br Our findings regarding the
Our findings regarding the associations of the baseline BMI, WC, and WHR with pancreatic cancer risk are also in agreement with the results of previous cohort studies [4e7]. However, we found little evidence of an association with BMI earlier in life, in contrast to the results of several previous analyses, including 2 pooled an-alyses [12e14]. This may be because of the reduced sample size with information on weight earlier in life in our study, and to the
fact that weight in earlier life was self-reported, which might have attenuated associations because of misclassification of the exposure.
Recently, a Mendelian randomization study  was carried out in a large series of pancreatic cancer cases and controls to examine the association between genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type II diabetes to evaluate their role in pancreatic cancer etiology. The results indicated causal associations with pancreatic cancer risk of increasing BMI in both sexes and of fasting insulin in males but not in females. No association was seen for variants asso-ciated with diabetes, fasting glucose, waist-to-hip ratio, or dys-lipidemia. The inconsistency regarding results for serum insulin by sex, as well as the lack of an association with diabetes or fasting glucose, underscore the need for further study of the inter-relationships between these factors in relation to pancre-atic cancer risk.
Adiposity could contribute to the development of pancreatic cancer via hyperinsulinemia and hyperglycemia. Insulin pro-motes cell proliferation and inhibits apoptosis, both by direct action and through increased bioavailability of IGF-1 [32,33], and elevated glucose concentrations can also promote cell pro-liferation [34,35] and enhance the invasive potential of pancre-atic cancer PSB 1115 . However, while the literature implicates excess adiposity and insulin resistance in the etiology of pancreatic cancer, the associations of anthropometric measures, insulin resistance, and diabetes are modest in magnitude, and there are inconsistencies in the results of different studies. A clearer understanding of the role of these factors in pancreatic carcinogenesis will require large studies with repeated mea-surements of risk factors to improve the precision of the esti-mates of these inter-related factors, as well as to clarify the temporal relationships among them. The possibility that adiposity and insulin resistance play a role in the development
of pancreatic cancer holds out the prospect of prevention by reversing insulin resistance through lifestyle changes, including improving energy balance through increased physical activity .
Strengths of the present study include the large number of pancreatic cancer cases, the availability of anthropometric factors measured at enrollment, low loss to follow-up (~1%), long-term follow-up, as well as self-reported weight (used to compute BMI) at earlier points in life, and detailed information on potential con-founding factors. Associations with measured anthropometric fac-tors were unchanged in sensitivity analyses. Limitations include the fact that fasting serum glucose and insulin levels were not available to assess current glycemic control status. Furthermore, by design, the WHI includes only postmenopausal women. The WHI is also not representative of the general population; thus, the results of this study may not be generalizable, although they should be internally valid. Finally, in the present study, we observed that after exclusion of the first 3 years of follow-up the association between diabetes and pancreatic cancer disappeared. This finding may be because of reduced power resulting from reduced sample size. However, it also suggests that cases diagnosed soon after enroll-ment may have contributed to the observed association, and therefore, reverse causality may have contributed to the observed associations.
In conclusion, our results suggest that both a history of diabetes and adiposity (overall and central) are associated with increased risk of pancreatic cancer.
This work was supported by institutional funds from the Albert Einstein College of Medicine. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through
Program office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Bur-wen, Joan McGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg; Investigators and Academic Centers: (Brig-ham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Pre-vention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (Univer-sity of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (Uni-versity at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, WinstoneSalem, NC) Sally Shumaker. Women's Health Initiative Memory Study: (Wake Forest University School of Medicine, WinstoneSalem, NC) Sally Shumaker.