to be a key pancreatic cancer risk factor.

The implications of these findings are important at several levels. Studies that examine how insulin resistance and hyperglycemia mediate pancreatic neoplastic transformation would allow a better understanding of the early steps in the development of this devastating illness. And, in the short run, physicans should be aware that early recognition and reversal of insulin resistance, aside from the obvious immediate health benefits, may be effective in preventing pancreatic cancer.

References

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2.  Chari ST, et al. Probability of pancreatic cancer following diabetes: A population-based study. Gastroenterology 2005;129:504-511.

3.  Gapstur SM, et al. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 2000;283:2552-2558.

4.  Grote VA, et al. Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: A study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Diabetologia 2011;54:3037-3046.

5.  Huxley R, et al. Type-II diabetes and pancreatic cancer: A meta-analysis of 36 studies. Br J Cancer 2005;92:2076-2083.

6.  Kahn SE, et al. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006;444:840-846.

7.  Roder ME, et al. Disproportionately elevated proinsulin levels reflect the degree of impaired B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1998;83:604-608.