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To describe and compare attendance rates and the proportions of people identified with Type 2 diabetes mellitus in people with previously unknown diabetes who participated in screening programmes undertaken in general practice in the UK, Denmark and the Netherlands as part of the ADDITION-Europe study.

Folate deficiency can affect DNA methylation and DNA synthesis. Both factors may be operative in colorectal carcinogenesis. Many enzymes, like methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), methionine synthase (MTR), and serine hydroxymethyltransferase (SHMT), are needed for conversions in folate metabolism. Flavin adenine dinucleotide, a metabolite of vitamin B2, is a cofactor for MTHFR; vitamin B6 is a cofactor for SHMT; and vitamin B12 is a cofactor for MTR. Polymorphisms exist in most of the genes encoding the enzymes that play a role in folate metabolism. Therefore, genetic variation might influence DNA methylation and synthesis processes and thus colorectal carcinogenesis. This thesis describes studies that have been conducted to clarify the role of folate, related B-vitamins, and genetic variation in colorectal carcinogenesis.In a meta-analysis of human observational studies on the association between folate intake and risk of colorectal adenomas, includingdata from 4 cohort studies and 10 case-control studies, pooled relative risks (95% confidence interval (CI)) for highestvs.lowest exposure category of 0.85 (0.71;1.01) for dietary folate intake and 0.75 (0.61;0.93) for total folate intake were found.In a Dutch case-control study, including data of colorectal adenoma cases (n=768) and endoscopy controls with no history colorectal polyps (n=709), a slightly positive association between folate and colorectal adenoma risk (odds ratio (OR) highest vs. lowest tertile 1.32, 95% CI 1.01;1.73), and an inverse association between vitamin B2 intake and colorectal adenoma risk (OR highestvs.lowest tertile 0.51, 95% CI 0.36;0.73) was found, especially among those withMTHFR 677 TTgenotype. A null association was found for vitamin B6 and vitamin B12. Furthermore, the combined intake of B-vitamins might be important: the positive association between folate intake and colorectal adenomas seemed to be more pronounced among those with low vitamin B2 intakes. The polymorphisms in the folate metabolism studied (MTHFR, TSandSHMT1) did not seem to influence colorectal adenoma risk when dietary factors were not taken into account. Furthermore, relatively high folate intake (>212μg/day) was mildly inversely associated with promoter methylation of six selected tumor suppressor and DNA repair genes in adenoma tissue as compared with low folate intake (

article i nfo Type 2 diabetes Cognitive functioning Intensive multifactorial therapy Randomized controlled trial Cohort study Complications Aim: To assess whether an intensive multifactorial treatment can reduce cognitive decrements and cognitive decline in screen-detected type 2 diabetes. Methods: The multinational ADDITION-study, a cluster-randomized parallel group trial in patients with screen- detected type 2 diabetes, compared the effectiveness of intensive multifactorial treatment (IT; lifestyle advice and strict regulation of metabolic parameters) with routine care (RC) on cardiovascular outcome. In The Netherlands randomization was stratified according to practice organization. Allocation was concealed from patients. The present study assessed the effect of IT on cognition through two neuropsychological assessments (NPA) on two occasions. The assessments took place three and six years after the start of the intervention. Non- diabetic controls served as reference group. The first NPA was performed in 183 patients (IT: 97; RC: 86) and 69 controls. The second NPA was performed in 135 patients (IT: 71; RC: 64) and 55 controls. Primary outcome was a composite score, including the domains memory, information-processing speed and attention and executive function. Comparisons between the treatment groups were performed with multi-level analyses. Results: The first NPAshowed no differences between the treatment groups(mean differencecomposite z-score: 0.00; 95%-CI −0.16 to 0.16; IT vs RC). Over the next three years cognitive decline in the diabetic groups was within the range of the reference group and did not differ between the treatment arms (difference decline between diabetic groups −0.12; −0.24 to 0.01; IT vs RC). Conclusions: Six years of IT in screen-detected type 2 diabetes had no benefit on cognitive functioning over RC.

In 2005 we investigated in a questionnaire survey in 1621 general practitioners (GPs) whether the practice organisation in primary care is equipped to provide optimal diabetes care. This was expressed in the Structure Index (SI), based on the presence of practice characteristics (score 0-4.5). The mean SI was 2.10.9 and was higher in training practices and in practices in which GPs started insulin treatment. About 75% of the GPs worked in practices that were average in organisation necessary to provide optimal diabetes care; the rest worked in practices poorly equipped or in practices well equipped to provide such care. In the questionnaire survey, we investigated the organisation of insulin therapy and assessed factors that were associated with providing insulin therapy in type 2 diabetes patients. 67% of the GPs start insulin therapy, especially male GPs and those older than 40, GPs working in a health centre and those working with a practice nurse. GPs working in urban regions less often start insulin. The most often mentioned barriers for starting insulin therapy were lack of knowledge, lack of time and insufficient financial incentives. We compared psychological well-being between type 2 diabetes patients using oral glucose lowering agents and patients on insulin therapy with or without oral agents. Insulin-users reported worse outcomes on Short Form-36 subdomains physical functioning and general health; and on Diabetes Health Profile (DHP) total score, barriers to activity and psychological distress. Insulin regimen and diabetes duration did not influence these outcomes. We reviewed 78 randomised clinical trials regarding insulin preparations in patients with type 2 diabetes. They showed that continuing oral glucose lowering agents after the start of basal insulin therapy resulted in better glycaemic control with less insulin requirements, less weight gain and less hypoglycaemic events than monotherapy. Long-acting insulin analogues were associated with similar glycaemic control, but less hypoglycaemia than NPH insulin. Premix insulin provided better glycaemic control than a basal insulin, but caused more hypoglycaemia. Analogue premix insulin provided similar glycaemic control, but lower postprandial glucose levels compared to human premix insulin. Drawing conclusions from the studies concerning basal-bolus regimen seemed not possible. In a randomised clinical trial 39 type 2 diabetes patients with inadequate glycaemic control on metformin and sulphonylurea, were randomised to continue or discontinue sulphonylurea, once they started insulin glargine therapy and continued metformin. After one year, the combination with sulphonylurea provided no significant differences in C-peptide-glucose ratio, an estimator for ?-cell function, compared to not using sulphonylurea. In the group continuing sulphonylurea the number of hypoglycaemic events was higher and also weight gain was, not statistically significant, higher in this group. We reviewed the effects of insulin monotherapy versus insulin-oral glucose lowering agents combination therapy in type 2 diabetes patients already treated with insulin in 38 randomised clinical trials. The addition of oral agents has positive effects on glycaemic control and insulin requirements. Combination with sulphonylurea or thiazolidinediones causes more hypoglycaemic events, thiazolidinediones more weight gain and metformin less weight gain. Side effects such as gastro-intestinal complaints and oedema also occurs.

The increasing number of type 2 diabetes patient and the strict targets for glycemic and cardiovascular control demand a good practice organisation and task delegation. The Diabetes Care Protocol (DCP) may improve diabetes management. It consists of a diabetes consultation hour run by a practice nurse, a computerized decision support system (CDSS) that contains a diagnostic and treatment algorithm based on the Dutch type 2 diabetes guidelines and provides patient-specific treatment advice, a recall system and feedback on performance. This thesis evaluates the effectiveness of the DCP. A before-after trial in 113 DCP practices showed improvements in the number of patients reaching treatment targets for HbA1c, blood pressure and cholesterol. This finding was then confirmed by a 1-year cluster randomized trial in 55 primary care practices. Mean changes in cardiovascular risk factors were calculated by generalized linear models. HbA1c difference was not significant, blood pressure, total cholesterol and LDL-cholesterol were. The 10-year UK prospective diabetes study coronary heart disease risk improved 1.4% (p