Diabetes mellitus, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk.

Genetic variation in the insulin-like growth factor (IGF) pathway may further increase the risk of colorectal cancer (CRC) associated with type 2 diabetes mellitus (T2DM). Joint effects of T2DM and genetic variation in the IGF pathway on CRC risk can increase mechanistic insights. Participants from the Netherlands Cohort Study (n = 120, 852) completed a baseline questionnaire in 1986 when 55-69 years old (case-cohort, nsubcohort = 5,000, ncases = 3,441 after 16.3 years follow-up). Self-reported DM at baseline with onset at ≥30 years was classified as T2DM. Eighteen single nucleotide polymorphisms (SNPs) from the IGF pathway were aggregated in a genetic risk score (GRS). Cox proportional hazard ratios (HRs) for CRC were estimated according to combinations of T2DM status with GRS tertiles and categories of an IGF1 19-CA repeat polymorphism. Baseline T2DM prevalence was 3.1% in subcohort members and 3.8% in CRC cases. Comparison of combined categories with non-T2DM individuals in the lowest GRS tertile as reference showed that those in the highest GRS tertiles with and without T2DM had significantly increased CRC risks, particularly those with T2DM (HR = 2.28, 95% CI: 1.11, 4.66). As compared to IGF1 19-CA wild-type carriers without T2DM, carrying two IGF1 19-CA variant repeat alleles were associated with a significantly decreased CRC risk in those without T2DM (HR = 0.76, 95% CI: 0.63-0.91). This association was absent when T2DM was present. Our study of joint effects indicated that the presence of unfavorable alleles in the IGF pathway may further increase the risk of CRC associated with T2DM.

Significantly higher rates of multiple and proximally located adenomas among patients with diabetes mellitus: A cross-sectional population-based study.

BACKGROUND: Diabetes mellitus (DM) is associated with a greater risk for colorectal cancer (CRC). OBJECTIVE: The objective of this article is to examine the endoscopic phenotype and histopathology of colorectal polyps in patients with vs without DM. METHODS: We conducted a cross-sectional study of patients who underwent colonoscopy at our university hospital and who completed a questionnaire. We collected endoscopy and histopathology data regarding colorectal adenomas and serrated polyps. Cox regression analyses were used to estimate adjusted prevalence ratios (PRs). RESULTS: We examined a total of 3654 patients (mean age (SD): 62 (12) years, 47% males). Of them, 360 (9.9%) had DM. Overall, the prevalence of colorectal adenomas (42% vs 32%, p < 0.01), multiple (≥3) adenomas (12% vs 7%, p = 0.01) and proximal adenomas (30% vs 19%, p < 0.01) was higher in patients with vs without DM. Multivariable analysis showed that the prevalence of adenomas (PR 1.17, 95% CI; 1.02-1.34), multiple (PR 1.37, 95% CI; 1.00-1.86) and proximal (PR 1.37, 95% CI; 1.16-1.62) adenomas was higher in patients with vs without DM, especially in men. CONCLUSION: Patients with DM harbor more frequently multiple and proximal adenomas than those without DM. Close colonoscopic surveillance of DM patients is important to maximize the effectiveness of colonoscopic CRC prevention.

Higher risk of colorectal cancer in patients with newly diagnosed diabetes mellitus before the age of colorectal cancer screening initiation.

Type 2 diabetes mellitus (T2DM) is associated with greater risk for colorectal cancer (CRC). The age of onset of T2DM is decreasing worldwide. An increased CRC risk in young T2DM patients could be relevant for the age at which to initiate CRC screening. We report on CRC risk in T2DM patients with attention to age of diagnosis. We used pharmacy data (from 1998 to 2010) from the PHARMO Database Network linked to the Eindhoven Cancer Registry. Multivariable time-dependent Cox regression analyses were conducted to calculate hazard ratios (HR) for developing CRC comparing T2DM with non-T2DM. During 2,599,925 years of follow-up, 394 CRC cases among 41,716 diabetes patients (mean age 64.0 yr, 48% men) and 1,939 CRC cases among 325,054 non-diabetic patients (mean age 51.2 yr, 46% men) were identified. Diabetes was associated with an increased CRC risk in both men and women (HR 1.3, 95% CI 1.2-1.5), particularly in the first 6 months after T2DM diagnosis and pronounced in the proximal colon. This risk was even higher in men younger than 55 years (HR 2.0, 95% CI 1.0-3.8). T2DM was associated with a time-varying and subsite-specific increased CRC risk, which was even higher in men aged <55 years.

No Decreased Risk of Gastrointestinal Cancers in Users of Metformin in The Netherlands; A Time-Varying Analysis of Metformin Exposure.

Previous studies on metformin use and gastrointestinal (GI) cancer risk have yielded inconclusive results on metformin's chemoprotective effects. We aimed to evaluate GI cancer risk in users of metformin in The Netherlands using a time-varying approach in a large population-based database. A cohort study was performed using the NCR-PHARMO database. Patients using ≥1 non-insulin antidiabetic drug (NIAD) during 1998 to 2011 were included (N = 57,621). Exposure to NIADs was modeled time-varyingly. Cox regression analysis estimated HRs of GI cancers in current metformin users versus current users of other NIADs. Covariables included age, sex, drugs known to impact cancer risk, history of hospitalization, and starting year of follow-up. A sensitivity analysis was performed, applying a new-user design. Current use of metformin was not associated with a decreased risk of GI cancer [HR, 0.97; 95% confidence interval (CI), 0.82-1.15] or specific GI cancer sites. The sensitivity analysis yielded comparable results. No decreasing trends were observed with increasing cumulative dose of metformin [HR 1.05, 95% CI, 0.85-1.28; HR 0.89, 95% CI, 0.73-1.10; HR 0.96, 95% CI, 0.77-1.19 for dose tertiles low (<405 g), medium (405-999 g), and high (≥999 g)]. In contrast, an increased risk of pancreatic cancer was found in current users of metformin plus insulin (HR, 4.90; 95% CI, 2.64-9.10). In conclusion, no decreased risk of GI cancer was found in current metformin users compared with current users of other NIADs. Variations in the exposure definition of metformin use may be one of the explanations of previously found reduced cancer risks in metformin users. Cancer Prev Res; 10(5); 290-7. ©2017 AACR.

Diabetes mellitus type 2 and subsite-specific colorectal cancer risk in men and women: results from the Netherlands Cohort Study on diet and cancer.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of colorectal cancer (CRC); however, studies differentiating between subsites of CRC are limited. We investigated how diabetes mellitus (DM) was associated with subsite-specific CRC risk in men and women. METHODS: The Netherlands Cohort Study on diet and cancer is a prospective study among 120 852 men and women aged 55-69 years old at baseline in 1986. Information on DM, anthropometric, dietary and lifestyle factors was self-reported at baseline. T2DM was defined as the diagnosis of DM after 30 years of age. Incident CRC cases were identified by record linkage with the Netherlands cancer registry and the Dutch pathology registry. After 17.3 years of follow-up, 1735 incident male CRC cases and 1321 female CRC cases were available for analyses. Subsite-specific hazard ratios (HRs) for CRC were estimated in case-cohort analyses using Cox regression. RESULTS: At baseline, 3.1% of subcohort members reported T2DM, of whom 80% were diagnosed after 50 years of age. Multivariable-adjusted models showed that the risk of proximal colon cancer was significantly increased in women with T2DM versus women without T2DM (HR=1.80, 95% confidence interval: 1.10-2.94). There was no association between T2DM and the risk of overall CRC, distal colon cancer and rectal cancer in women. In men, T2DM was not associated with overall CRC (HR=0.98, 95% confidence interval: 0.64-1.50), or with risk at any subsite. CONCLUSIONS: This prospective study showed an increased risk of proximal colon cancer in women with T2DM compared with non-T2DM women.

Gastrointestinal symptoms in diabetes mellitus, and their relation to anxiety and depression.

BACKGROUND: Prevalence of gastrointestinal (GI) symptoms is increased in patients with diabetes mellitus. In general, GI symptoms are influenced by psychological factors such as anxiety and depression, but little is known about this association in diabetic patients. AIM: We tested the hypothesis that anxiety and depression have major impact on GI symptoms in diabetic patients. METHODS: 280 diabetic patients and 355 non-diabetic, age and sex matched controls were studied by validated questionnaires: (1) PAGI-SYM and GSRS for common GI symptoms and (2) HADS for anxiety and depression. Data were compared using logistic regression analysis. RESULTS: Patients with diabetes scored significantly (p<0.05) higher on the symptoms diarrhea (OR 1.64, 95% CI 1.05-2.56), early satiety (OR 2.50, 95% CI 1.39-4.49) and bloating (OR 1.58, 95% CI 1.03-2.43), but not on other symptoms. Prevalence of anxiety and depression (HADS scores ≥ 8) in diabetics and controls was respectively 27.5% and 20.6% for anxiety (p<0.05), and 19.6% and 13.4% for depression (p<0.05). After adjusting for anxiety and depression only the GI symptom "early satiety" remained significantly more prevalent in the patients with diabetes. CONCLUSIONS: The prevalence of the gastrointestinal symptoms diarrhea, bloating and early satiety, and of anxiety and depression is significantly increased in our cohort of predominantly patients with longstanding type 2 diabetes mellitus compared to controls. When adjusted for anxiety and depression, only the gastrointestinal symptom "early satiety" remained more prevalent in these diabetic patients, pointing to a somatic based origin. Thus, in our diabetic population psychological factors to a large extent are associated with gastrointestinal symptoms and should be taken into account when considering treatment of the gastrointestinal symptoms.