Prediagnostic Plasma C-Peptide and Pancreatic Cancer Risk in Men and Women

Department of Nutrition , Harvard University, Cambridge, Massachusetts, United States
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 11/2007; 16(10):2101-9. DOI: 10.1158/1055-9965.EPI-07-0182
Source: PubMed


Hyperinsulinemia and insulin resistance have been proposed as underlying mechanisms for the increase in pancreatic cancer among long-standing diabetics and obese individuals. An association between serum insulin levels and pancreatic cancer risk was reported in a recent study, but the population was composed of heavy smokers and their findings may not be generalizable to nonsmokers.
Pancreatic cancer cases and matched controls were obtained from four large-scale prospective cohorts to examine the association between prediagnostic plasma levels of C-peptide and insulin and pancreatic cancer. One hundred ninety-seven pancreatic cancer cases were diagnosed during a maximum of 20 years of follow-up, after excluding cases diagnosed within 2 years of blood collection or with baseline diabetes. We estimated OR and confidence intervals (CI) using conditional logistic regression with adjustment for pancreatic cancer risk factors.
Prediagnostic plasma C-peptide was positively associated with pancreatic cancer risk (OR, 1.52; 95% CI, 0.87-2.64, highest compared with the lowest quartile, P(trend) = 0.005). The association was not modified by body mass index or physical activity but seemed to be slightly stronger among never smokers than ever smokers. Fasting C-peptide and insulin were not related to pancreatic cancer; however, we observed a strong linear association for nonfasting C-peptide and pancreatic cancer (OR, 4.24; 95% CI, 1.30-13.8, highest versus lowest quartile, P(trend) < 0.001).
Based on our finding of a strong positive association with nonfasting C-peptide levels, we propose that insulin levels in the postprandial state may be the relevant exposure for pancreatic carcinogenesis; however, other studies will need to examine this possibility.

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Available from: Michael Pollak
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    • "preceded by a long period of insulin resistance with a compensatory hyperinsulinaemia and hyperglycaemia, which may promote carcinogenesis. High circulating levels of insulin, glycated haemoglobin (HbA1c), a form of haemoglobin that reflects the average plasma glucose concentration over prolonged periods of time (8–12 weeks), or C-peptide (a component of proinsulin used as a marker of endogenous insulin production) in diabetic patients might increase pancreatic cancer risk (Stolzenberg-Solomon et al, 2005; Michaud et al, 2007; Grote et al, 2011; Wolpin et al, 2013). Second, obesity is a risk factor for both diabetes and pancreatic cancer, which might be in the causal pathway. "
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    ABSTRACT: Background: Associations between type 2 diabetes, anti-diabetic medications and pancreatic cancer are controversial. This study aims to clarify such associations with new-onset type 2 diabetes and repeated measurements of glycated haemoglobin (HbA1c) levels. Methods: A nested case-control study was initiated from the Health Improvement Network (THIN) in UK from 1996 to 2010. Information of pancreatic cancer cases was retrieved electronically from the medical records and manually validated. Control subjects were randomly selected and frequency-matched to the cases on sex, age, and calendar years. Multivariable unconditional logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI), and adjusted for potential confounders. Results: Among 1 574 768 person-years of follow-up, 529 pancreatic cancer cases and 5000 controls were identified. Type 2 diabetes, or changed HbA1c levels (rather than HbA1c levels at diabetes diagnosis) in diabetes patients (⩾4 mmol mol(-1) compared with <0 mmol mol(-1)) were followed by an increased OR of pancreatic cancer (OR, 2.16, 95% CI 1.72-2.72 and OR, 5.06, 95% CI 1.52-16.87, respectively). Among the anti-diabetic medications in diabetes patients, the OR for insulin users was 25.57 (95% CI 11.55-56.60), sulphonylureas 2.22 (95% CI 1.13, 4.40), and metformin users 1.46 (95% CI 0.85-2.52), compared with no use of any anti-diabetic medications. Conclusions: New-onset type 2 diabetes and, particularly, diabetes with rising HbA1c seem to be independent risk factors for pancreatic cancer. The relation between different anti-diabetic medications and pancreatic cancer seems to vary in strength, with the highest risk among users of insulin.British Journal of Cancer advance online publication, 17 November 2015; doi:10.1038/bjc.2015.353
    Full-text · Article · Nov 2015 · British Journal of Cancer
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    • "As with colorectal cancer, studies are divided for breast cancer (no association [48–56]; positive association [57–64]), endometrial cancer (no association [65,66]; positive association [67–69]) and prostate cancer (no association [70–72]; positive association [73,74]). Two studies of pancreatic cancer both found a positive association [75,76]. "
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    ABSTRACT: Experimental, epidemiological and clinical evidence implicates insulin resistance and its accompanying hyperinsulinaemia in the development of cancer, but the relative importance of these disturbances in cancer remains unclear. There are, however, theoretical mechanisms by which hyperinsulinaemia could amplify such growth-promoting effects as insulin may have, as well as the growth-promoting effects of other, more potent, growth factors. Hyperinsulinaemia may also induce other changes, particularly in the IGF (insulin-like growth factor) system, that could promote cell proliferation and survival. Several factors can independently modify both cancer risk and insulin resistance, including subclinical inflammation and obesity. The possibility that some of the effects of hyperinsulinaemia might then augment pro-carcinogenic changes associated with disturbances in these factors emphasizes how, rather than being a single causative factor, insulin resistance may be most usefully viewed as one strand in a network of interacting disturbances that promote the development and progression of cancer.
    Full-text · Article · Nov 2009 · Clinical Science
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    • "Diabetes also has been linked to greater risk of pancreatic cancer, and meta-analyses suggest that this link may be causal, or at least that metabolic conditions predisposing to diabetes precede pancreatic cancer [2, 3]. Four prospective studies that examined banked serum have linked higher fasting glucose levels with subsequent risk of pancreatic cancer several years later [4–7], and pre-diagnostic plasma C-peptide levels have been linked to greater risk of pancreatic cancer [8]. In vitro, insulin increases pancreatic cancer cell proliferation in a dose-dependent manner [9]. "
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    ABSTRACT: We examined the associations between sweets, sweetened and unsweetened beverages, and sugars and pancreatic cancer risk. We conducted a population-based case-control study (532 cases, 1,701 controls) and used multivariate logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI). Because associations were often different by sex, we present results for men and women combined and separately. Among men, greater intakes of total and specific sweets were associated with pancreatic cancer risk (total sweets: OR = 1.9, 95% CI: 1.0, 3.6; sweet condiments: OR = 1.9, 95% CI: 1.2, 3.1; chocolate candy: OR = 2.4, 95% CI: 1.1, 5.0; other mixed candy bars: OR = 3.3, 95% CI: 1.5, 7.3 for 1 + servings/day versus none/rarely). Sweets were not consistently associated with risk among women. Sweetened beverages were not associated with increased pancreatic cancer risk. In contrast, low-calorie soft drinks were associated with increased risk among men only; while other low-/non-caloric beverages (e.g., coffee, tea, and water) were unassociated with risk. Of the three sugars assessed (lactose, fructose, and sucrose), only the milk sugar lactose was associated with pancreatic cancer risk (OR = 2.0, 95% CI: 1.5, 2.7 comparing extreme quartiles). These results provide limited support for the hypothesis that sweets or sugars increase pancreatic cancer risk.
    Preview · Article · Apr 2009 · Cancer Causes and Control
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