Urinary markers of nucleic acid oxidation and cancer in type 2 diabetes.

AIMS/HYPOTHESIS: We investigated whether urinary markers of nucleic acid oxidation are associated with an increased risk of cancer in type 2 diabetes patients. METHODS: Urine samples from 1381 newly diagnosed diabetes patients were assayed for the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo). Cox proportional hazards regression was used to examine the relationship between the urinary markers and cancer incidence. RESULTS: The crude analyses showed an association between overall cancer and urinary excretion of the RNA oxidation marker 8-oxoGuo (unadjusted hazard ratio for cancer per natural log increase in 8-oxoGuo 1.35 [95% CI, 1.01-1.81]), however, in the adjusted analyses, no significant associations between 8-oxodG or 8-oxoGuo and overall cancer were found. For site-specific cancers 8-oxodG was associated with breast cancer in the crude analyses (unadjusted hazard ratio for breast cancer per natural log increase in 8-oxodG was 2.37 [95% CI, 1.07-5.26]), although the association was attenuated in the adjusted analyses (sex- and age-adjusted hazard ratio 2.15 [95% CI, 0.92-5.02] and multivariate adjusted hazard ratio1.98 [95% CI, 0.95-4.10]). CONCLUSIONS: Urinary excretion of the nucleic acid oxidation markers 8-oxodG and 8-oxoGuo at the time of diagnosis was not associated with cancer overall in type 2 diabetes patients. For site-specific cancers, risk elevations were seen for breast cancer (8-oxodG). These findings should be examined in future and larger studies.

Association between urinary markers of nucleic acid oxidation and mortality in type 2 diabetes: a population-based cohort study.

OBJECTIVE: We recently showed that RNA oxidation, estimated by urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo), independently predicted mortality in a cohort of 1,381 treatment-naive patients with newly diagnosed type 2 diabetes. In the present investigation, we analyzed urine collected 6 years after the diagnosis to assess the association between urinary markers of nucleic acid oxidation and mortality in patients with established and treated diabetes. RESEARCH DESIGN AND METHODS: We used data from the 970 patients who attended the screening for diabetes complications 6 years after the diagnosis. Cox proportional hazards regression was used to examine the relationship between urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG] [n = 938]) and RNA oxidation (8-oxoGuo [n = 936]) and mortality. RESULTS: During a median of 9.8 years of follow-up, 654 patients died. Urinary 8-oxoGuo assessed 6 years after the diagnosis was significantly associated with mortality. The multivariate-adjusted hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.86 (95% CI 1.34-2.58) and 1.72 (1.11-2.66), respectively. Conversely, 8-oxodG was not associated with mortality. In addition, we found an association between changes in 8-oxoGuo from diagnosis to 6-year follow-up and mortality, with increased risk in patients with an increase and decreased risk in patients with a decrease in 8-oxoGuo. CONCLUSIONS: The RNA oxidation marker 8-oxoGuo is an independent predictor of mortality in patients with established and treated type 2 diabetes, and changes in 8-oxoGuo during the first 6 years after diagnosis are associated with mortality.

Increasing the general level of academic capacity in general practice: introducing mandatory research training for general practitioner trainees through a participatory research process.

BACKGROUND: To obtain good quality evidence-based clinical work there needs to be a culture of critical appraisal, and strong bridges between the clinical and the academic worlds in general practice. AIM: The aim was to educate the general practitioner (GP) trainees to obtain critical appraisal skills, and through the development and implementation of the mandatory programme to gradually empower the GP community to achieve academic capacity by creating a link between the GP researchers and the GP training community. This was done by developing a faculty, giving teaching skills to GP academics, and research skills to GP clinicians; and creating an awareness of the potential benefits of critical appraisal in training GP surgeries. METHODS: Development and implementation of a faculty and a programme through a participatory action research-inspired project, with process evaluation from the beginning of the planning phase. RESULTS: From 2006 to 2009, we built a teaching faculty of 25 teachers among clinical GPs and GP academics; developed the training programme; and delivered the programme to 95 GP trainees. Some of the GP trainees later showed an interest in more substantial research projects, and GP trainers with no previous association with the research environment started to show an interest through their function as GP trainers. The GP academics of the faculty, however, felt that it was difficult to continue the engagement because of the still increasing demand for published knowledge production in academia. CONCLUSION: It is possible to support the development of general academic capacity in general practice using participatory design in collaboration with GP academics and clinicians, building bridges between academia and clinical work, as well as within academia between research publication and teaching. There is, however, a generic barrier in the regulation of academia itself.

Urinary markers of nucleic acid oxidation and long-term mortality of newly diagnosed type 2 diabetic patients.

OBJECTIVE: We analyzed data from a cohort of 1,381 newly diagnosed type 2 diabetic patients to test the hypothesis that urinary markers of nucleic acid oxidation are independent predictors of mortality. RESEARCH DESIGN AND METHODS: We examined the relationship between urinary excretion of markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) and RNA oxidation (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and long-term mortality using Cox proportional hazards regression. RESULTS: After multivariate adjustment, the hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.44 (1.12-1.85) and 1.54 (1.13-2.10), respectively. Conversely, no significant associations between 8-oxodG and mortality were found in the adjusted analyses. CONCLUSIONS: Urinary excretion of the RNA oxidation marker 8-oxoGuo measured shortly after diagnosis of type 2 diabetes predicts long-term mortality independently of conventional risk factors. This finding suggests that 8-oxoGuo could serve as a new clinical biomarker in diabetes.

Patients newly diagnosed with clinical type 2 diabetes during oral glucocorticoid treatment and observed for 14 years: all-cause mortality and clinical developments.

Chronic exposure to glucocorticoids (GCs) has many side effects including glucose intolerance and diabetes and may accelerate the occurrence of cardiovascular disease and increase mortality. We studied the 14-year clinical development of diabetes in patients diagnosed with diabetes during GC treatment. A population-based sample of 1369 people newly diagnosed with clinical type 2 diabetes underwent a clinical examination at diagnosis, and surviving patients were followed up 6 and 14 years later. Patients receiving oral GC treatment at diagnosis were compared with the other patients. Of 1369 patients, 35 (2.6%) were treated with oral GCs at diabetes diagnosis. At that point, patients on GC therapy were older (69.9 versus 65.3 years, p = 0.007, sex-adjusted) and tended to have lower BMI (26.1 versus 29.1 kg/m(2) , p = 0.023), also 6 years after diagnosis (24.8 versus 28.4, p = 0.011), than patients not being treated with GCs. In a univariate Cox regression model, GC treatment at diagnosis increased all-cause mortality with a hazard ratio (95% confidence interval) of 2.01 (1.39-2.89, p = 0.0002, n = 1369), while this decreased to 1.41 (0.98-2.04, p = 0.065, n = 1369) when adjusted for age and sex and to 1.39 (0.92-2.11, p = 0.12, n = 1086) when risk factors, complications and cancer were added to the model. Apart from differences in age and overweight, patients in this relatively small sample of those diagnosed with clinical type 2 diabetes during GC treatment were comparable at diagnosis and during 14 years of follow-up with those not treated with GCs, including with regard to the adjusted mortality rate.

Predictors of mortality of patients newly diagnosed with clinical type 2 diabetes: a 5-year follow up study.

BACKGROUND: At diabetes diagnosis major decisions about life-style changes and treatments are made based on characteristics measured shortly after diagnosis. The predictive value for mortality of these early characteristics is widely unknown. We examined the predictive value of patient characteristics measured shortly after diabetes diagnosis for 5-year all-cause and cardiovascular mortality with special reference to self-rated general health. METHODS: Data were from a population-based sample of 1,323 persons newly diagnosed with clinical diabetes and aged 40 years or over. Possible predictors of mortality were investigated in Cox regression models. RESULTS: Multivariately patients who rated their health less than excellent experienced increased all-cause and cardiovascular mortality. These end-points also increased with sedentary life-style, relatively young age at diagnosis and presence of cardiovascular disease (CVD) at diagnosis. Further predictors of all-cause mortality were male sex, low body mass index and cancer, while cardiovascular mortality increased with urinary albumin concentration. CONCLUSIONS: We found that patients who rated their health as less than excellent had increased 5-year mortality, similar to that of patients with prevalent CVD, even when biochemical, clinical and life-style variables were controlled for. This finding could motivate doctors to discuss perceptions of health with newly diagnosed diabetic patients and be attentive to patients with suboptimal health ratings. Our findings also confirm that life-style changes and optimizing treatment are particularly relevant for relatively young and inactive patients and those who already have CVD or (micro)albuminuria at the time of diabetes diagnosis.

Changes in levels of haemoglobin A1c during the first 6 years after diagnosis of clinical type 2 diabetes.

OBJECTIVE: To assess the variability in levels of glycosylated haemoglobin (HbA(1c)) during the first six years after diagnosis of clinical type 2 diabetes in relation to possible predictors. MATERIAL AND METHODS: Data were from a population-based sample from general practice of 581 newly diagnosed diabetic patients aged 40 or over. Estimation of HbA(1c) was centralized. The changes in levels of HbA(1c) were described by HbA(1c) at diagnosis and a regression line fitted to the HbA(1c) measurements after 1-year follow-up for each patient. The predictive effect of patient characteristics for changes in HbA(1c) was investigated in a multivariate mixed model. RESULTS: During the first year after diabetes diagnosis, HbA(1c) dropped to near normal average level and then started rising almost linearly. A sharp rise in long-term glycaemic level was observed in approximately a quarter of the patients, especially the relatively young. Of 581 patients, 156 (26.9%) patients, however, experienced a fall in HbA(1c) after 1-year follow-up and another quarter showed constant or only slowly rising HbA(1c). The changes in levels of HbA(1c) were only predicted by diagnostic HbA(1c) and age. CONCLUSIONS: During the first 6 years after the diagnosis of clinical type 2 diabetes, changes in levels of HbA(1c) show considerable inter-individual variability with age as the only long-term predictor. The results indicate that it is important to monitor changes in HbA(1c) more closely and intensify treatment of those often relatively young patients who actually experience the beginning of an apparently relentless deterioration of their glycaemic control.

16-year excess all-cause mortality of newly diagnosed type 2 diabetic patients: a cohort study.

BACKGROUND: Studies have shown that type 2 diabetic patients have higher all-cause mortality than people without diabetes, but it is less clear how diabetes affects mortality in elderly patients and to what degree mortality differs between diabetic men and women. The aim of the present study is to investigate the age- and sex-specific all-cause mortality pattern in patients with type 2 diabetes in comparison with the Danish background population. METHODS: Population-based cohort study of 1323 patients, diagnosed with clinical type 2 diabetes in 1989-92 and followed for 16 years. Median (interquartile range) age at diagnosis was 65.3 (55.8-73.6) years. The age- and sex-specific hazard rates were estimated for the cohort using the life table method and compared with the expected hazard rates calculated with Danish register data from the general population. RESULTS: In comparison with the general population, diabetic patients had a 1.5-2.5 fold higher risk of dying depending on age. The over-mortality was higher for men than for women. It decreased with age in both sexes, and among patients over 80 years at diagnosis the difference between the observed and the expected survival was small. CONCLUSION: We found an excess mortality of type 2 diabetic patients compared with the background population in all age groups. The excess mortality was most pronounced in men and in young patients.

Individualised treatment goals in diabetes care.

OBJECTIVES: To examine 1) patients' characteristics according to the treatment goal chosen at diabetes diagnosis, and 2) the association between individualised goals for glycated haemoglobin (HbA1c), blood pressure (BP) and lipids, and the risk factor level subsequently achieved. DESIGN: Follow-up study embedded in a multifaceted intervention study directed at doctors encouraging individualised goal-setting in newly diagnosed diabetic patients aged > or = 40 years. SETTING: General practice. SUBJECTS: In all, 243 general practitioners and 674 patients participated. MAIN OUTCOME MEASURES: Risk factors for diabetic complications. RESULTS: Relatively young age, low diagnostic plasma glucose, low BMI, a moderate or high level of physical activity and normoalbuminuria were associated with a treatment goal of good control at diagnosis. After 5 years, median HbA1c was 8.2%, 8.6% and 8.0% in patients with a goal of good, acceptable and poor control, respectively. Patients with a goal of good control versus those with a goal of acceptable control had a lower HbA1c level in a regression analysis adjusted for age, sex, HbA1c at diagnosis, BMI, total cholesterol, fasting triglycerides, BP, physical activity, smoking status and diabetes duration. We found no association between goals and the level of BP and lipids. CONCLUSION: Doctors tend to pursue normoglycaemia in relatively young patients with low blood glucose, low BMI, high activity level and normoalbuminuria. Patients for whom a goal of normoglycaemia was chosen at diagnosis achieved favourable glycaemic control at 5-year follow-up. Whether doctors choosing the goals were good at predicting future glycaemic control, or whether goal-setting is an important motivational factor in achieving optimal glycaemic control needs to be explored.

Encouraging structured personalised diabetes care in general practice. A 6-year follow-up study of process and patient outcomes in newly diagnosed patients.

OBJECTIVE: To evaluate the quality of diabetes care achieved on the process and outcomes of care in the context of a multifaceted intervention directed at general practitioners (GPs) encouraging regular follow-up and individualised goal-setting. DESIGN: A 6-year follow-up study. SETTING: A total of 243 Danish GPs and a population-based sample of 729 newly diagnosed, predominantly type 2 diabetic patients participated. MAIN OUTCOME MEASURES: Questionnaires and laboratory assessments were used to determine the proportion of patients reviewed regularly, and their pharmacological treatment and risk factors. RESULTS: During the study, the proportion of patients who had an annual clinical examination decreased from 100% to 77%. The proportion given oral anti-diabetic agents or insulin increased from 43% to 71%. Median glycated haemoglobin (HbA1c) dropped in the 2nd year to 7.7% (normal range 5.4-7.4%), after which it increased gradually, but remained on average at 1.3% above the upper limit of the normal range. Median blood pressure (systolic/diastolic), total cholesterols and fasting triglycerides were maintained at 145-150/81-85 mmHg, 6.0-6.2 mmol/l and 1.66-1.96 mmol/l, respectively. Initial weight loss was partly regained over 6 years. CONCLUSION: Among centrally supported GPs, most patients were regularly reviewed and obtained acceptable levels of risk factors for at least 6 years, although glycaemic control progressively deteriorated after an initial drop to near-normal average level.

Doctors' characteristics do not predict long-term glycaemic control in type 2 diabetic patients.

Glycaemic control in type 2 diabetic patients varies widely between general practitioners (GPs). To increase our understanding of this variation, linear random effects models were used to examine the predictive value of GP characteristics on the course of annual HbA1c measurements, in 688 newly diagnosed type 2 diabetic patients between one and five years after diabetes diagnosis. We found that characteristics of centrally supported GPs, such as interest in diabetes, experience, practice type, list size, and weekly working hours, did not predict their patients' glycaemic control.