Showing papers by "John Michael Gaziano published in 2013"

Hyperglycemia, Insulin Resistance, Impaired Pancreatic β-Cell Function, and Risk of Pancreatic Cancer

Abstract: Methods This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. 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. All P values were two-sided. Results The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, Ptrend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; Ptrend .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 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 to 4.21; Ptrend < .001). Conclusions Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk. J Natl Cancer Inst;2013;105:1027–1035

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

Abstract: 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.

Association between modifiable lifestyle factors and residual lifetime risk of diabetes

Abstract: Background and aims While clinical trials have reported beneficial effects of diet, exercise, and weight loss on incident diabetes in subjects with obesity or impaired glucose tolerance, little is known about the incremental benefit of not smoking and moderate drinking on diabetes risk. We sought to examine the association between modifiable lifestyle factors and residual lifetime risk of diabetes.