Fetuin-A and risk of diabetes-related vascular complications: a prospective study.

BACKGROUND: Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops. METHODS: Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression. RESULTS: In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints). CONCLUSIONS: Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease.

Advanced glycation end-products, measured as skin autofluorescence, associate with vascular stiffness in diabetic, pre-diabetic and normoglycemic individuals: a cross-sectional study.

BACKGROUND: Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We aimed to investigate the relationships between advanced glycation end-products, measured as skin autofluorescence, and vascular stiffness in various glycemic strata. METHODS: We performed a cross-sectional analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, comprising n = 3535 participants (median age 67 years, 60% women). Advanced glycation end-products were measured as skin autofluorescence with AGE-Reader™, vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index with Vascular Explorer™. A subset of 1348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Associations between skin autofluorescence and various indices of vascular stiffness were assessed by multivariable regression analyses and were adjusted for age, sex, measures of adiposity and lifestyle, blood pressure, prevalent conditions, medication use and blood biomarkers. RESULTS: Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and - 0.04 (- 0.05; - 0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (- 0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. CONCLUSIONS: Our findings indicate that advanced glycation end-products measured as skin autofluorescence might be involved in vascular stiffening independent of age and other cardiometabolic risk factors not only in individuals with diabetes but also in normoglycemic and prediabetic conditions. Skin autofluorescence might prove as a rapid and non-invasive method for assessment of macrovascular disease progression across all glycemic strata.

BMI and BMI change following incident type 2 diabetes and risk of microvascular and macrovascular complications: the EPIC-Potsdam study.

AIMS/HYPOTHESIS: Studies suggest decreased mortality risk among people who are overweight or obese compared with individuals with normal weight in type 2 diabetes (obesity paradox). However, the relationship between body weight or weight change and microvascular vs macrovascular complications of type 2 diabetes remains unresolved. We investigated the association between BMI and BMI change with long-term risk of microvascular and macrovascular complications in type 2 diabetes in a prospective cohort study. METHODS: We studied participants with incident type 2 diabetes from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, who were free of cancer, cardiovascular disease and microvascular disease at diagnosis (n = 1083). Pre-diagnosis BMI and relative annual change between pre- and post-diagnosis BMI were evaluated in multivariable-adjusted Cox models. RESULTS: There were 85 macrovascular (myocardial infarction and stroke) and 347 microvascular events (kidney disease, neuropathy and retinopathy) over a median follow-up of 10.8 years. Median pre-diagnosis BMI was 29.9 kg/m2 (IQR 27.4-33.2), and the median relative annual BMI change was -0.4% (IQR -2.1 to 0.9). Higher pre-diagnosis BMI was positively associated with total microvascular complications (multivariable-adjusted HR per 5 kg/m2 [95% CI]: 1.21 [1.07, 1.36], kidney disease 1.39 [1.21, 1.60] and neuropathy 1.12 [0.96, 1.31]) but not with macrovascular complications (HR 1.05 [95% CI 0.81, 1.36]). Analyses according to BMI categories corroborated these findings. Effect modification was not evident by sex, smoking status or age groups. In analyses according to BMI change categories, BMI loss of more than 1% indicated a decreased risk of total microvascular complications (HR 0.62 [95% CI 0.47, 0.80]), kidney disease (HR 0.57 [95% CI 0.40, 0.81]) and neuropathy (HR 0.73 [95% CI 0.52, 1.03]), compared with participants with a stable BMI; no clear association was observed for macrovascular complications (HR 1.04 [95% CI 0.62, 1.74]). The associations between BMI gain compared with stable BMI and diabetes-related vascular complications were less apparent. Associations were consistent across strata of sex, age, pre-diagnosis BMI or medication but appeared to be stronger among never-smokers compared with current or former smokers. CONCLUSIONS/INTERPRETATION: Among people with incident type 2 diabetes, pre-diagnosis BMI was positively associated with microvascular complications, while a reduced risk was observed with weight loss when compared with stable weight. The relationships with macrovascular disease were less clear.

Opposing Associations of NT-proBNP With Risks of Diabetes and Diabetes-Related Complications.

OBJECTIVE: Circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) is a classic diagnostic and prognostic marker for heart failure. However, it is inversely associated with diabetes risk. We aimed to investigate relationships of NT-proBNP with risk of diabetes-related complications in initially healthy individuals. RESEARCH DESIGN AND METHODS: We performed a case-cohort study within the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort including a random subcohort (n = 1,294) and incident cases of type 2 diabetes (n = 649) and cardiovascular diseases (n = 478). Incident cases of type 2 diabetes (n = 545) were followed up for microvascular (n = 133) and macrovascular (n = 50) complications. Plasma NT-proBNP was measured at baseline in initially healthy participants. RESULTS: In multivariable models, NT-proBNP was linearly inversely associated with incident type 2 diabetes with a hazard ratio (HR) (95% CI) per doubling in NT-proBNP of 0.91 (0.86, 0.98). The association was only observable in women (0.80 [0.72, 0.90]) compared with men (0.98 [0.91, 1.07]). Among people with incident diabetes, NT-proBNP was positively associated with diabetes complications: overall, 1.31 (1.13, 1.53); microvascular complications, 1.20 (1.01, 1.43); and macrovascular complications, 1.37 (1.03, 1.83). CONCLUSIONS: Although higher NT-proBNP levels are associated with lower diabetes risk, NT-proBNP is a biomarker for vascular complications in people who develop diabetes independent of potential confounders. Thus, NT-proBNP might be informative to monitor risk for diabetes-related microvascular and macrovascular complications, which should be further explored in future prospective studies.

Height and body fatness and colorectal cancer risk: an update of the WCRF-AICR systematic review of published prospective studies.

PURPOSE: There is no published dose-response meta-analysis on the association between height and colorectal cancer risk (CRC) by sex and anatomical sub-site. We conducted a meta-analysis of prospective studies on the association between height and CRC risk with subgroup analysis and updated evidence on the association between body fatness and CRC risk. METHODS: PubMed and several other databases were searched up to November 2016. A random effects model was used to calculate dose-response summary relative risks (RR's). RESULTS: 47 studies were included in the meta-analyses including 50,936 cases among 7,393,510 participants. The findings support the existing evidence regarding a positive association of height, general and abdominal body fatness and CRC risk. The summary RR were 1.04 [95% (CI)1.02-1.05, I² = 91%] per 5 cm increase in height, 1.02 [95% (CI)1.01-1.02, I² = 0%] per 5 kg increase in weight, 1.06 [95% (CI)1.04-1.07, I² = 83%] per 5 kg/m2 increase in BMI, 1.02 [95% (CI)1.02-1.03, I² = 4%] per 10 cm increase in waist circumference, 1.03 [95% (CI)1.01-1.05, I² = 16%] per 0.1 unit increase in waist to hip ratio. The significant association for height and CRC risk was similar in men and women. The significant association for BMI and CRC risk was stronger in men than in women. CONCLUSION: The positive association between height and risk of CRC suggests that life factors during childhood and early adulthood might play a role in CRC aetiology. Higher general and abdominal body fatness during adulthood are risk factors of CRC and these associations are stronger in men than in women.

Carbohydrates, glycemic index, glycemic load, and breast cancer risk: a systematic review and dose-response meta-analysis of prospective studies.

Context: The investigation of dose-response associations between carbohydrate intake, glycemic index, glycemic load, and risk of breast cancer stratified by menopausal status, hormone receptor status, and body mass index (BMI) remains inconclusive. Objective: A systematic review and dose-response meta-analyses was conducted to investigate these associations. Data Sources: As part of the World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project, PubMed was searched up to May 2015 for relevant studies on these associations. Study Selection: Prospective studies reporting associations between carbohydrate intake, glycemic index, or glycemic load and breast cancer risk were included. Data Extraction: Two investigators independently extracted data from included studies. Results: Random-effects models were used to summarize relative risks (RRs) and 95%CIs. Heterogeneity between subgroups, including menopausal status, hormone receptor status, and BMI was explored using meta-regression. Nineteen publications were included. The summary RRs (95%CIs) for breast cancer were 1.04 (1.00-1.07) per 10 units/d for glycemic index, 1.01 (0.98-1.04) per 50 units/d for glycemic load, and 1.00 (0.96-1.05) per 50 g/d for carbohydrate intake. For glycemic index, the association appeared slightly stronger among postmenopausal women (summary RR per 10 units/d, 1.06; 95%CI, 1.02-1.10) than among premenopausal women, though the difference was not statistically significant (Pheterogeneity = 0.15). Glycemic load and carbohydrate intake were positively associated with breast cancer among postmenopausal women with estrogen-negative tumors (summary RR for glycemic load, 1.28; 95%CI, 1.08-1.52; and summary RR for carbohydrates, 1.13; 95%CI, 1.02-1.25). No differences in BMI were detected. Conclusions: Menopausal and hormone receptor status, but not BMI, might be potential influencing factors for the associations between carbohydrate intake, glycemic index, glycemic load, and breast cancer.

An update of the WCRF/AICR systematic literature review on esophageal and gastric cancers and citrus fruits intake.

PURPOSE: The 2007 World Cancer Research Fund/American Institute for Cancer Research expert report concluded that foods containing vitamin C probably protect against esophageal cancer and fruits probably protect against gastric cancer. Most of the previous evidence was from case-control studies, which may be affected by recall and selection biases. More recently, several cohort studies have examined these associations. We conducted a systematic literature review of prospective studies on citrus fruits intake and risk of esophageal and gastric cancers. METHODS: PubMed was searched for studies published until 1 March 2016. We calculated summary relative risks and 95 % confidence intervals (95 % CI) using random-effects models. RESULTS: With each 100 g/day increase of citrus fruits intake, a marginally significant decreased risk of esophageal cancer was observed (summary RR 0.86, 95 % CI 0.74-1.00, 1,057 cases, six studies). The associations were similar for squamous cell carcinoma (RR 0.87, 95 % CI 0.69-1.08, three studies) and esophageal adenocarcinoma (RR 0.93, 95 % CI 0.78-1.11, three studies). For gastric cancer, the nonsignificant inverse association was observed for gastric cardia cancer (RR 0.75, 95 % CI 0.55-1.01, three studies), but not for gastric non-cardia cancer (RR 1.02, 95 % CI 0.90-1.16, four studies). Consistent summary inverse associations were observed when comparing the highest with lowest intake, with statistically significant associations for esophageal (RR 0.77, 95 % CI 0.64-0.91, seven studies) and gastric cardia cancers (RR 0.62, 95 % CI 0.39-0.99, three studies). CONCLUSIONS: Citrus fruits may decrease the risk of esophageal and gastric cardia cancers, but further studies are needed.