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  • 1
    Keywords: CANCER ; cohort studies ; RISK-FACTORS ; PREVALENCE ; nutrition ; GENETIC EPIDEMIOLOGY ; PHYSICAL-ACTIVITY ; CORONARY-HEART-DISEASE ; SPAIN ; type 2 diabetes ; LOCI ; Diabetes Mellitus ; GENOME-WIDE ASSOCIATION ; Epidemiologic research design ; Gene-lifestyle interaction ; POPULATION-BASED INCIDENCE
    Abstract: Studying gene-lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene-lifestyle studies are lacking. This case-cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes. Incident cases of type 2 diabetes occurring in European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts between 1991 and 2007 from eight of the ten EPIC countries were ascertained and verified. Prentice-weighted Cox regression and random-effects meta-analyses were used to investigate differences in diabetes incidence by age and sex. A total of 12,403 verified incident cases of type 2 diabetes occurred during 3.99 million person-years of follow-up of 340,234 EPIC participants eligible for InterAct. We defined a centre-stratified subcohort of 16,154 individuals for comparative analyses. Individuals with incident diabetes who were randomly selected into the subcohort (n = 778) were included as cases in the analyses. All prevalent diabetes cases were excluded from the study. InterAct cases were followed-up for an average of 6.9 years; 49.7% were men. Mean baseline age and age at diagnosis were 55.6 and 62.5 years, mean BMI and waist circumference values were 29.4 kg/m(2) and 102.7 cm in men, and 30.1 kg/m(2) and 92.8 cm in women, respectively. Risk of type 2 diabetes increased linearly with age, with an overall HR of 1.56 (95% CI 1.48-1.64) for a 10 year age difference, adjusted for sex. A male excess in the risk of incident diabetes was consistently observed across all countries, with a pooled HR of 1.51 (95% CI 1.39-1.64), adjusted for age. InterAct is a large, well-powered, prospective study that will inform our understanding of the interplay between genes and lifestyle factors on the risk of type 2 diabetes development
    Type of Publication: Journal article published
    PubMed ID: 21717116
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  • 2
    Keywords: MORTALITY ; score ; prevention ; PROSPECTIVE COHORT ; MYOCARDIAL-INFARCTION ; ADULTS ; CORONARY-HEART-DISEASE ; METAANALYSIS ; GLYCATED HEMOGLOBIN ; A1C
    Abstract: This study aimed to assess the cardiovascular risk of individuals with fasting plasma glucose (FPG)- and/or HbA(1c)-defined prediabetes (5.6-6.9 mmol/l and 39-47 mmol/mol [5.7-6.4%], respectively) or manifest diabetes mellitus and to evaluate whether FPG or HbA(1c) can improve risk prediction beyond that estimated by the Systematic Coronary Risk Evaluation (SCORE) chart in individuals without diabetes mellitus. Cox regression was employed to estimate HRs for primary incident cardiovascular events (CVEs) in a cohort of 8,365 individuals aged 50-74 years. Furthermore, HbA(1c) and FPG were added individually to the variables of the SCORE and measures of model discrimination and reclassification were assessed. During 8 years of follow-up, 702 individuals had a primary CVE. After adjusting for conventional cardiovascular risk factors, HRs were attenuated close to one for the prediabetes groups (especially for women), whereas a 1.7- and a 1.9-fold increased risk persisted for men and women with diabetes, respectively. Extension of the SCORE variables by either FPG or HbA(1c) did not improve its predictive abilities in individuals without diabetes. There was a non-significant net reclassification improvement for men when HbA(1c) was added (2.2%, p = 0.16). The increased cardiovascular risk of individuals with FPG- or HbA(1c)-defined prediabetes can mainly be explained by other cardiovascular risk factors. Adding FPG or HbA(1c) did not significantly improve CVE risk prediction by the SCORE variables in individuals without diabetes mellitus.
    Type of Publication: Journal article published
    PubMed ID: 22986731
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  • 3
    Keywords: CANCER ; COHORT ; RISK ; BODY-WEIGHT ; WOMEN ; OBESITY ; DIETARY ; PROJECT ; metabolic syndrome ; WEIGHT-GAIN
    Abstract: 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.
    Type of Publication: Journal article published
    PubMed ID: 23620057
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  • 4
    Keywords: GENE-EXPRESSION ; DIABETES-MELLITUS ; OXIDATIVE STRESS ; COMPLICATIONS ; C-ELEGANS ; METHYLGLYOXAL ; GLYOXALASE-I ; GLYCATION ; Longevity ; SPAN
    Abstract: The aim of this study was to determine the protective effects of human insulin and its analogues, B28Asp human insulin (insulin aspart) and B29Lys(epsilon-tetradecanoyl),desB30 human insulin (insulin detemir), against glucose-induced lifespan reduction and neuronal damage in the model organism Caenorhabditis elegans and to elucidate the underlying mechanisms. Nematodes were cultivated under high glucose (HG) conditions comparable with the situation in diabetic patients and treated with human insulin and its analogues. Lifespan was assessed and neuronal damage was evaluated with regard to structural and functional impairment. Additionally, the activity of glyoxalase-1 and superoxide dismutase (SOD) and the formation of reactive oxygen species (ROS) and AGEs were determined. Insulin and its analogues reversed the life-shortening effect of HG conditions and prevented the glucose-induced neuronal impairment. Insulin treatment under HG conditions was associated with reduced concentration of glucose, as well as a reduced formation of ROS and AGEs, and increased SOD activity. These effects were dependent on the Forkhead box O (FOXO) homologue abnormal dauer formation (DAF)-16. Furthermore, glyoxalase-1 activity, which was impaired under HG conditions, was restored by human insulin. This was essential for the insulin-induced lifespan extension under HG conditions, as no change in lifespan was observed following either suppression or overexpression of glyoxalase-1. Human insulin and its analogues prevent the reduction in lifespan and neuronal damage caused by HG conditions. The effect of human insulin is mediated by a daf-2/insulin receptor and daf-16/FOXO-dependent pathway and is mediated by upregulation of detoxifying mechanisms.
    Type of Publication: Journal article published
    PubMed ID: 25322843
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    Abstract: AIMS/HYPOTHESIS: Studies on weight cycling and the risk of type 2 diabetes have revealed inconsistent results, possibly due to differences in the definition of weight fluctuations. Here, we investigated whether weight cycling during adulthood is related to diabetes risk in a large cohort study, using a complementary approach to define patterns of weight development. METHODS: Weight cycling, weight loss and weight gain were defined (1) a priori, using distinct categories, and (2) by functional principal component analysis (FPCA) to capture weight patterns in greater detail. Associations of weight cycling, weight loss and weight gain with the risk of type 2 diabetes were evaluated by Cox regression models. RESULTS: A priori defined weight cycling was associated with increased diabetes risk, compared with stable weight (HR 1.36 [95% CI 1.09, 1.68]). No significant association between FPCA-derived weight cycling and risk of diabetes was observed after adjustment for concurrent weight patterns (HR 1.19 [95% CI 0.89, 1.60]). Subgroup analyses showed that FPCA-derived weight cycling during net weight gain was associated with a higher risk of diabetes (HR 1.68 [95% CI 1.14, 2.48]). A priori defined weight gain (HR 2.08 [95% CI 1.60, 2.70]) was more clearly related to the risk of diabetes than FPCA-derived weight gain (HR 1.20 [95% CI 0.95, 1.51]), while no significant associations were observed for weight loss. CONCLUSIONS/INTERPRETATION: Overall, weight cycling may not be an independent risk factor for type 2 diabetes when accounting for concurrent patterns of weight development. However, weight cycling may pose a stronger risk of diabetes than non-cycling during net weight gain.
    Type of Publication: Journal article published
    PubMed ID: 26376796
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  • 7
    Abstract: AIMS/HYPOTHESIS: Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation technology. METHODS: A long-acting leptin version was prepared by genetic fusion with a 600 residue polypeptide made of Pro, Ala and Ser (PASylation), which enlarges the hydrodynamic volume and, thus, retards renal filtration, allowing less frequent injection. LD was induced in C57BL/6J mice by feeding a diet supplemented with conjugated linoleic acid (CLA). Chronic and acute effects of leptin treatment were assessed by evaluating plasma insulin levels, insulin tolerance, histological liver sections, energy expenditure, energy intake and body composition. RESULTS: In a cohort of female mice, 4 nmol PAS-leptin (applied via four s.c. injections every 3 days) successfully alleviated the CLA-induced LD phenotype, which was characterised by hyperinsulinaemia, insulin intolerance and hepatosteatosis. The same injection regimen had no measurable effect when unmodified recombinant leptin was administered at an equivalent dose. In a cohort of LD males, a single s.c. injection of PAS-leptin did not affect energy expenditure but inhibited food intake and promoted a shift in fuel selection towards preferential fat oxidation, which mechanistically substantiates the metabolic improvements. CONCLUSIONS/INTERPRETATION: The excellent pharmacological properties render PASylated leptin an agent of choice for refining both animal studies and therapeutic strategies in the context of LD syndromes and beyond.
    Type of Publication: Journal article published
    PubMed ID: 27272237
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  • 8
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; carcinoma ; CELL ; Germany ; human ; KINASE ; MODEL ; MODELS ; COMMON ; SYSTEM ; NEW-YORK ; RISK ; PROTEIN ; PROTEINS ; METABOLISM ; TRANSDUCTION ; CARCINOGENESIS ; RAT ; animals ; RATS ; CONTRAST ; protein kinase ; PROTEIN-KINASE ; signal transduction ; treatment ; SIGNAL ; LESIONS ; PATTERNS ; NUMBER ; SIGNAL-TRANSDUCTION ; leukemia ; PRODUCT ; ONCOGENE ; TRANSFORMATION ; EPITHELIAL-CELLS ; GLUCOSE ; DIABETES-MELLITUS ; RECEPTORS ; ORIGIN ; insulin ; MELLITUS ; FACTOR-ALPHA ; IGF-I ; CELL CARCINOMA ; renal cell carcinoma ; PATTERN ; SYNTHASE ; TRANSITION ; development ; GROWTH-FACTOR-I ; SUBSTRATE ; LEVEL ; ENZYME ; methods ; SIZE ; EPITHELIAL TUMORS ; USA ; PROLIFERATIVE ACTIVITY ; PHOSPHATASE ; GEFITINIB ; INCREASED RISK ; CANCER-RISK ; E ; KINASE-1 ; PRECURSOR ; animal ; Diabetes Mellitus ; viral ; TGF-ALPHA ; - ; GROWTH-FACTORS ; ACIDOPHILIC CELL TUMORS ; Armanni-Ebstein lesion ; diabetic tubulopathy ; distal tubule ; ENZYMATIC PATTERNS ; hyperglycaemia ; IGF ; IGF-I receptor ; INSULIN-LIKE ; KIDNEY TUMORS ; nephrocarcinogenesis ; PANCREATIC-ISLET TRANSPLANTATION ; PRENEOPLASTIC HEPATIC FOCI ; SUBSTRATE-1 ; TRANSITIONS
    Abstract: Aims/hypothesis There is an increased risk of renal cell carcinoma (RCC) in human diabetes mellitus. We therefore examined the influence of hyperglycaemia and glucose-lowering treatment on nephrocarcinogenesis in rats. Methods Rats (n= 850), which were either spontaneously diabetic, streptozotocin-diabetic or normoglycaemic, were examined with special reference to Armanni-Ebstein lesions (AEL). Results Irrespective of the cause of diabetes, diabetic but not normoglycaemic rats developed typical glycogenotic clear-cell AEL. AEL showed strong proliferative activity, which was nearly completely inhibited by EGF receptor blockade (Gefitinib treatment). Many findings suggested a stepwise development of RCCs from AEL. Whereas the number and size of RCCs gradually increased in all diabetic groups, beginning at 6 months after onset of diabetes, normoglycaemic controls did not developed RCC. After 28 months, up to 82% of diabetic animals had at least one RCC. In contrast to the proximal tubules, the distal tubular system, including glycogenotic AEL, had the same levels of enzyme activities as RCC (e. g. high glycogen phosphorylase and synthase activity, lack of glucose 6- phosphatase activity) and the same expression patterns of cytokeratin 7 and several growth factors, along with their receptors and signal transduction proteins (TGF-alpha, EGF receptor, IGF-I, IGF-I receptor, IGF-II receptor, insulin receptor substrate 1, v-raf-1 murine leukemia viral oncogene homologue 1 and mitogen activated protein kinase kinase 1). In addition, direct morphological transitions between distal tubules, AEL and RCCs were frequently observed. All these findings indicate a common origin and a precursor - product relationship of AEL and RCCs. Conclusions/interpretation Nephrocarcinogenesis in diabetic rats results from sustained hyperglycaemia, resulting in an adaptive metabolic response, altered growth factor signalling and subsequent neoplastic transformation of the tubular epithelial cells
    Type of Publication: Journal article published
    PubMed ID: 17952403
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  • 9
    Keywords: DIAGNOSIS ; cohort study ; MORTALITY ; WOMEN ; CIGARETTE-SMOKING ; MEN ; OBESITY ; diabetes ; GLUCOSE ; EPIC ; pancreatic cancer ; METAANALYSIS ; INSULIN-RESISTANCE ; OVERWEIGHT ; C-PEPTIDE ; HbA(1c)
    Abstract: 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
    Type of Publication: Journal article published
    PubMed ID: 21953276
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