Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort.

BACKGROUND: Evidence on associations between self-reported diabetes mellitus, diabetes duration, age at diabetes diagnosis, insulin treatment, and risk of biliary tract cancer (BTC) and hepatocellular carcinoma (HCC), independent of general and abdominal obesity is scarce. PATIENTS AND METHODS: We conducted a prospective analysis in the EPIC-cohort study among 363 426 participants with self-reported diabetes data. Multivariable adjusted relative risks and 95% confidence intervals were estimated from Cox regression models. In a nested case-control subset, analyses were carried out in HCV/HBV-negative individuals. RESULTS: During 8.5 years of follow-up, 204 BTC cases [including 75 gallbladder cancer (GBC) cases], and 176 HCC cases were identified. Independent of body mass index and waist-to-height ratio diabetes status was associated with higher risk of BTC and HCC [1.77 (1.00-3.13) and 2.17 (1.36-3.47)]. For BTC, the risk seemed to be higher in participants with shorter diabetes duration and those not treated with insulin. Regarding cancer subsites, diabetes was only associated with GBC [2.72 (1.17-6.31)]. The risk for HCC was particularly higher in participants treated with insulin. The results were not appreciably different in HCV/HBV-negative individuals. CONCLUSION(S): This study supports the hypothesis that diabetes is a risk factor for BTC (particularly GBC) and HCC. Further research is required to establish whether diabetes treatment or duration is associated with these cancers.

Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct.

AIMS/HYPOTHESIS: Consumption of sugar-sweetened beverages has been shown, largely in American populations, to increase type 2 diabetes incidence. We aimed to evaluate the association of consumption of sweet beverages (juices and nectars, sugar-sweetened soft drinks and artificially sweetened soft drinks) with type 2 diabetes incidence in European adults. METHODS: We established a case-cohort study including 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 participants selected from eight European cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. After exclusions, the final sample size included 11,684 incident cases and a subcohort of 15,374 participants. Cox proportional hazards regression models (modified for the case-cohort design) and random-effects meta-analyses were used to estimate the association between sweet beverage consumption (obtained from validated dietary questionnaires) and type 2 diabetes incidence. RESULTS: In adjusted models, one 336 g (12 oz) daily increment in sugar-sweetened and artificially sweetened soft drink consumption was associated with HRs for type 2 diabetes of 1.22 (95% CI 1.09, 1.38) and 1.52 (95% CI 1.26, 1.83), respectively. After further adjustment for energy intake and BMI, the association of sugar-sweetened soft drinks with type 2 diabetes persisted (HR 1.18, 95% CI 1.06, 1.32), but the association of artificially sweetened soft drinks became statistically not significant (HR 1.11, 95% CI 0.95, 1.31). Juice and nectar consumption was not associated with type 2 diabetes incidence. CONCLUSIONS/INTERPRETATION: This study corroborates the association between increased incidence of type 2 diabetes and high consumption of sugar-sweetened soft drinks in European adults.

Inflammation marker and risk of pancreatic cancer: a nested case-control study within the EPIC cohort.

BACKGROUND: Established risk factors for pancreatic cancer include smoking, long-standing diabetes, high body fatness, and chronic pancreatitis, all of which can be characterised by aspects of inflammatory processes. However, prospective studies investigating the relation between inflammatory markers and pancreatic cancer risk are scarce. METHODS: We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition, measuring prediagnostic blood levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble receptors of tumour necrosis factor-α (sTNF-R1, R2) in 455 pancreatic cancer cases and 455 matched controls. Odds ratios (ORs) were estimated using conditional logistic regression models. RESULTS: None of the inflammatory markers were significantly associated with risk of pancreatic cancer overall, although a borderline significant association was observed for higher circulating sTNF-R2 (crude OR=1.52 (95% confidence interval (CI) 0.97-2.39), highest vs lowest quartile). In women, however, higher sTNF-R1 levels were significantly associated with risk of pancreatic cancer (crude OR=1.97 (95% CI 1.02-3.79)). For sTNF-R2, risk associations seemed to be stronger for diabetic individuals and those with a higher BMI. CONCLUSION: Prospectively, CRP and IL-6 do not seem to have a role in our study with respect to risk of pancreatic cancer, whereas sTNF-R1 seemed to be a risk factor in women and sTNF-R2 might be a mediator in the risk relationship between overweight and diabetes with pancreatic cancer. Further large prospective studies are needed to clarify the role of proinflammatory proteins and cytokines in the pathogenesis of exocrine pancreatic cancer.

Concentrations of IGF-I and IGFBP-3 and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Insulin-like growth factors (IGFs) and their binding proteins (BPs) regulate cell differentiation, proliferation and apoptosis, and may have a role in the aetiology of various cancers. Information on their role in pancreatic cancer is limited and was examined here in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. METHODS: Serum concentrations of IGF-I and IGFBP-3 were measured using enzyme-linked immunosorbent assays in 422 cases and 422 controls matched on age, sex, study centre, recruitment date, and time since last meal. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) adjusted for confounding variables. RESULTS: Neither circulating levels of IGF-I (OR=1.21, 95% CI 0.75-1.93 for top vs bottom quartile, P-trend 0.301), IGFBP-3 (OR=1.00, 95% CI 0.66-1.51, P-trend 0.79), nor the molar IGF-I/IGFBP-3 ratio, an indicator of free IGF-I level (OR=1.22, 95% CI 0.75-1.97, P-trend 0.27), were statistically significantly associated with the risk of pancreatic cancer. In a cross-classification, however, a high concentration of IGF-I with concurrently low levels of IGFBP-3 was related to an increased risk of pancreatic cancer (OR=1.72, 95% CI 1.05-2.83; P-interaction=0.154). CONCLUSION: On the basis of these results, circulating levels of components of the IGF axis do not appear to be the risk factors for pancreatic cancer. However, on the basis of the results of a subanalysis, it cannot be excluded that a relatively large amount of IGF-1 together with very low levels of IGFBP-3 might still be associated with an increase in pancreatic cancer risk.

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.

AIMS/HYPOTHESIS: There has been long-standing debate about whether diabetes is a causal risk factor for pancreatic cancer or a consequence of tumour development. Prospective epidemiological studies have shown variable relationships between pancreatic cancer risk and blood markers of glucose and insulin metabolism, overall and as a function of lag times between marker measurements (blood donation) and date of tumour diagnosis. METHODS: Pre-diagnostic levels of HbA(1c) and C-peptide were measured for 466 participants with pancreatic cancer and 466 individually matched controls within the European Prospective Investigation into Cancer and Nutrition. Conditional logistic regression models were used to estimate ORs for pancreatic cancer. RESULTS: Pancreatic cancer risk gradually increased with increasing pre-diagnostic HbA(1c) levels up to an OR of 2.42 (95% CI 1.33, 4.39 highest [≥ 6.5%, 48 mmol/mol] vs lowest [≤ 5.4%, 36 mmol/mol] category), even for individuals with HbA(1c) levels within the non-diabetic range. C-peptide levels showed no significant relationship with pancreatic cancer risk, irrespective of fasting status. Analyses showed no clear trends towards increasing hyperglycaemia (as marked by HbA(1c) levels) or reduced pancreatic beta cell responsiveness (as marked by C-peptide levels) with decreasing time intervals from blood donation to cancer diagnosis. CONCLUSIONS/INTERPRETATION: Our data on HbA(1c) show that individuals who develop exocrine pancreatic cancer tend to have moderate increases in HbA(1c) levels, relatively independently of obesity and insulin resistance-the classic and major risk factors for type 2 diabetes. While there is no strong difference by lag time, more data are needed on this in order to reach a firm conclusion.

Diabetes mellitus type 2 - an independent risk factor for cancer?

Epidemiological findings have shown up to two-fold increases in the risks of cancers of the colorectum, breast, endometrium, kidney (renal cell tumours), liver and pancreas among diabetes patients. In the present review, we address the question whether, on the basis of these epidemiological observations, type 2 diabetes should be considered a specific and independent risk factor for these various forms of cancer, due to its particular metabolic characteristics of glucose intolerance and hyperinsulinemia. On the basis of further epidemiological evidence among non-diabetic individuals, as well as recent studies examining the effects of different types of diabetes treatment on cancer risks, we conclude that chronic elevations in fasting and non-fasting blood levels of glucose and/or insulin are plausible independent risk factors for cancer, but that much of the increase in cancer risks associated with these two metabolic factors may occur within the normoglycaemic and insulinemic (non-diabetic) ranges. Furthermore, for some tumour types (e. g. cancer of the endometrium) the associations of risk with type 2 diabetes may to a large extent be due to, and at least partially confounded by, other obesity-related alterations in (e. g. sex steroid) metabolism that in part are independent of glucose and/or insulin metabolism. Specifically for pancreatic cancer, a major question, addressed in detail by other reviews, is whether associations of risk with plasma glucose, insulin or overt type 2 diabetes could be either a cause, or possibly also a consequence of tumour development (or both).