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Background: Survival from many cancer types is steadily increasing, and as a result, a growing number of cancer patients will live with other chronic diseases, of which diabetes is one of the most prevalent. This study aims to describe the impact of cancer on health outcomes in patients with type 2 diabetes and to compare the effectiveness of a multifactorial intervention in diabetes patients with and without cancer., Methods: The randomized controlled trial Diabetes Care in General Practice (DCGP) included 1381 patients newly diagnosed with type 2 diabetes. Patients were randomized to either six years of structured personal diabetes care or routine care. In a post hoc analysis, we followed patients for 19 years in Danish national registries for the occurrence of diabetes-related outcomes. We used Cox regression models to estimate hazard ratios for outcomes., Results: At diagnosis 48 patients had cancer, and 243 patients were diagnosed with cancer during follow up. Patients with diabetes and cancer had excess all-cause mortality (HR 3.33; 95%CI 2.72-4.06), as well as an increased incidence of myocardial infarction (HR 1.76; 95%CI 1.29-2.39) and any diabetes-related outcome (HR 1.36; 95%CI 1.07-1.71). The intervention reduced the risk of both these endpoints in patients without cancer. Furthermore, there was no statistically significant difference in the effectiveness of the intervention among patients with and without cancer., Conclusions: Diabetes patients with cancer had an increased risk of myocardial infarction and any diabetes-related outcome. The observed positive effect of structured personal diabetes care on clinical outcomes did not differ between patients with and without cancer. Attention to and prevention of diabetes complications in patients with both type 2 diabetes and cancer is warranted., Trial Registration: ClinicalTrials.gov NCT01074762 (February 24, 2010).

Aims: The urinary marker of RNA oxidation, 8‑oxo‑7,8‑dihydroguanosine (8-oxoGuo), but not the corresponding marker of DNA oxidation, 8‑oxo‑7,8‑dihydro‑2'‑deoxyguanosine (8-oxodG), is a prognostic biomarker in patients with type 2 diabetes (T2D). The aim of the present study was to investigate the effect of structured personal care (individualized multifactorial treatment) versus standard care on RNA oxidation level in patients with T2D and to assess if the effect of structured personal care on all-cause and diabetes-related mortality was modified by RNA oxidation level., Methods: Urine samples were analyzed for 8-oxoGuo/8-oxodG from 1381 newly diagnosed T2D patients from the cluster randomized trial Diabetes Care in General Practice cohort, and 970 patients were reexamined after six years of intervention., Results: The yearly variation in RNA oxidation levels were not significantly different between the structured personal care group and standard care group. The effect of treatment on all-cause and diabetes-related mortality was not modified by the level of RNA oxidation. No changes in DNA oxidation were seen., Conclusions: Structured personal care does not influence RNA oxidation level nor is it better for patients with high RNA oxidation level. Thus, structured personal care may not impact the disease-related aspects identified by RNA oxidation level in T2D patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: To investigate, in a large population in primary care, the relationship between fasting plasma glucose and HbA 1c measurements, as well as the clinical implications of anaemia or chronic kidney disease for the interpretation of HbA 1c values., Methods: From a primary care resource, we examined HbA 1c and fasting plasma glucose as well as haemoglobin and estimated GFR. We stratified observations by chronic kidney disease stage and anaemia level. The estimation of the mean fasting plasma glucose level from HbA 1c alone, and from HbA 1c , haemoglobin and estimated GFR, respectively, was evaluated., Results: In 198 346 individuals, the fasting plasma glucose-HbA 1c relationship mimicked the regression described in the A1c-Derived Average Glucose (ADAG) study, which was based on average capillary and interstitial glucose. The fasting plasma glucose-HbA 1c relationship was unaffected in mild to moderate chronic kidney disease and in mild to moderate anaemia. The correlation changed only in severe hyperglycaemia and concurrent severe anaemia or when estimated GFR was <45 ml/min/1.73m², so that glucose concentration was underestimated by HbA 1c in anaemia and overestimated in chronic kidney disease. The prevalence of estimated GFR <30 ml/min/1.73m² was 0.82%, while the prevalence of haemoglobin <81 g/l (5.0 mmol/l) was 0.11%., Conclusions: The relationship between fasting plasma glucose and HbA 1c mimics that of the people with diabetes included in the ADAG study. Mild to moderate anaemia and CKD do not have a significant impact on the interpretation of HbA 1c as a marker of retrograde glycaemia. Hence, it seems justified to use HbA 1c without adjustment in primary care., (© 2018 Diabetes UK.)

Aims: To explore the effect of structured personal care on diabetes symptoms and self-rated health over 14 years after diabetes diagnosis while patients are gradually diagnosed with other chronic conditions (multimorbidity)., Methods: Post hoc analysis of the Danish randomized controlled trial Diabetes Care in General Practice including 1381 patients newly diagnosed with type 2 diabetes. The effect of structured personal care compared with routine care on diabetes symptoms and self-rated health was analysed 6 and 14 years after diagnosis with a generalized multilevel Rasch model., Results: Structured personal care reduced the overall likelihood of reporting diabetes symptoms at the end of the intervention (OR 0.79; 95% CI: 0.64-0.97), but this effect was not explained by glycaemic control or multimorbidity. There was no effect of the intervention on diabetes symptoms after 14 years or on self-rated health after 6 years or 14 years., Conclusions: Structured personal care had a beneficial effect on diabetes symptoms 6 years after diagnosis, but not on self-rated health at either follow up point. To optimally manage patients over time it is important to supplement clinical information by information provided by the patients., (Copyright © 2018 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Urinary albumin is an important biomarker used to identify high risk patients with diabetes, but there is a need for new biomarkers that alone or in combination with urinary albumin could give an even better prediction of clinical patient outcomes. One promising biomarker is 8-oxo-7,8-dihydroguanosine (8-oxoGuo) that represents intracellular oxidative stress. We investigated the ability of microalbuminuria (MA) and urinary 8-oxoGuo, alone and in combination, to predict mortality and cardiovascular disease (CVD) in patients with type 2 diabetes. We used data from 1381 newly diagnosed diabetes patients, and urinary albumin and 8-oxoGuo were assessed in morning urine collected at the time of diabetes diagnosis and at a follow-up visit 6 years later. Associations between the urinary markers and mortality and CVD were assessed in Cox proportional hazards regression models. Test performance was assessed using sensitivity, specificity, positive predictive value and negative predictive value for 10-year mortality and 10-year incidence of CVD. Both 8-oxoGuo and urinary albumin were statistically significantly associated with all-cause mortality at diagnosis as well as at 6-year follow-up. At diagnosis only urinary albumin was associated with CVD. In contrast, only 8-oxoGuo was associated with CVD at 6-year follow-up. When investigating test performance, we found that by combining information from MA and 8-oxoGuo the ability to correctly identify patients at risk could be improved. The findings suggest that measurement of urinary 8-oxoGuo provides additional information about risk to that obtained from urinary albumin, and that the combined use of 8-oxoGuo and urinary albumin could be useful for a better identification of patients at risk of CVD and death., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims/hypothesis: The aim of this study was to assess gender differences in mortality and morbidity during 13 follow-up years after 6 years of structured personal care in patients with type 2 diabetes mellitus., Methods: In the Diabetes Care in General Practice (DCGP) multicentre, cluster-randomised, controlled trial (ClinicalTrials.gov registration no. NCT01074762), 1,381 patients newly diagnosed with type 2 diabetes were randomised to receive 6 years of either structured personal care or routine care. The intervention included regular follow-up, individualised goal setting and continuing medical education of general practitioners participating in the intervention. Patients were re-examined at the end of intervention. This observational analysis followed 970 patients for 13 years thereafter using national registries. Outcomes were all-cause mortality, incidence of diabetes-related death, any diabetes-related endpoint, myocardial infarction, stroke, peripheral vascular disease and microvascular disease., Results: In women, but not men, a lower HR for structured personal care vs routine care emerged for any diabetes-related endpoint (0.65, p = 0.004, adjusted; 73.4 vs 107.7 events per 1,000 patient-years), diabetes-related death (0.70, p = 0.031; 34.6 vs 45.7), all-cause mortality (0.74, p = 0.028; 55.5 vs 68.5) and stroke (0.59, p = 0.038; 15.6 vs 28.9). This effect was different between men and women for diabetes-related death (interaction p = 0.015) and all-cause mortality (interaction p = 0.005)., Conclusions/interpretation: Compared with routine care, structured personal diabetes care reduced all-cause mortality and diabetes-related death in women but not in men. This gender difference was also observed for any diabetes-related outcome and stroke but was not statistically significant after extensive multivariate adjustment. These observational results from a post hoc analysis of a randomised controlled trial cannot be explained by intermediate outcomes like HbA1c alone, but involves complex social and cultural issues of gender. There is a need to rethink treatment schemes for both men and women to gain benefit from intensified treatment efforts.

Objective: This study examined the influence of weight loss on long-term morbidity and mortality in overweight (BMI≥25 kg/m2) patients with type 2 diabetes, and tested the hypothesis that therapeutic intentional weight loss supervised by a medical doctor prolongs life and reduces the risk for cardiovascular disease in these patients., Methods: This is a 19 year cohort study of patients in the intervention arm of the randomized clinical trial Diabetes Care in General Practice. Weight and prospective intentions for weight loss were monitored every third month for six years in 761 consecutive patients (≥40 years) newly diagnosed with diabetes in general practices throughout Denmark in 1989-92. Multivariable Cox regression was used to estimate the association between weight change during the monitoring period (year 0 to 6) and the outcomes during the succeeding 13 years (year 6 to 19) in 444 patients who were overweight at diagnosis and alive at the end of the monitoring period (year 6). The analysis was adjusted for age, sex, education, BMI at diagnosis, change in smoking, change in physical activity, change in medication, and the Charlson comorbidity 6-year score. Outcomes were from national registers., Results: Overall, weight loss regardless of intention was an independent risk factor for increased all-cause mortality (P<0.01). The adjusted hazard ratio for all-cause mortality, cardiovascular mortality, and cardiovascular morbidity attributable to an intentional weight loss of 1 kg/year was 1.20 (95%CI 0.97-1.50, P = 0.10), 1.26 (0.93-1.72, P = 0.14), and 1.06 (0.79-1.42, P = 0.71), respectively. Limiting the analysis to include only those patients who survived the first 2 years after the monitoring period did not substantially change these estimates. A non-linear spline estimate indicated a V-like association between weight change and all-cause mortality, suggesting the best prognosis for those who maintained their weight., Conclusions: In this population-based cohort of overweight patients with type 2 diabetes, successful therapeutic intentional weight loss, supervised by a doctor over six years, was not associated with reduced all-cause mortality or cardiovascular morbidity/mortality during the succeeding 13 years.

Objective: To assess the effectiveness of an intervention in Type 2 diabetic patients with concurrent psychiatric illness (PI) and compare this with the effectiveness in patients without PI., Method: In the Diabetes Care in General Practice trial, 1381 patients newly diagnosed with Type 2 diabetes were randomized to 6 years of structured personal diabetes care or routine diabetes care (ClinicalTrials.gov NCT01074762). In this observational post-hoc analysis, the effectiveness of the intervention for diabetes in 179 patients with concurrent PI was analyzed., Results: During the 19-year follow-up period, patients with PI in the structured personal care group experienced a lower risk for all-cause mortality [105.3 vs. 140.4 events per 1000 patient-years; hazard ratio (HR): 0.63, P=0.023, multivariably adjusted], diabetes-related death (66.0 vs. 95.1; HR: 0.57, P=0.015), any diabetes-related endpoint (169.5 vs. 417.5; HR: 0.47, P=0.0009) and myocardial infarction (54.1 vs. 104.4; HR: 0.48, P=0.013), compared to patients with PI in the routine care group. This translates into a number needed to treat over 10 years of three or lower for these outcomes., Conclusion: These findings suggest that in primary care, structured diabetes care allowing for individualization was highly effective among diabetic patients with co-occurring PI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: The association between recent and more distant weight changes before and after the diagnosis of type 2 diabetes has been little researched. The aim of this study is to determine the influence of patients' weight history before diabetes diagnosis on the observed 6-year weight changes after diagnosis., Methods: A clinical cohort study combined with self-reported past weight history. In total 885 patients aged ≥40 years and newly diagnosed with clinical type 2 diabetes were included. Body weight was measured immediately after diabetes diagnosis and again at the 6-year follow up examination (median, 5.7 years). At diagnosis patients reported their weight 1 year and 10 years previously, and also at the age of 20. Multivariate linear regression analyses controlled for 20 baseline patient characteristics., Results: The median (interquartile range) age at diagnosis was 63.2 (53.9; 71.4) years. Median body weight was 80.0 (72.0; 90.0) kg 10 years before diagnosis, 85.0 (75.0; 95.0) kg 1 year before diagnosis, 82.4 (72.0; 94.0) kg at diagnosis, and 80.0 (70.0; 91.1) kg at 6-year follow up. Each kg of weight gain during the year preceding the diagnosis was associated with a weight change (95% CI) of -0.20 (-0.28; -0.13) kg during the follow up period. In all models age and body mass index at diagnosis predicted future weight changes, while the weight at age 20 (-0.01 (-0.06; 0.03) kg/kg), and the weight change from 10 years to 1 year before diagnosis (-0.01 (-0.06; 0.04) kg/kg), did not predict weight change after diagnosis., Conclusions: During the first on average 5.7 years after diagnosis of type 2 diabetes, patients generally follow a course of declining average weight, and these weight developments are related primarily to recent weight changes, body mass index, and age, but not to the more distant weight history.

Objective: This study explored the impact of involvement in cooking on long-term morbidity and mortality among patients newly diagnosed with type 2 diabetes mellitus (T2DM)., Design and Subjects: Data are from the population-based study Diabetes Care in General Practice. In baseline questionnaires, 1348 patients newly diagnosed with T2DM gave information on how frequently they consumed a warm main meal and how often they cooked it themselves. The selected patients were followed up for 19 years in the Danish National Patient Registry and the Danish Register of Causes of Death., Main Outcome Measures: This study analysed the association between involvement in cooking and each of seven pre-specified outcomes was analysed in Cox regression models with stepwise adjustment for possible confounders and mediators., Results: 92% of the patients with T2DM consumed a warm main meal ≥ five times per week. Among these, women who cooked for themselves less than once a week had a higher risk of diabetes-related deaths (HR 1.86 [95% CI 1.03-3.35], p = 0.039) and stroke (HR 2.47 [95% CI 1.08-5.65], p = 0.033), after adjustment for confounders. For men, infrequent cooking was not related to increased risk for the outcomes investigated., Conclusions: In patients newly diagnosed with T2DM and with a regular intake of warm main meals, infrequent involvement in cooking was associated with an increased risk of diabetes-related death and stroke for women, but not for men. General practitioners should pay special attention to managing diabetes treatment in female patients newly diagnosed with T2DM who report infrequent involvement in cooking.

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., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To investigate the predictive value of both patients' motivation and effort in their management of Type 2 diabetes and their life circumstances for the development of foot ulcers and amputations., Methods: This study was based on the Diabetes Care in General Practice study and Danish population and health registers. The associations between patient motivation, effort and life circumstances and foot ulcer prevalence 6 years after diabetes diagnosis and the incidence of amputation in the following 13 years were analysed using odds ratios from logistic regression and hazard ratios from Cox regression models, respectively., Results: Foot ulcer prevalence 6 years after diabetes diagnosis was 2.93% (95% CI 1.86-4.00) among 956 patients. General practitioners' indication of 'poor' vs 'very good' patient motivation for diabetes management was associated with higher foot ulcer prevalence (odds ratio 6.11, 95% CI 1.22-30.61). The same trend was seen for 'poor' vs 'good' influence of the patient's own effort in diabetes treatment (odds ratio 7.06, 95% CI 2.65-18.84). Of 1058 patients examined at 6-year follow-up, 45 experienced amputation during the following 13 years. 'Poor' vs 'good' influence of the patients' own effort was associated with amputation (hazard ratio 7.12, 95% CI 3.40-14.92). When general practitioners assessed the influence of patients' life circumstances as 'poor' vs 'good', the amputation incidence increased (hazard ratio 2.97, 95% CI 1.22-7.24). 'Poor' vs 'very good' patient motivation was also associated with a higher amputation incidence (hazard ratio 7.57, 95% CI 2.43-23.57), although not in fully adjusted models., Conclusions: General practitioners' existing knowledge of patients' life circumstances, motivation and effort in diabetes management should be included in treatment strategies to prevent foot complications., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Aims/hypothesis: The estimation of effect size in clinical trials commonly disregards recurrent outcomes. We investigated the effectiveness of a complex intervention on recurrent outcomes in patients with type 2 diabetes., Methods: In the Diabetes Care in General Practice (DCGP) randomised controlled trial, 1,381 patients newly diagnosed with type 2 diabetes were randomised to 6 years of structured personal care or routine care (ClinicalTrials.gov NCT01074762). The trial had 19 years of registry-based follow-up and was analysed with Cox regression models. Repeated occurrences in the same patient of outcomes (any diabetes-related endpoint, myocardial infarction [MI], stroke, peripheral vascular disease and microvascular disease) were accounted for with the Wei, Lin and Weissfeld method., Results: As previously shown, the intervention reduced the rates of first occurrence of both MI and any diabetes-related endpoint. However, for all outcomes, the HR for a second event showed a statistically non-significant tendency to be increased. We estimated a combined HR for all marginal failure times, regardless of whether they were first, second or later events. This showed that the intervention had no effect on the rate of any of the outcomes, including MI (HR 0.89, 95% CI 0.76, 1.05) and any diabetes-related endpoint (HR 0.98, 95% CI 0.87, 1.09)., Conclusions/interpretation: In the DCGP study, a smaller proportion of patients who received structured care experienced a first occurrence of MI or any diabetes-related endpoint compared with patients who received routine care. However, the patients who received structured care tended to experience more recurrent outcomes, so the total outcome rate was not affected by the intervention.

Aims: To determine the prevalence of foot ulcers and the incidence of amputations in patients with Type 2 diabetes observed for 19 years after diagnosis. We investigated the role of gender, age and co-morbidities., Methods: From the Diabetes Care in General Practice study, 1381 patients were included and examined at diabetes diagnosis, at 6 years and at 14 years after diagnosis. Register-based follow-up was for 19 years. Foot ulcers and amputations were related to gender, age and co-morbidities by odds and hazard ratios from logistic and Cox regression models, respectively., Results: The incidence of any amputation and major amputation was 400 (95% CI 307-512) and 279 (95% CI 203-375) per 100,000 patient-years, respectively. At the three observation points, the foot ulcer prevalences were 2.76% (95% CI 1.89-3.63), 2.93% (95% CI 1.86-4.00) and 4.96% (95% CI 3.10-6.82). Multivariate analyses showed associations between foot ulcers and peripheral neuropathy, peripheral arterial disease, male gender, retinopathy and myocardial infarction. After multivariate adjustment, significant predictors (hazard ratio; 95% CI) of any amputation were peripheral neuropathy (hazard ratio 2.09; 95% CI 1.19-3.69), peripheral arterial disease (hazard ratio 3.43; 95% CI 1.65-7.12), microalbuminuria (hazard ratio 2.11; 95% CI 1.21-3.67), retinopathy (hazard ratio 6.42; 95% CI 2.59-15.90), impaired vision (hazard ratio 6.92; 95% CI 2.35-20.38) and male gender (hazard ratio 2.40; 95% CI 1.31-4.41). For women, the risk of amputation increased with age, but for men the risk was higher when diagnosed with diabetes at a younger age., Conclusions: Despite improved treatment regimens, the incidence of amputations is still high in this population-based patient sample. Men diagnosed with diabetes before age 65 years and patients with diabetes-related co-morbidities are at particularly high risk of foot ulcers and amputations., (© 2013 The Authors. Diabetic Medicine © 2013 Diabetes UK.)

Aims/hypothesis: This study is a 19 year observational follow-up of a pragmatic open multicentre cluster-randomised controlled trial of 6 years of structured personal diabetes care starting from diagnosis., Methods: A total of 1,381 patients aged ≥ 40 years and newly diagnosed with type 2 diabetes were followed up in national registries for 19 years. Clinical follow-up was at 6 and 14 years after diabetes diagnosis. The original 6 year intervention included regular follow-up and individualised goal setting, supported by prompting of doctors, clinical guidelines, feedback and continuing medical education (ClinicalTrials.gov NCT01074762). The registry-based endpoints were: incidence of any diabetes-related endpoint; diabetes-related death; all-cause mortality; myocardial infarction (MI); stroke; peripheral vascular disease; and microvascular disease., Results: At 14 year clinical follow-up, group differences in risk factors from the 6 year follow-up had levelled out, although the prevalence of (micro)albuminuria and level of triacylglycerols were lower in the intervention group. During 19 years of registry-based monitoring, all-cause mortality was not different between the intervention and comparison groups (58.9 vs 62.3 events per 1,000 patient-years, respectively; for structured personal care, HR 0.94, 95% CI 0.83, 1.08, p = 0.40), but a lower risk emerged for fatal and non-fatal MI (27.3 vs 33.5, HR 0.81, 95% CI 0.68, 0.98, p = 0.030) and any diabetes-related endpoint (69.5 vs 82.1, HR 0.83, 95% CI 0.72, 0.97, p = 0.016). These differences persisted after extensive multivariable adjustment., Conclusions/interpretation: In concert with features such as prompting, feedback, clinical guidelines and continuing medical education, individualisation of goal setting and drug treatment may safely be applied to treat patients newly diagnosed with type 2 diabetes to lower the risk of diabetes complications.

Aims: To investigate whether long-term mortality or clinical outcomes differed between patients diagnosed with type 2 diabetes mellitus and presenting with HbA1c within or above normal range at time of diagnosis., Methods: Data were from a population-based sample of 1136 individuals with newly diagnosed type 2 diabetes mellitus. The diagnosis was confirmed with a single fasting whole blood/plasma glucose ≥7.0/8.0mmol/l. The median time from day of diagnosis until end of follow up was 18.8years. Patients were grouped according to normal HbA1c and elevated HbA1c at diagnosis. The effect of elevated HbA1c on a number of clinical outcomes and all-cause mortality was assessed in Cox regression models., Results: At diagnosis, 97 patients (8.5%) had an HbA1c level within normal range. Age (mean (SD)) at diagnosis was 64.5 (11.5) years. Both unadjusted and adjusted hazard ratios for the effect of HbA1c on mortality and other outcomes were not statistically significant., Conclusions: Patients who are diagnosed with type 2 diabetes mellitus by means of elevated fasting whole blood/plasma glucose but have HbA1c within reference range at diagnosis do not seem to have a relatively benign long-term clinical course. Therefore new diagnostic procedures should preferably be able to identify these individuals., (Copyright © 2012 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

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.

Background: Many diabetic patients fear visual loss as the worst consequence of diabetes. In most studies the main eye pathology is assigned as the cause of visual impairment. This study analysed a broad range of possible ocular and non-ocular predictors of visual impairment prospectively in patients newly diagnosed with clinical type 2 diabetes., Methods: Data were from a population-based cohort of 1,241 persons newly diagnosed with clinical, often symptomatic type 2 diabetes aged ≥ 40 years. After 6 years, 807 patients were followed up. Standard eye examinations were done by practising ophthalmologists., Results: At diabetes diagnosis median age was 65.5 years. Over 6 years, the prevalence of blindness (visual acuity of best seeing eye ≤ 0.1) rose from 0.9% (11/1,241) to 2.4% (19/807) and the prevalence of moderate visual impairment (> 0.1; < 0.5) rose from 5.4% (67/1,241) to 6.7% (54/807). The incidence (95% confidence interval) of blindness was 40.2 (25.3-63.8) per 10,000 patient-years. Baseline predictors of level of visual acuity (age, age-related macular degeneration (AMD), cataract, living alone, low self-rated health, and sedentary life-style) and speed of continued visual loss (age, AMD, diabetic retinopathy (DR), cataract, living alone, and high fasting triglycerides) were identified., Conclusions: In a comprehensive assessment of predictors of visual impairment, even in a health care system allowing self-referral to free eye examinations, treatable eye pathologies such as DR and cataract emerge together with age as the most notable predictors of continued visual loss after diabetes diagnosis. Our results underline the importance of eliminating barriers to efficient eye care by increasing patients' and primary care practitioners' awareness of the necessity of regular eye examinations and timely surgical treatment.

The aim was to estimate and illustrate the weight history of 1,320 newly diagnosed diabetic patients according to patient characteristics at diagnosis. The median recalled weight gain from age 20 to diabetes diagnosis at a median age of 65.3 years was 14.7 kg. The average weight gain from 10 years prior to diabetes diagnosis until diagnosis, however, was only 1 kg and varied with e.g. age, sex, diagnostic plasma glucose, and presence of diabetic retinopathy. The findings contribute to the evidence basis of general practitioners' weight advice both before and after diabetes diagnosis.

Aims: To estimate and illustrate how the 10 years of weight change immediately preceding diabetes diagnosis vary with weight at the age of 20 years and with socio-demographic variables, risk factors and comorbidities at diagnosis., Methods: Data were from a population-based cohort of 1320 persons newly diagnosed with diabetes aged > or = 40 years. Patients' weight at diagnosis was measured by the doctor, while patients recalled their weight approximately 1, 5 and 10 years prior to diagnosis and at age 20 years., Results: Median weight gain from age 20 years to diabetes diagnosis at median age 65.3 years was 14.7 kg (interquartile range 6.0-23.0). Women gained weight more than men, and the lower the weight at age 20 years, the greater the weight gain. The average weight gain from 10 years prior to diabetes diagnosis until diagnosis, however, was only 1 kg and decreased markedly with age. These 10 years of weight change were also associated with sex and the following baseline characteristics: diagnostic plasma glucose, urinary glucose, urinary albumin, fasting triglycerides, systolic blood pressure, smoking habits, and presence of diabetic retinopathy., Conclusions: The results add to the evidence that it is important to advise young patients in particular, especially women, who have gained and sustained considerable weight to curb this upward weight trend in order to prevent the development of diabetes.

Background: Continuity of care may not only save time and money for the health care system, but may also be beneficial for the individual patient. How well GPs know their patients may potentially lead to an early diagnosis of a slowly progressive chronic disease like type 2 diabetes mellitus (T2DM). The aim of this paper is to investigate this hypothesis., Methods: A cross-sectional, population-based study of 1136 patients newly diagnosed with T2DM by their GP. Our main outcomes were how well the GPs' knew their patients (questionnaire) and centralized analysis of glycosylated haemoglobin A(1c). Multivariate linear regression models were used to allow adjustment for confounding variables., Results: GPs classified how well they knew their patients as being not well for 13.5% (153/1136) of their patients, as fairly well for 38.6% (438/1136) and as very well for 48.0% (545/1136). Patients whom the GPs classified as not knowing well had relatively high glycaemic levels compared with levels among other patients, a finding that was confirmed in multivariate linear regression models., Conclusions: Our data show that the glycaemic level among patients whom the GP characterize as knowing well or fairly well is relatively low compared with among patients whom the GP characterize as not knowing well. We suggest that this reflects a late diagnosis in these patients, and that GPs should be especially aware of undiagnosed T2DM among patients whom they do not know well.

Background: The ratio between urinary albumin concentration (UAC) and urinary creatinine concentration (UCC) is widely used to estimate renal involvement. We examined how UAC and UCC associate with each other, with other risk factors, and with diabetic complications in a population-based sample of Type 2 diabetic patients., Methods: A freshly voided morning urine specimen was provided by 1,284 consecutive, newly diagnosed diabetic patients aged 40 years or over in general practice. Albumin was measured by a polyethyleneglycol radioimmunoassay and creatinine by a modified Jaffe method., Results: In a multivariate model including UAC, UCC, age, sex, HbA1c, and urinary glucose concentration, UAC increased with both age (P=.042) and HbA1c (P=.014), while UCC decreased (P<.001 and P<.001, respectively). In two regression models, the prevalence of diabetic retinopathy (P<.001) and relatively high resting heart rate (P<.001) increased with increasing UAC but decreased with increasing UCC (P=.002 and P=.005, respectively)., Conclusion: The use of albumin/creatinine ratio (ACR) may introduce bias of unpredictable size and direction in comparisons of ACR with variables that are associated with UCC in their own right. In daily clinical practice, renal involvement in the individual patient can be estimated reliably with UAC or ACR measured in a freshly voided morning urine specimen, especially when considered together. However, the associations of the combined measure ACR should be interpreted with great caution in clinical and epidemiological research.

Aiming to improve the quality of diet recording and instruction in primary care, we developed a simple semi-quantitative food frequency questionnaire for type 2 diabetic patients and had doctors record each other's diet habits with the same questionnaire. The analysis of the diet composition was given to the doctors who considered the educational model to be fun, instructive and thought-provoking. Doctors with a relatively unhealthy diet and a relatively high body weight tended to show dissatisfaction with their own diet, had poor self-assessed knowledge about nutrition, and even a wish to improve their own diet after having seen the result of the diet interview. The proportion of diabetic patients being treated with diet alone tended to decrease with their doctors' decreasing diet counselling skills, which indicates that doctors' attitudes may exert an effect at patient level.

Aims/hypothesis: To document the prevalence of typical diabetic symptoms, signs and complications in the diagnosis of type 2 diabetes mellitus, examine their pre-diagnostic duration, and analyse associations with glycaemic level, blood pressure (BP), and weight., Methods: An epidemiological population-based study of 1137 Danish patients with type 2 diabetes newly diagnosed by general practitioners (GPs). GPs and patients together filled in a questionnaire about typical symptoms, signs and complications preceding the diagnosis., Results: Abnormal thirst, frequent urination, weight loss, genital itching, stomatitis, visual disturbances, fatigue, confusion and (in men) balanitis were associated with glycaemic level irrespective of age, sex, BMI, BP, complications and antihypertensive treatment. Eighty-nine percent of the patients presented with one or more of these hyperglycaemic symptoms and signs, and the pre-diagnostic duration was typically less than 3 months. Only a few symptoms, signs and complications were associated with weight and BP., Conclusions/interpretation: In patients newly diagnosed with type 2 diabetes in family practice, typical diabetic symptoms, signs and complications are common. Typical diabetic symptoms and signs are associated with hyperglycaemia. The pre-diagnostic duration of hyperglycaemic symptoms and signs were typically short, thus questioning the feasibility of early detection relying on increased anticipatory care by GPs. In contrast, elevated levels of cardiovascular risk factors and longer pre-diagnostic duration of cardiovascular complications suggest these might have a central role in an early diagnosis of type 2 diabetes.

Objectives: We examined whether the finding of glycosuria and its level in themselves give information of clinical relevance, apart from being an unreliable indicator of glycemic control., Methods: Subjects were a population-based sample of 1,284 newly diagnosed type 2 diabetic patients. Median age was 65.2 years. Urinary glucose concentration (UGC) was determined quantitatively in a freshly voided morning urine specimen., Results: The over-all prevalence of peripheral vascular disease (PVD) was 16.5%. Bivariately, high values of UGC were associated with low prevalence of PVD (p<0.001, chi2-test). The predictive value of PVD--together with HbA1c, glomerular filtration rate (GFR) and 10 other possible predictors--was confirmed in a logistic regression analysis with glycosuria (Y/N) as outcome variable (p=0.0004)., Conclusion: Surprisingly, type 2 diabetic patients with PVD tend not to have glycosuria as compared to patients without PVD. PVD may be indicative of generalized atherosclerotic lesions in the major vessels, including the renal arteries. This could lead to a lowering of GFR and thereby of the amount of glucose filtered. Assuming no, or only a minor direct effect of PVD on tubular function, this would lead to an increased renal threshold for glucose in patients with PVD.

World wide the prevalence of type 2 diabetes is increasing and 30-50% of patients are undiagnosed. Early detection and intervention may decrease the risk of late diabetic complications, and thus clear guidelines for early detection and diagnosis of type 2 diabetes are needed. We recommend those individuals with either previous gestational diabetes; obesity (BMI > 30 kg/m2) and/or two or more relatives with diabetes should be considered eligible for testing for diabetes. In order to make the diagnosis two diabetic glucose values on separate days are required. The diagnosis may be made using plasma glucose or capillary whole blood, but quality control measures are essential for glucose measurements in general practice as well as in departments of clinical biochemistry.

According to new proposals from the American Diabetes Association (ADA) and WHO, venous peripheral plasma is the preferred system for measuring glucose for diagnosing diabetes mellitus. Owing to the instability of glucose in plasma after blood sampling, strict well-defined and standardized preanalytical conditions are essential to ensure that glucose concentration measured in plasma reflects real blood glucose in the patient. This is in contrast to the capillary whole blood measurements, which are easy to perform and well established. We investigated whether it is possible to perform analysis on capillary whole blood but express the results as plasma glucose values and hence obtain comparable results and the same predictive values for diagnosis in the individual patient? The conclusion of our investigations is that these two systems are not interchangeable and that conversion should not be done for diagnostic purposes where plasma determinations are recommended.

Introduction: We assessed the effect of a multifaceted intervention directed at general practitioners to improve type 2 diabetes care., Materials and Methods: Three hundred and eleven Danish practices with 474 general practitioners were randomised to structured personal care (intervention group) or routine care (comparison group). Of 970 surviving patients (aged 40+ years) diagnosed with diabetes in 1989-1991, 874 (90.1%) were assessed after 6 years. Intervention comprised regular follow-up and individualized goal-setting, supported by reminders to doctors, clinical guidelines, feed-back, and continuing medical education., Results: Predefined non-fatal outcomes and mortality were the same in both groups. The following risk factor levels were lower in the intervention patients than in the comparison patients: fasting plasma glucose (7.9 vs 8.7 mmol/l, medians, P = 0.0007), haemoglobin A1c (8.5 vs 9.0%, P < 0.0001, normal range 5.4-7.4%), systolic blood pressure (145 vs 150 mmHg, P = 0.0004), and cholesterols (6.0 vs 6.1 mmol/l, P = 0.029, baseline-adjusted). Both groups had sustained a weight loss since diagnosis (2.6 vs 2.0 kg). Metformin was the only drug used more frequently in the intervention group (24 vs 15%). Intervention doctors arranged more follow-up consultations, referred fewer patients to diabetes clinics, and were more optimistic in their goal-setting., Discussion: In primary care, individualized goal-setting with educational and surveillance support may for at least six years bring risk factors of patients with type 2 diabetes to a level that in other trials has been shown to reduce diabetic complications, but without adverse weight gain.

Background: The exact role of factors such as serum lipids, body mass index and (micro-)albuminuria as possible determinants of diabetic retinopathy remains to be determined. We have scrutinized the prevalence of diabetic retinopathy and its concomitants in terms of risk factors and other diabetic complications in newly diagnosed diabetic patients., Methods: A population-based sample of 1,251 newly diagnosed diabetic patients aged 40 years or over was established in general practice. Median age was 65.3 years. Funduscopy was performed by practising ophthalmologists. Blood and urine analyses were centralised., Results: The overall prevalence of diabetic retinopathy was 5.0%. Only three patients had proliferative diabetic retinopathy. As expected, diabetic retinopathy and renal involvement, as expressed by the urinary albumin/creatinine ratio. were strongly positively associated. An intriguing finding was that of an inverse relationship between fasting triglycerides and diabetic retinopathy, an association that proved to be confined to microalbuminuric patients. An inverse association between body mass index and diabetic retinopathy was found only univariately., Conclusion: The low prevalence of diabetic retinopathy cannot be explained by the screening method alone, but rather by early detection of diabetes in a non-selective patient sample. It seems that renal involvement modifies the expected relationship between diabetic retinopathy and triglycerides, but a pathophysiological mechanism is not available.

The aim of the study was to establish a reference interval of fasting venous plasma glucose (FPG) from healthy individuals. A prospective modified cross-sectional population-based study was made with random selection of 2100 persons in age-stratified groups > or = 18 years identified from the local Personal Identification Register. The invitation was accepted by 755 persons, of which 726 aged 18-92 years were eligible. They did not have a diabetes diagnosis, were non-pregnant and capable of fasting for 8 h. All participants filled in a questionnaire on medical risk factors. Blood for the FPG and haemoglobin Alc (HbAlc) measurements was drawn in accordance with a standardized procedure. A total of 302 participants carried diabetes risk indicators and were ruled out. The FPG concentrations in the remaining low-risk population (n=424) was ln Gaussian distributed. The FPG 97.50 centile in this group was 6.4 mmol/L (95% CI: 6.3-6.5 mmol/L), in contrast to the WHO and ADA theoretical limit of 6.1 mmol/L. Their diagnostic decision limit of 7.0 mmol/L FPG corresponded to the 99.86 centile of the FPG reference distribution (95% CI: 6.8-7.1). Subclassification of the reference population showed increasing FPG with increasing BMI and age and was higher in men than in women. The study determined the FPG 95% interfractile reference interval in a healthy population. The interval in glucose concentration between the 97.5 centile of the reference interval and the ADA-WHO diagnostic limit is very narrow. The clinical application of the diagnostic discriminator and the interpretation of the WHO-ADA grey zone from 6.1 to 7.0 mmol/L FPG may consequently be biased because of poorly defined limits and influence from BMI, age and gender.

On behalf of the Danish Society of Clinical Endocrinology and the Danish Society of Clinical Chemistry we were commissioned to evaluate the influence of analytical and pre-analytical systematic and random factors on the diagnosis of diabetes, in order to provide a tool for conclusions on the analytical quality specifications needed to diagnose diabetes. A systems analysis was performed in accordance with the principles for evaluation of analytical quality specifications. The clinical setting was defined--diagnosis of diabetes in accordance with the WHO and ADA criteria with determination of fasting plasma glucose concentration (FPG) > or =7.0 mmol/L in two independent samples--with well-documented data on In (loge)-Gaussian distribution of reference values from a low-risk population and values for within-subject biological variation taken from the literature. An investigation was made of the consequences for the clinical setting of assumed errors related to the measurement of FPG. Four approaches were investigated for a single sampling and measurement and also for two independent samples: one showing the percentage of healthy individuals who had values > or = 7.0 mmol/L, one illustrating the origin of biological set-points for results > or = 7.0 mmol/L, one showing the risk of being measured > or =7.0 mmol/L when the biological set-point is known, and one showing the combined bias and imprecision for assumed percentages of false-positive (FP), defined as measurements > or = 7.0 mmol/L for the low-risk population and false-negative (FN), defined as measurements <6.4 mmol/L (the upper reference limit) for diabetics. This leaves a "grey zone" which includes the upper part of low-risk individuals, and defined by ADA and WHO as "impaired fasting glucose" (IFG). In the analysis, increasing systematic and random errors (combined analytical and pre-analytical) were assumed, and for each error condition the fractions of FP and FN were calculated. This gave plots from which the combined allowable systematic and random errors could be read off for pre-determined clinically acceptable fractions of FP and FN. The analysis does not distinguish between pre-analytical and analytical errors, as specified information on one of these is needed for specification of the other. The investigation provides a reliable basis for estimation of the needed analytical quality, and thereby for decisions about analytical quality specifications for analysis of FPG in relation to diagnosis of diabetes under optimized pre-analytical and analytical conditions. Consequences of deviations from these ideal conditions are illustrated in the figures, and should be considered for the different approaches with different performance conditions.

The new diagnostic criteria for type 2 diabetes from the American Diabetes Association (ADA) and World Health Organization (WHO) recommend measurements on plasma and a lowering of the glucose threshold for diabetes by 0.8 mmol/L. This narrows the distance between the upper end of the reference limit and the discriminatory level to a degree where analytical quality becomes critical. The quality demands for the preanalytical and analytical phase and their consequences on diagnostic performance have to be established in the new technical system, measuring in plasma rather than in capillary whole blood. Because of the instability of glucose in blood samples it is necessary to clarify the influence of different preanalytical and analytical factors on the number of false-positive and false-negative classifications. Thus the aim of the present study was to find optimal conditions for sampling, additives, storage, transport and analysis of plasma glucose combining feasibility with an analytical bias close to zero and a within-imprecision around 1%. We have documented the analytical performance of the method itself and its traceability to an international standard. The preanalytical conditions, such as influence of antiglycolytic agent NaF, conditions for plasma separation, storage temperature and storage time before and after plasma separation were investigated. In conclusion, we recommend that blood should be drawn in tubes containing heparin and NaF and kept on ice water for not more than 1 h until centrifugation at minimum 1000 x g for 10 min. The plasma is then stable for at least 48 h at room temperature.

According to international consensus, microalbuminuria is defined as an elevated urinary albumin excretion rate (UAER) of 20-200 micrograms/min, which is below the proteinuric range. Nephropathy is a major complication in IDDM, seen in about 30% of patients after many years of diabetes. Increasing microalbuminuria is an excellent marker of subsequent nephropathy in these patients. End-stage diabetic nephropathy is also important in NIDDM, but in most Western countries this serious complication eventually develops in only 5 to 10% of cases, whereas the majority of patients die before this from cardiovascular disease. In completely healthy individuals there is no clear correlation between age and UAER, at least up to about 70 years of age. The mean excretion rate is around 5 micrograms/min, with a considerable range, but excretion only rarely exceeds 15 micrograms/min. In population studies among middle-aged and elderly individuals, higher values are seen. In newly diagnosed NIDDM about 40% of patients show an excretion rate above 15-20 micrograms/min. There is a significant but not precise correlation between albumin excretion rate and glycemic control, and usually UAER is reduced by standard antidiabetic treatment. In a considerable number of patients, high values cannot be reduced. In the course of NIDDM about 20-30% of patients show microalbuminuria. In patients with known diabetes, microalbuminuria is related not only to subsequent diabetic proteinuria, but even more strongly to early death, mainly from cardiovascular disease. Even slight microalbuminuria (15-40 mg/l in early morning urines) is clearly associated with increased mortality. In subjects with newly detected elevated blood glucose (by screening) microalbuminuria also predicts early mortality. The mechanisms are not established, but several arteriosclerosis-related risk factors are seen more frequently in patients with microalbuminuria, e.g. lipid abnormalities, elevated systolic blood pressure (BP), hemostatic measures, as well other markers of cardiovascular disease. Usually there is a significant but not precise correlation between BP and UAER in groups of patients throughout the course of diabetes. New studies document that also in the elderly background population microalbuminuria is a significant risk factor for early death, maybe even stronger than the established risk markers, which thus may be confounded with the presence of microalbuminuria.