Factors associated with potential over- and undertreatment of hyperglycaemia and annual measurement of HbA1c in type 2 diabetes in norwegian general practice.

AIMS: To identify individual and general practitioner (GP) characteristics associated with potential over- and undertreatment of hyperglycaemia in type 2 diabetes and with HbA1c not being measured. METHODS: A cross-sectional study that included 10233 individuals with type 2 diabetes attending 282 GPs. Individuals with an HbA1c measurement during the last 15 months were categorized as potentially overtreated if they were prescribed a sulphonylurea and/or insulin when the HbA1c was less than 53 mmol/mol (7%) when aged over 75 years or less than 48 mmol/mol (6.5%) when aged between 65 and 75 years. Potential undertreatment was defined as age less than 60 years and HbA1c > 64 mmol/mol (8.0%) or HbA1c > 69 mmol/mol (8.5%) and treated with lifestyle modification and/or monotherapy. We used multilevel binary and multinominal logistic regression models to examine associations. RESULTS: Overall, 4.1% were potentially overtreated, 7.8% were potentially undertreated and 11% did not have HbA1c measured. Characteristics associated with potential overtreatment were as follows: long diabetes duration, prescribed antihypertensive medication, cardiovascular disease and renal failure. Potential undertreatment was associated with male gender, non-western origin and low educational level. Characteristics associated with not having an HbA1c measurement performed were male gender, age < 50 years and cardiovascular diseases. GP specialist status and GPs' use of a Noklus diabetes application reduced the risk of not having an HbA1c measurement performed. CONCLUSION: Potential overtreatment in elderly individuals with type 2 diabetes was relatively low. Nevertheless, appropriate de-intensification or intensification of treatment and regular HbA1c measurement in identified subgroups is warranted.

High adherence to recommended diabetes follow-up procedures by general practitioners is associated with lower estimated cardiovascular risk.

AIMS: To explore whether the general practitioners' (GPs') performance of recommended processes of care was associated with estimated risk of cardiovascular disease (CVD) and poor glycaemic control in patients with type 2 diabetes. METHODS: A cross-sectional study from Norwegian general practice including 6015 people with type 2 diabetes <75 years old, without CVD and their 275 GPs. The GPs were split into quintiles based on each GP's average performance of six recommended processes of care. The quintiles were the exposure variable in multilevel regression models with 10-year risk of cardiovascular events estimated by NORRISK 2 (total and modifiable fraction) and poor glycaemic control (HbA1c >69 mmol/mol (>8.5%)) as outcome variables. RESULTS: The mean total and modifiable estimated 10-year CVD risk was 12.3% and 3.3%, respectively. Compared with patients of GPs in the highest-performing quintile, patients treated by GPs in the lowest quintile had an adjusted total and modifiable CVD risk that was 1.88 (95% CI 1.17-2.60) and 1.78 (1.14-2.41) percent point higher. This represents a relative mean difference of 16.6% higher total and 74.8% higher modifiable risk among patients of GPs in the lowest compared with the highest quintile. For patients with GPs in the lowest-performing quintile, the adjusted odds of poor glycaemic control was 1.77 (1.27-2.46) times higher than that for patients with a GP in the highest quintile. CONCLUSIONS: We found a pattern of lower CVD risk and better glycaemic control in patients of GPs performing more recommended diabetes processes of care.

Factors associated with treatment in primary versus specialist care: A population-based study of people with type 2 and type 1 diabetes.

AIMS: The objectives of this study are to identify the proportion and characteristics of people with type 1 and 2 diabetes treated in primary, specialist and shared care and to identify the proportion of persons with type 2 diabetes reaching HbA1c treatment targets and the clinical risk factors and general practitioner and practice characteristics associated with treatment in specialist care. METHODS: Population-based cross-sectional study including all adults ≥18 years diagnosed with diabetes in primary and specialist care in Salten, Norway. We used multivariable mixed-effects logistic regression models with level of care as outcome variable and population, general practitioner, and practice characteristics as exposure variables. RESULTS: Of 2704 people with type 2 diabetes, 13.5% were treated in shared care and 2.1% in specialist care only. Of 305 people with type 1 diabetes, 14.4% received treatment in primary care only. The HbA1c treatment target of 53 mmol/mol (7.0%) was reached by 67.3% of people with type 2 diabetes in primary care versus 30.4% in specialist care. HbA1c , use of insulin, coronary heart disease, retinopathy and urban practice location were positively associated with treatment in specialist care. General practitioners' use of a structured form and a diabetes nurse were negatively associated with specialist care. CONCLUSIONS: Of people with type 2 diabetes, 16% were treated in specialist care. They had higher HbA1c and more vascular complications, as expected from priority guidelines. The use of a structured diabetes form and diabetes nurses seem to support type 2 diabetes follow-up in primary care.

Radiological glenohumeral osteoarthritis in long-term type 1 diabetes. Prevalence and reliability of three classification systems. The Dialong shoulder study.

OBJECTIVE: In the present study, we evaluate the intra- and interrater agreement of radiological glenohumeral OA using three different classification systems and estimate the prevalence of radiological and clinical glenohumeral OA in patients with type 1 diabetes mellitus (DM1), for over 45 years and controls (The Dialong study). MATERIALS AND METHODS: We included 102 patients with DM1 (49% women, mean age, 61.9 years) and 73 controls (57% women, mean age, 62.6 years). Anterior-posterior shoulder radiographs were interpreted by two observers applying the Kellgren-Lawrence (K-L), Samilson-Prieto (S-P) and Samilson-Prieto Allain (S-PA) classifications. RESULTS: The interrater agreement was moderate (weighted kappa, 0.46 to 0.48) for all classifications and the intrarater agreement mainly substantial (0.48-0.86) for both observers. The agreed prevalence of radiological OA was 26 and 18% (OR 1.6 (0.8 to 3.3), p = 0.22, 44 and 26% (OR 2.2 (1.2 to 4.2), p = 0.02) and 30 and 17% (OR 2.1 (1.0 to 4.5), p = 0.05) for the K-L, S-P and S-PA classifications respectively in the diabetes and control groups. The prevalence of moderate or severe radiological OA was 1 to 6% and clinical OA 1 to 2% with no difference between the groups. CONCLUSION: The prevalence of radiological glenohumeral OA was higher in the diabetes group with the Samilson-Prieto classification systems, but not associated with clinical OA. The interrater agreement was moderate. We recommend the Samilson-Prieto Allain classification for glenohumeral OA to avoid interpretation of osteophytes < 1 mm as OA in patient groups with a low pre-test likelihood of glenohumeral OA.

Are general practitioners characteristics associated with the quality of type 2 diabetes care in general practice? Results from the Norwegian ROSA4 study from 2014.

OBJECTIVE: To explore the associations between general practitioners (GPs) characteristics such as gender, specialist status, country of birth and country of graduation and the quality of care for patients with type 2 diabetes (T2DM). DESIGN: Cross-sectional survey. SETTING AND SUBJECTS: The 277 GPs provided care for 10082 patients with T2DM in Norway in 2014. The GPs characteristics were self-reported: 55% were male, 68% were specialists in General Practice, 82% born in Norway and 87% had graduated in Western Europe. Of patients, 81% were born in Norway and 8% in South Asia. Data regarding diabetes care were obtained from electronic medical records and manually verified. MAIN OUTCOME MEASURES: Performance of recommended screening procedures, prescribed medication and level of HbA1c, blood pressure and LDL-cholesterol stratified according to GPs characteristics, adjusted for patient and GP characteristics. RESULT: Female GPs, specialists, GPs born in Norway and GPs who graduated in Western Europe performed recommended procedures more frequently than their counterparts. Specialists achieved lower mean HbA1c (7.14% vs. 7.25%, p < 0.01), a larger proportion of their patients achieved good glycaemic control (HbA1c = 6.0%-7.0%) (49.1% vs. 44.4%, p = 0.018) and lower mean systolic blood pressure (133.0 mmHg vs. 134.7 mmHg, p < 0.01) compared with non-specialists. GPs who graduated in Western Europe achieved lower diastolic blood pressure than their counterparts (76.6 mmHg vs. 77.8 mmHg, p < 0.01). CONCLUSION: Several quality indicators for type 2 diabetes care were better if the GPs were specialists in General Practice. Key Points Research on associations between General Practitioners (GPs) characteristics and quality of care for patients with type 2 diabetes is limited. Specialists in General Practice performed recommended procedures more frequently, achieved better HbA1c and blood pressure levels than non-specialists. GPs who graduated in Western Europe performed screening procedures more frequently and achieved lower diastolic blood pressure compared with their counterparts. There were few significant differences in the quality of care between GP groups according to their gender and country of birth.

Glyoxalase 1 enzyme activity in erythrocytes and Ala111Glu polymorphism in type 1-diabetes patients.

AIMS/HYPOTHESIS: The enzyme glyoxalase 1 (GLO1) can inactivate the glycoxidation product methylglyoxal that is thought to be an important contributor to the pathogenesis of vascular complications in diabetes. We aimed to study erythrocyte GLO1 activity and whether the Ala111Glu GLO1 gene polymorphism affected GLO1 activity. METHODS: Fasting erythrocyte GLO1 activity was measured spectrophotometrically. The A111G gene polymorphism, assessed in DNA from leucocytes was analyzed in patients with type 1-diabetes and normal kidney function and compared with a control group. RESULTS: Sixty-one patients with type 1-diabetes duration of 26.1 (10.7) years, mean (SD) with a HbA1c of 7.8 (0.9)%, 61.7 (9.9) mmol/mol and normal glomerular filtration rate were compared with 62 age- and sex-matched healthy controls. GLO1 activity was 0.206 (0.183-0.231) median (25-75% percentiles) U/mg Hb in the control group vs. 0.192 (0.165-0.224) in the diabetes group, (p = 0.149). In the diabetes group GLO1 correlated with HbA1c (r = 0.33, p < 0.01) and oxidized glutathione (GSSG) (r = - 0.34, p < 0.01) and in the control group with GSH (r = 0.37, p < 0.005) and fasting glucose (r = 0.26, p < 0.04). In a multiple regression analysis with GLO1 activity as the dependent variable, including the Ala111Glu polymorphism, the significant independent variables were log GSSG (ß - 0.318, p = 0.02) and HbA1c (ß 0.285, p = 0.041) in the diabetes group and log GSH, (ß 0.407, p = 0.004) in the control group. CONCLUSIONS/INTERPRETATION: Erythrocyte glyoxalase 1 activity did not differ between patients with type 1-diabetes and controls. The Ala111Glu glyoxalase gene polymorphism did not have an effect on glyoxalase 1 activity in either group.

Development of a prototype toe sensor for detection of diabetic peripheral small fiber neuropathy.

Diabetic peripheral neuropathy (DPN) affects a large proportion of people with diabetes, and early detection is essential to prevent further progression. Widespread clinical testing relies on simplicity and cost-effectiveness of examination. Early signs of DPN may be detected by assessing the sudomotor nerves, and sudomotor activity can be measured by bioimpedance. We present a prototype toe probe for DPN detection including sensors for measuring skin AC conductance, skin temperature and humidity. The prototype was tested on five participants with DPN and five healthy age-matched controls in a pilot study. Sudomotor sensor responses to a simple deep breathing test were very weak or absent in the DPN group, with all controls having larger responses than the DPN group. Evaporation was lower for the DPN group, and skin temperature was higher on average. For the same foot, the results for sudomotor responses were in agreement with sensory neurography amplitudes from the sural nerve whereas the monofilament test gave normal results for two of the DPN participants. If sufficient detection accuracy is confirmed in larger studies, the method may provide a simple and cost-effective tool to support clinical examination. Clinical Relevance- We present the early realization and testing of a simple device to support early detection of diabetic peripheral neuropathy.

Reduced glutathione concentrations are not decreased in red blood cells of patients with long term type 1-diabetes.

AIMS/HYPOTHESIS: Glutathione is a major part of the intracellular antioxidant defence against reactive oxygen species (ROS). We aimed to study the erythrocyte concentrations of reduced glutathione (GSH) and oxidized glutathione (GSSG) in patients with long term type 1-diabetes and normal kidney function compared to a control group. METHODS: Fasting erythrocyte concentrations of GSH and GSSG were measured by HPLC with column switching. RESULTS: Fifty-nine patients with type 1-diabetes for 26 (10.7) years, mean (SD) with a HbA(1c) of 7.8 (0.9) % and normal concentrations of S-creatinine were compared with 57 age- and sex-matched healthy controls. GSH (µmol/g protein) concentrations were 5.25 (4.59-6.23) (median and 95% CI) in the control group vs. 5.12 (4.43-5.99) in the diabetes group (p = 0.39). GSSG (µmol/g protein) concentrations were 0.092 (0.063-0.179) in the control group vs. 0.138 (0.067-0.247) in the diabetes group (p = 0.15). Concentrations of GSH correlated with diabetes duration (r = 0.36, p < 0.01) and serum concentrations of methylglyoxal-derived hydroimidazolone MG-H1 (r = 0.41; p < 0.005). In the control group, GSH correlated with MG-H1 (r = 0.27; p < 0.05). In a multiple regression analysis in the diabetes group with GSH as the dependent variable; the significant independent variables were MG-H1 (p = 0.001) and diabetes duration (p = 0.008). CONCLUSIONS/INTERPRETATION: Despite a significant positive association between GSH and methylglyoxal-derived hydroimidazolone MG-H1 and diabetes duration the concentrations of GSH and GSSG in erythrocytes did not differ between patients with type 1-diabetes and controls.

Renal tubulointerstitial expansion is associated with endothelial dysfunction and inflammation in type 1 diabetes.

OBJECTIVE: Diabetic nephropathy has been considered to be primarily of glomerular origin, but there is now compelling evidence that disruption of the tubulointerstitial architecture determines the outcome of diabetic nephropathy in interplay with the glomerular damage. We investigated whether reactive oxidative species, pro-inflammatory cytokines and endothelial dysfunction were implicated in the progression of tubulointerstitial damage in young subjects with type 1 diabetes. MATERIAL AND METHODS: In a prospective study, we investigated 18 young subjects (mean age 21 years) with type 1 diabetes and microalbuminuria. Quantitative morphometry concerning glomerular and tubulointerstitial changes was performed at baseline (i.e. mean duration of diabetes 10 years) and 2.5 and 8 years later. Markers of endothelial activation and inflammation, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumour necrosis factor-alpha, interleukin-6, interleukin-8 and highly sensitive C-reactive protein were measured at baseline and after 8 years. Tissue plasminogen activator antigen and plasminogen activator inhibitor (PAI-1 activity) and asymmetric dimethylargine (ADMA) were measured at baseline and after 2.5 years. RESULTS: PAI-1 activity at baseline was a significant independent variable of the 8-year increment in interstitial volume fraction (Vv(Int/cortex)). ADMA/L-arginine ratio at baseline was associated with the increment in Vv(Int/cortex) during 2.5 years (p<0.01), still significant after adjustment for covariates (p = 0.02). No associations between Vv(Int/cortex) and glomerular parameters, HaemoglobinA1c and urinary albumin excretion were observed. CONCLUSIONS: Biomarkers involved in interstitial volume expansion seem to be different from those of mesangial expansion in early diabetic nephropathy. PAI-1 activity may have a predictive role in the development of the tubulointerstitial expansion.

Exploring the relationship between coronary heart disease and type 2 diabetes: a cross-sectional study of secondary prevention among diabetes patients.

BACKGROUND: Coronary heart disease (CHD) and stroke are the major causes of death among people with diabetes. AIM: To describe the prevalence and onset of CHD and stroke among patients with type 2 diabetes mellitus (T2DM) in primary care in Norway, and explore the quality of secondary prevention. DESIGN & SETTING: A cross-sectional study of data was undertaken from electronic medical records (EMRs) of 10 255 patients with T2DM in general practice. The study took place in five counties of Norway (Oslo, Akershus, Rogaland, Hordaland, and Nordland). Quality of care was assessed based on national guideline recommendations. METHOD: Summary statistics with adjustments and binary logistic regression models were used. RESULTS: In total, 2260 patients (22.1%) had CHD and 759 (7.4%) had stroke. South Asians had significantly more CHD than ethnic Norwegians (29.5%, 95% confidence interval [CI] = 26.1 to 33.0 versus 21.5%, CI = 20.6 to 22.3) and other ethnic groups, and experienced onset of CHD or stroke at a mean of 7 years before Norwegians. In 47.9% of the patients, CHD was diagnosed before T2DM. Treatment target for low-density lipoprotein (LDL) cholesterol was reached for 30.0% and for systolic blood pressure (SBP) for 65.1% of the patients with CHD. Further, 20.9% of patients with CHD were present smokers, and only 5.0% of patients reached all four treatment targets (no smoking, HbA1c ≤7.0%, SBP <135 mmHg, LDL-cholesterol <1.8 mmol/l). CONCLUSION: The diagnosis of CHD preceded the diagnosis of T2DM in half of the patients. The prevalence of CHD was highest and onset earlier among ethnic South Asians. More intensive treatment of lipids, blood pressure, and smoking are needed in patients with T2DM and CHD.

Increased serum levels of the specific advanced glycation end product methylglyoxal-derived hydroimidazolone are associated with retinopathy in patients with type 2 diabetes mellitus.

Advanced glycation end products (AGEs) are thought to play a major pathogenic role in diabetic retinopathy. The most important AGE is unknown, but as increased serum methylglyoxal-derived hydroimidazolone has been demonstrated in patients with type 2 diabetes mellitus, the aim of the present study was to elucidate possible associations between serum levels of hydroimidazolone and retinopathy in patients with type 2 diabetes mellitus. We recruited 227 patients with type 2 diabetes mellitus and retinopathy ranging from none to proliferative. Level of retinopathy was determined from 7 standard field stereo photographs per eye according to the Early Treatment Diabetic Retinopathy Study. The patients were 66 +/- 11 years old, with a known diabetes duration of 14 +/- 9 years. Serum levels of hydroimidazolone were determined with a competitive immunoassay. Serum levels of hydroimidazolone were increased in nonproliferative (median, 4.50 U/mL; interquartile range, 3.69-5.77 U/mL) and proliferative retinopathy (median, 4.88 U/mL; interquartile range, 3.70-6.52 U/mL) compared with patients without retinopathy (median, 4.02 U/mL; interquartile range, 3.47-4.88 U/mL) (P = .008 and .002, respectively). There was no association between hydroimidazolone and hemoglobin A1c (r = 0.04, P = .57). In addition, patients with proliferative retinopathy and a relatively short known duration of diabetes, that is, less than the median of 14 years, had increased serum levels of hydroimidazolone (median, 6.91 U/mL; interquartile range, 4.70-8.91 U/mL) compared with those with nonproliferative retinopathy (median, 4.34; interquartile range, 3.86-5.53U/mL, P = .015). Serum levels of hydroimidazolone are increased in type 2 diabetic patients with retinopathy. This association is independent of hitherto known associated factors, such as hemoglobin A1c.

High serum levels of advanced glycation end products predict increased coronary heart disease mortality in nondiabetic women but not in nondiabetic men: a population-based 18-year follow-up study.

BACKGROUND: Advanced glycation end products (AGEs), modification products of glycation or glycoxidation of proteins and lipids, have been linked to premature atherosclerosis in patients with diabetes as well as in nondiabetic subjects. METHODS AND RESULTS: Serum levels of AGEs were measured with an immunoassay in samples obtained at baseline examination of a random sample of 1141 nondiabetic individuals (535 men and 606 women), aged 45 to 64 years, living in Kuopio, East Finland, or Turku, West Finland in 1982 to 1984. After 18 years of follow-up, all-cause mortality, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality were registered on the basis of copies of death certificates. Multivariate Cox regression model showed a significant association of serum AGEs with all-cause (P=0.012), CVD (P=0.018), and CHD (P=0.008) mortality in women but not in men. Fasting serum AGEs in the highest quartile were an independent risk factor for all-cause (hazards ratio [HR], 1.90; 95% CI, 1.16 to 3.11; P=0.011) and CHD (HR, 6.51; 95% CI, 1.78 to 23.79; P=0.005) mortality in women, even after the adjustment for confounding factors, including highly sensitive C-reactive protein. CONCLUSIONS: The present study is the first to show that serum levels of AGEs can predict total, CVD, and CHD mortality in nondiabetic women.

Optimal blood glucose control during 18 years preserves peripheral nerve function in patients with 30 years' duration of type 1 diabetes.

OBJECTIVE: To assess the association between 18 years of mean HbA(1c) and nerve conduction parameters of the lower limb in patients with type 1 diabetes of 30 years' duration. RESEARCH DESIGN AND METHODS: HbA(1c) has been examined prospectively since 1982 in a group of 39 patients with type 1 diabetes. Mean age at baseline was 25 years (range 18-40) with 12 years' disease duration. The mean age at diagnosis of diabetes was 12.5 years. Nerve function of lower limbs was assessed at baseline, after 8 years, and after 18 years. RESULTS: A total of 23 men and 16 women were studied. Mean age was 43 years. Mean HbA(1c) was 8.2% (range 6.6-11.3) during 18-year follow-up. Nerve conduction velocity (NCV) and nerve action potential amplitude (NAPA) at the last examination were significantly associated with mean HbA(1c) (P < 0. 05). From 1982 to 1999, there was a significant reduction in nerve function in patients with mean HbA(1c) >or=8.4% (highest tertile). For example, the mean NCV in the tibial nerve was reduced from 47 to 31 m/s (P < 0.01). The number of nerves with NCV (P < 0.01) and NAPA (P = 0.01) reduced to below the reference level in each patient was also significantly associated to mean HbA(1c). No significant associations were found between nerve function parameters, sex, disease duration, blood pressure, serum cholesterol, microalbuminuria, or smoking. CONCLUSIONS: The present study shows that mean HbA(1c) is a strong predictor of nerve function. Mean HbA(1c) <8.4% over 18 years was associated with near-normal nerve function.

Eighteen years of fair glycemic control preserves cardiac autonomic function in type 1 diabetes.

OBJECTIVE: To study the association between 18 years of mean HbA(1c) and cardiac autonomic function in type 1 diabetic patients having used intensive insulin treatment. RESEARCH DESIGN AND METHODS: A total of 39 patients with type 1 diabetes were followed during 18 years, and HbA(1c) was measured yearly. At 18 years follow-up heart rate variability (HRV) measurements were used to assess cardiac autonomic function. Standard cardiac autonomic tests during normal breathing, deep breathing, the Valsalva maneuver, and the tilt test were performed. Maximal heart rate increase during exercise electrocardiogram and minimal heart rate during sleep were also used to describe cardiac autonomic function. RESULTS: We present the results for patients with mean HbA(1c) <8.4% (two lowest HbA(1c) tertiles) compared with those with HbA(1c) > or = 8.4% (highest HbA(1c) tertile). All of the cardiac autonomic tests were significantly different in the high- and the low-HbA(1c) groups, and the most favorable scores for all tests were seen in the low-HbA(1c) group. In the low-HbA(1c) group, the HRV was 40% during deep breathing, and in the high-HbA(1c) group, the HRV was 19.9% (P = 0.005). Minimal heart rate at night was significantly lower in the low-HbA(1c) groups than in the high-HbA(1c) group (P = 0.039). With maximal exercise, the increase in heart rate was significantly higher in the low-HbA(1c) group compared with the high-HbA(1c) group (P = 0.001). CONCLUSIONS: Mean HbA(1c) during 18 years was associated with cardiac autonomic function. Cardiac autonomic function was preserved with HbA(1c) <8.4%, whereas cardiac autonomic dysfunction was impaired in the group with HbA(1c) > or = 8.4%.

Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry.

OBJECTIVE: Primary adrenal insufficiency [Addison's disease (AD)] is rare, and systematic studies are few, mostly conducted on small patient samples. We aimed to determine the clinical, immunological, and genetic features of a national registry-based cohort. DESIGN: Patients with AD identified through a nationwide search of diagnosis registries were invited to participate in a survey of clinical features, health-related quality of life (HRQoL), autoantibody assays, and human leukocyte antigen (HLA) class II typing. RESULTS: Of 664 registered patients, 64% participated in the study. The prevalence of autoimmune or idiopathic AD in Norway was 144 per million, and the incidence was 0.44 per 100,000 per year (1993-2007). Familial disease was reported by 10% and autoimmune comorbidity by 66%. Thyroid disease was most common (47%), followed by type 1 diabetes (12%), vitiligo (11%), vitamin B12 deficiency (10%), and premature ovarian insufficiency (6.6% of women). The mean daily treatment for AD was 40.5 mg cortisone acetate and 0.1 mg fludrocortisone. The mean Short Form 36 vitality scores were significantly diminished from the norm (51 vs. 60), especially among those with diabetes. Concomitant thyroid autoimmunity did not lower scores. Anti-21-hydroxylase antibodies were found in 86%. Particularly strong susceptibility for AD was found for the DR3-DQ2/ DRB1*0404-DQ8 genotype (odds ratio, 32; P = 4 x 10(-17)), which predicted early onset. CONCLUSIONS: AD is almost exclusively autoimmune, with high autoimmune comorbidity. Both anti-21-hydroxylase antibodies and HLA class II can be clinically relevant predictors of AD. HRQoL is reduced, especially among diabetes patients, whereas thyroid disease did not have an impact on HRQoL. Treatment modalities that improve HRQoL are needed.

Increased vitreous levels of hydroimidazolone in type 2 diabetes patients are associated with retinopathy: a case-control study.

PURPOSE: As advanced glycation endproducts (AGEs) and the vitreous body are both considered to be involved in the development of diabetic retinopathy and hydroimidazolone is one of the most prominent AGEs, we compared vitreous and serum hydroimidazolone in diabetes patients with proliferative diabetic retinopathy (PDR) to levels in non-diabetes controls, co-measuring vitreous albumin and vascular endothelial growth factor (VEGF). METHODS: In a cross-sectional case-control study design, we used immunoassays to compare vitreous and serum hydroimidazolone and VEGF levels in 23 consecutive type 2 diabetes mellitus patients with a median known diabetes duration of 12 years (range 1-38 years) with those in 32 non-diabetes age-matched controls undergoing vitrectomy. RESULTS: Vitreous hydroimidazolone was increased in the PDR group (median 1.3 U/ml, range 0.5-3.3 U/ml) compared with controls (median 0.8 U/ml, 0.5-2.5 U/ml) (p = 0.026). Hydroimidazolone levels in serum and vitreous correlated (r = 0.49, p = 0.019). In PDR, vitreous VEGF levels were increased (median 1600 pg/ml, range 20-14 700 pg/ml) compared with controls (median 7 pg/ml, range 2-500 pg/ml) (p < 0.001). Similarly, vitreous albumin concentration was increased in PDR (median 1.6 g/l, range 0.7-3.0 g/l) compared with controls (median 0.3 g/l, range 0.08-1.9 g/l) (p < 0.001). Albumin could not explain the differences in vitreous VEGF levels in a logistic regression analysis. No correlation was found between vitreous levels of VEGF and hydroimidazolone (r = 0.12, p = 0.59). CONCLUSIONS: Increased vitreous hydroimidazolone is associated with diabetic retinopathy, possibly due to a blood-retinal barrier breakdown. Irrespective of origin, it may add to the ocular damage and needs further causal investigation. Increased VEGF in diabetic vitreous is probably of intraocular origin. It is not associated with vitreous hydroimidazolone.

Lack of recognition of Nepsilon-(carboxymethyl)lysine by the mouse liver reticulo-endothelial system: implications for pathophysiology.

Advanced glycation end products (AGEs) are known to be associated with a number of pathological conditions, such as diabetes mellitus, Alzheimer's disease, uremia, as well as with normal aging. This study was undertaken to investigate whether Nepsilon-(carboxymethyl)lysine (CML), a major structure among numerous AGEs, engenders hepatic AGE clearance. For this purpose uptake of BSA substituted with heterogeneous AGEs or with CML only was monitored in vivo and in cultured hepatic scavenger cells. Here, we show that following intravenous administration of 125I-AGE-BSA and 125I-CML-BSA, blood radioactivity was reduced by 50% after 50s and >100 min, respectively. Recoveries from the circulation at 6 min after injection were: 5% for AGE-BSA, 95% for CML-BSA. More than 80% of the injected AGE-BSA was recovered from the liver. AGE-BSA, but not CML-BSA, was avidly endocytosed by cultured liver scavenger cells. Our results suggest that CML does not engender AGE-BSA clearance. Macromolecules substituted with CML only may escape elimination and cause pathological effects.