A Prospective Study of Plasma Adiponectin and Pancreatic Cancer Risk in Five US Cohorts

Ying Bao; Edward L. Giovannucci; Peter Kraft; Meir J. Stampfer; Shuji Ogino; Jing Ma; Julie E. Buring; Howard D. Sesso; I-Min Lee; John Michael Gaziano; Nader Rifai; Michael N. Pollak; Barbara B. Cochrane; Virginia Kaklamani; Jennifer H. Lin; JoAnn E. Manson; Charles S. Fuchs; Brian M. Wolpin

Disclosures

J Natl Cancer Inst. 2013;105(2):95-103. 

In This Article

Abstract and Introduction

Abstract

Background The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and chronic inflammation, the mechanistic basis of the associations is poorly understood.
Methods To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case–control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, Women's Health Initiative, and Women's Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided.
Results Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P heterogeneity = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios ([ORs] 95% confidence intervals [CIs]) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P trend = .04). Restricted cubic spline regression confirmed a nonlinear association (P nonlinearity < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P interaction > .10).
Conclusions In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.

Introduction

Pancreatic cancer is the fourth leading cause of cancer death in the United States,[1] yet little is known about its etiology. In addition to smoking, chronic pancreatitis, and diabetes mellitus, accumulating evidence has implicated obesity as an important risk factor for pancreatic cancer. The 2009 report from the World Cancer Research Fund concluded that the strength of the evidence supporting an association between obesity and pancreatic cancer is convincing.[2] Multiple biological mechanisms have been proposed to explain this association, including insulin resistance and subsequent hyperinsulinemia, circulating insulin-like growth factors, and chronic inflammation,[2] but the role of these mechanistic pathways remains poorly understood.

Discovered in 1995, adiponectin is a hormone primarily secreted by adipose tissue.[3–6] Animal studies have shown that adiponectin enhances insulin sensitivity and ameliorates insulin resistance.[7–9] Consistent with this observation, in humans, circulating adiponectin is inversely correlated with plasma insulin and is reduced in individuals with insulin-resistant conditions such as obesity and type 2 diabetes mellitus.[10] Low prediagnostic adiponectin levels are also associated with an increased risk of developing type 2 diabetes mellitus.[11] In addition, prediagnostic plasma adiponectin levels have been inversely associated with several obesity-related cancers, including colorectal, endometrial, and postmenopausal breast cancers.[12–15]

Given its essential role in mediating insulin sensitivity, adiponectin may be an important biological link in the development of obesity-associated malignancies, such as pancreatic cancer. Adiponectin receptors AdipoR1 and AdipoR2 are expressed on human pancreatic beta cells[16] and pancreatic tumor cells.[17] Animal studies of pancreatic cancer have shown that rapid tumor growth correlated inversely with serum adiponectin concentration.[18] Interestingly, a recent genome-wide association study identified the nuclear receptor 5A2 (NR5A2) gene, which is involved in transcriptional activation of the adiponectin gene,[19] as an important predisposing factor for pancreatic cancer.[20] These observations suggest a possible role for adiponectin in the development of pancreatic cancer. However, epidemiological data regarding circulating adiponectin and pancreatic cancer risk are limited and inconsistent.[17,21–24] To investigate the role of adiponectin in the development of pancreatic cancer, we examined the association between prediagnostic plasma adiponectin and subsequent risk of pancreatic cancer in five US prospective cohorts with up to 26 years of follow-up since blood collection.

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