Cognitive rehabilitation in multiple sclerosis: a randomized controlled trial.

BACKGROUND: The evidence base in cognitive rehabilitation in multiple sclerosis (MS) is still sparse. OBJECTIVE: The aim of the study was to investigate the effects of cognitive rehabilitation on cognitive and executive coping, psychological well-being and psychological aspects of health-related quality of life (HRQoL) in patients with MS. METHODS: One hundred and twenty patients with cognitive complaints, taking part in a 4-week multidisciplinary rehabilitation, were randomized to an intervention group (n = 60) and a control group (n = 60). Both groups underwent neuropsychological assessment with subsequent feedback and took part in general multidisciplinary MS rehabilitation. Additionally, the intervention group participated in cognitive group sessions as well as individual sessions. The main focus was to formulate Goal Attainment Scaling goals for coping with cognitive challenges. For 3 months past rehabilitation, the intervention group received biweekly telephone follow-up, focusing on goal attainment. RESULTS: Executive functioning improved significantly from baseline to four and 7 months in both groups. Improvements in psychological well-being and psychological aspects of HRQoL occurred only in the intervention group. CONCLUSION: Multicomponent cognitive rehabilitation administered within the context of multidisciplinary rehabilitation can improve psychological well-being and psychological aspects of HRQoL.

Predictors of executive complaints and executive deficits in multiple sclerosis.

OBJECTIVES: To investigate executive complaints and objective executive deficits and their relations to both depression and neurological function in multiple sclerosis (MS). MATERIALS AND METHODS: One hundred and twenty MS patients participating in multidisciplinary rehabilitation underwent assessment with the Expanded Disability Status Scale (EDSS), neuropsychological tests of executive function, self-report measures of executive function (BRIEF-A), and depression (BDI-II). RESULTS: Multivariate regression analysis showed that moderate depression and above (BDI-II > 20) significantly predicted a high degree of subjective executive complaints. Multivariate regression analysis showed that EDSS scores above 4.3 significantly predicted executive cognitive deficit, measured by neuropsychological tests. CONCLUSION: Among the study variables, depression was the strongest predictor of executive complaints. A high degree of neurological disability was the strongest predictor for executive deficit, measured by neuropsychological tests.

The effect of strength training volume on satellite cells, myogenic regulatory factors, and growth factors.

The aim of this work was to study the effect of training volume on activation of satellite cells. Healthy untrained men were randomly assigned into two groups. The 3L-1UB group (n = 10) performed three-set leg exercises and single-set upper body exercises, and the 1L-3UB group (n = 11) performed single-set leg exercises and three-set upper body exercises. Both groups performed three sessions (80-90 min) per week for 11 weeks. Biopsies were taken from m. vastus lateralis and m. trapezius. The number of satellite cells, satellite cells positive for myogenin and MyoD, and the number of myonuclei were counted. Homogenized muscle was analyzed for myogenin and MyoD, and extracted ribonucleic acid (RNA) was monitored for selected growth factor transcripts. Knee extensor strength increased more in the 3L-1UB group than in the 1L-3UB group (48 ± 4% vs 29 ± 4%), whereas the strength gain in shoulder press was similar in both training groups. The number of satellite cells in m. vastus lateralis increased more in the 3L-1UB group than in the 1L-3UB group. The number of myonuclei increased similarly in both groups. The messenger RNA expression of growth factors peaked after 2 weeks of training. In conclusion, increasing training volume enhanced satellite cell numbers in the leg muscle, but not in the upper body muscle.

Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes.

OBJECTIVE: Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE. DESIGN: Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. SETTING: Antenatal clinics. POPULATION: Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21). METHODS: Maternal serum levels of sRAGE (total circulating pool), N(ε)-(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays. MAIN OUTCOME MEASURES: Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-). RESULTS: In DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P < 0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. CONCLUSIONS: In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM.

Strength training elevates HSP27, HSP70 and αB-crystallin levels in musculi vastus lateralis and trapezius.

A single bout of high-force exercise has been shown to increase the muscle levels of heat shock proteins (HSPs). Here, changes in the levels of HSPs after 2 and 11 weeks of strength training with either one or three sets per exercise were examined. Fifteen young men (27 ± 6 years, 182 ± 8 cm and 82 ± 13 kg) were randomized to train either one set in lower-body exercises and three sets in upper-body exercises (1L-3UB), or three sets in lower-body exercises and one set in upper-body exercises (3L-1UB). Biopsies from vastus lateralis and trapezius were obtained before, during (2 weeks) and after 11 weeks of strength training (3 bouts per week). The biopsies were analysed for HSP27 (cytosolic and cytoskeletal fractions) and HSP70 and αB-crystallin (cytosolic fraction). No evidence for an effect of training volume (1 vs. 3 sets) on the HSP response was found. For all subjects combined, HSP27 [186 ± 69% (mean ± SD)], HSP70 (146 ± 51%) and αB-crystallin (184 ± 82%) increased in the cytosolic fraction of vastus lateralis after 11 weeks of training. In the trapezius, the only observed increase was for HSP27 in the cytosolic fraction after 2 weeks of training (149 ± 59%). However, the trapezius contained somewhat higher levels of HSP70 and αB-crystallin than vastus lateralis at baseline. The HSP27 levels in the cytoskeletal compartment did not increase significantly in either muscle. In conclusion, strength training resulted-independent of training volume-in elevated levels of HSP27, HSP70 and αB-crystallin in the cytosolic compartment of the vastus lateralis. In the trapezius, only the cytosolic HSP27 levels were increased with training.

Perinatal and infant mortality in term and preterm births among women with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to estimate the risks of adverse birth outcomes such as stillbirth, infant death, preterm birth and pre-eclampsia in women with type 1 diabetes, compared with the background population. We further aimed to explore the risks of adverse birth outcomes in preterm and term deliveries separately. METHODS: By linkage of two nationwide registries, the Medical Birth Registry of Norway and the Norwegian Childhood Diabetes Registry, we identified 1,307 births among women with pregestational type 1 diabetes registered in the Diabetes Registry, and 1,161,092 births in the background population during the period 1985-2004. The ORs with 95% CIs for adverse outcome among women with type 1 diabetes vs the background population were estimated using logistic regression. RESULTS: The OR for stillbirth (≥22 weeks of gestation) was 3.6 (95% CI 2.5, 5.3), and for perinatal death (stillbirth or death in the first week of life) it was 2.9 (95% CI 2.0, 4.1). The OR for infant death (first year of life) was 1.9 (95% CI 1.1, 3.2). For preterm birth (< 37 weeks of gestation) and pre-eclampsia the ORs were 4.9 (95% CI 4.3, 5.5) and 6.3 (95% CI 5.5, 7.2), respectively. When preterm and term deliveries were analysed separately, the excess risk of stillbirth and infant death in women with diabetes was confined to term deliveries. CONCLUSIONS/INTERPRETATION: Pregestational type 1 diabetes was associated with a considerably higher risk of adverse pregnancy outcomes, including infant death, compared with the background population. A novel finding of the study was that the increased risk was confined to term births.

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women.

AIMS/HYPOTHESIS: Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFbeta1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia. METHODS: Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term. RESULTS: Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n = 26) vs those without hypertensive complications (diabetic normotensive, n = 95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p < 0.05) and the normal rise of PlGF during pregnancy was blunted (p < 0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r(2) = 42%, p < 0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p < 0.0001). CONCLUSIONS/INTERPRETATION: Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

Comparison of genetic risk in three candidate genes (TCF7L2, PPARG, KCNJ11) with traditional risk factors for type 2 diabetes in a population-based study--the HUNT study.

UNLABELLED: We studied the impact of genetic and traditional risk factors for type 2 diabetes in a large, population-based study from Nord-Trøndelag county in Norway (HUNT), in both cross-sectional and prospective design. MATERIAL AND METHODS: 65,905 individuals participated in the HUNT study. We studied a randomly selected group of 869 individuals with self-reported diabetes or non-fasting serum glucose >or=11.1 mmol/L and 2,080 non-diabetic control subjects with non-fasting serum glucose <5.5 mmol/L. Four candidate polymorphisms in the three genes TCF7L2 (rs12255372 and rs7903146), PPARG (rs1801282), KCNJ11 (rs5219) and traditional risk factors were studied. RESULTS: Risk alleles of the TCF7L2 gene showed increased risk of diabetes even when controlled for traditional diabetes risk factors (diabetes in family, waist circumference, physical activity, BMI, SBP and total and HDL-cholesterol) in both a cross-sectional and prospective setting (cross-sectional: rs12255372 OR 1.61 (1.31-1.99), rs7903146 OR 1.48 (1.20-1.83) and prospective: rs12255372 OR 1.59 (1.22-2.07), rs7903146 OR 1.47 (1.11-1.93)). The risk alleles of TCF7L2 indicated impaired beta-cell function in patients and control subjects. The population attributable risks for diabetes with TCF7L2 risk alleles were 15 % and with diabetes in a first-degree relative 31 %. CONCLUSION: The risk alleles of the TCF7L2 gene (rs12255372 and rs7903146) were strongly associated with type 2 diabetes, even after controlling for traditional risk factors in both a cross-sectional and prospective setting. These risk alleles were associated with indices of reduced beta-cell function.

Biosynthesis and release of thyrotropin-releasing hormone immunoreactivity in rat pancreatic islets in organ culture. Effects of age, glucose, and streptozotocin.

Thyrotropin-releasing hormone immunoreactivity (TRH-IR) was measured in isolated islets and in medium from rat pancreatic islets maintained in organ culture. TRH-IR in methanol extracts of both islets and culture medium was eluted in the same position as synthetic TRH by ion-exchange and gel chromatography and exhibited dilution curves parallel with synthetic TRH in radioimmunoassay. [3H]Histidine was incorporated into a component that reacted with TRH antiserum and had the same retention time as synthetic TRH on reversed-phase high-performance liquid chromatography. A continuous release of TRH-IR into the culture medium was observed from islets of both 5-d-old (newborn) and 30-d-old (adult) rats with a maximum on the second day of culture (28.7 +/- 7.0 and 13.3 +/- 3.6 fmol/islet per d, respectively). The content of TRH-IR was higher in freshly isolated islets from newborn rats (22.4 +/- 2.3 fmol/islet) than in adult rat islets, which, however, increased their content from 1.3 +/- 0.5 to 7.0 +/- 0.5 fmol/islet during the first 3 d of culture. Adult rat islets maintained in medium with 20 mM glucose released significantly more TRH-IR than islets in 3.3 mM glucose medium (13.0 +/- 0.7 vs. 4.3 +/- 0.3 fmol/islet per d). In contrast, the content of TRH-IR in the islets was reversed (1.4 +/- 0.3 vs. 4.7 +/- 1.6 fmol/islet). By exposing islets from newborn rats to streptozotocin 0.7 mg/ml for 30 min, a 50% reduction of TRH-IR content in the islets compared with the non-treated islets was seen after subsequent culture for 7 d. The insulin content was reduced by 80%, while glucagon was slightly elevated. In conclusion, these results indicate that TRH is synthesized in rat pancreatic islets, and that the release is stimulated by glucose.

Blood glucose control and microvascular and macrovascular complications in diabetes.

High blood glucose levels for several years is the major factor in the development and progression of microvascular complications in IDDM. Reducing mean blood glucose reduces the risk of progression of diabetic microvascular complications substantially. A curve-linear relationship exists between HbA1c levels and progression of diabetic retinopathy. Recent evidence also points to a close relationship between high blood glucose levels and progression of microvascular complications in NIDDM. The relationship between mean blood glucose and cardiovascular disease in diabetes has been unclear. Recent population-based studies give evidence for a linear association of glycemic control with the risk for cardiovascular disease in patients with NIDDM. However, randomized studies comparing different degrees of glycemic control in NIDDM and their impact on cardiovascular morbidity and mortality are urgently needed.

Increase in insulin antibodies during continuous subcutaneous insulin infusion and multiple-injection therapy in contrast to conventional treatment.

Forty-five insulin-dependent diabetics were randomized to 1 yr treatment with either continuous subcutaneous insulin infusion (CSII), multiple insulin injections (MI), or continued conventional treatment. The CSII group used regular insulin only, the MI group used 4-6 premeal injections of regular insulin and intermediate insulin at night, and the conventional group used two daily injections of combined regular and intermediate insulin. Only highly purified porcine insulin was used. Near normoglycemia was obtained during CSII and MI but not during conventional treatment. Antibodies against insulin were measured in serum samples by measuring the binding of iodinated porcine insulin to serum after removal of free and antibody-bound insulin from the samples by acid charcoal. The percent binding of 125I-labeled insulin increased significantly during MI and CSII, in contrast to conventional treatment. Nineteen patients had sufficient binding capacity for Scatchard analysis. In the CSII and MI groups, high- or low-affinity antibodies or both were induced. When insulin was administered subcutaneously during MI or CSII for 1 yr, the insulin antibody production increased, in contrast with conventional treatment.

Relationship between cows' milk consumption and incidence of IDDM in childhood.

OBJECTIVE: To compare age-standardized incidence rates of diabetes in children 0-14 yr of age and cows' milk consumption in various countries. RESEARCH DESIGN AND METHODS: Ecological correlation study. Only incidence rates from diabetes registries carefully validated by the Diabetes Epidemiology Research International Study Group were used-Finland, Sweden, Norway, Great Britain, Denmark, United States, New Zealand, Netherlands, Canada, France, Israel, and Japan. Data on fluid cows' milk consumption in corresponding countries were obtained from the International Dairy Federation. RESULTS: Correlation between milk consumption and incidence of insulin-dependent diabetes mellitus (IDDM) was 0.96. The data fit a linear regression model, and analysis showed that 94% of the geographic variation in incidence might be explained by differences in milk consumption. CONCLUSIONS: The results support the hypothesis that cows' milk may contain a triggering factor for the development of IDDM.

The effect of cooking upon the blood glucose response to ingested carrots and potatoes.

Ten insulin-dependent diabetic subjects were given the following tests in randomized order: 50 g glucose dissolved in water, 250 g raw and cooked potato (equal to 50 g carbohydrate), 270 g raw and cooked carrot (equal to 25 g carbohydrate), and 4 h of fasting. Blood glucose was measured for 4 h following the tests. The postprandial blood glucose responses after pure glucose and cooked potato were almost similar (90-min values: glucose 8.8 mmol/L, cooked potato 8.0 mmol/L), while the response after raw potato was considerably slower and weaker (90-min value: 3.3 mmol/L). There were no differences between the postprandial blood glucose responses after raw and cooked carrot (90-min values: raw carrot 3.2 mmol/L, cooked carrot 2.8 mmol/L), but the responses were statistically different from blood glucose values during fasting alone (90-min value: 0.8 mmol/L). The study shows that cooking is responsible for the rapid increase in blood glucose after ingestion of cooked potato, while no such phenomenon is seen after cooking of carrots.

New semiquantitative dipstick test for microalbuminuria.

OBJECTIVE: We compared a new semiquantitative dipstick test for microalbuminuria (Micral-Test) with a quantitative immunoturbidimetric method. RESEARCH DESIGN AND METHODS: This correlation study was performed at a pediatric and medical outpatient clinic at a university hospital. Overnight urine samples containing less than 200 mg/L albumin from 186 diabetic patients were analyzed. RESULTS: The correlation coefficient between the new semiquantitative method and the immunoturbidimetric reference method was 0.82. Elevated albumin concentration was defined as greater than 20 mg/L albumin in overnight urine, and the prevalence of samples with values above this level was 28%. By this definition, the Micral-Test assay level greater than or equal to 20 mg/L had a sensitivity of 92.3% and a specificity of 82.1%. Of the diabetic subjects, 84.9% were correctly classified as having elevated urinary albumin concentration or not. CONCLUSIONS: The Micral-Test is useful for in-clinic screening for elevated urinary albumin concentration and monitoring the development of urinary albumin excretion in the low microalbuminuric range.

Increased serum levels of advanced glycation end products (AGEs) in children and adolescents with IDDM.

OBJECTIVE: To investigate whether the serum levels of advanced glycation end products (AGEs) are increased in IDDM children and adolescents and to study the effect of puberty on serum levels of AGEs (S-AGEs). RESEARCH DESIGN AND METHODS: A total of 68 children and adolescent IDDM patients (age, 13.3 +/- 4.0 years; duration of diabetes, 5.0 +/- 3.6 years; HbA1c, 8.2 +/- 2.0%; Tanner stage [public hair], 1 vs. 2-5, 24/42) recruited from the pediatric outpatient clinic at Aker University Hospital were compared with 25 healthy nondiabetic control subjects. S-AGEs were measured by a fluoremetric immunoassay. RESULTS: S-AGEs were significantly elevated in the diabetic group when compared with the control group (14.4 +/- 3.5 vs. 11.7 +/- 3.0 U/ml, P < 0.002). A significant correlation (r = 0.26, P < 0.04) was found between S-AGEs and HbA1c in the diabetic group but not in the control group. No significant correlation was found between S-AGEs and the duration of diabetes in the diabetic group or S-AGEs and blood glucose concentration or age in either group. We found no difference between S-AGEs in boys and girls and in prepubertal and pubertal diabetic or control subjects. CONCLUSIONS: S-AGEs are increased in young patients with diabetes before puberty. Since AGEs are linked to the pathogenesis of vascular complications, this observation suggests that the pathological processes leading to diabetic late complications start even before puberty.

Serum levels of advanced glycation end products are increased in patients with type 2 diabetes and coronary heart disease.

OBJECTIVE: To investigate whether serum levels of advanced glycation end products (AGEs) and the glycoxidation product Nepsilon-(carboxymethyl)lysine (CML) are increased in patients with type 2 diabetes compared with nondiabetic control subjects and whether levels of AGEs and/or CML differ in patients with type 2 diabetes with or without coronary heart disease (CHD). RESEARCH DESIGN AND METHODS: Serum levels of AGEs and CML were measured with an immunoassay in 32 men and 21 women aged 59.3+/-6.2 years (means +/- SD) with type 2 diabetes for 7.3 + 3.1 years and in 17 men and 17 women aged 56.2+/-4.2 years without diabetes. Of the patients with diabetes, 18 had CHD. RESULTS: The serum levels of AGEs and CML were significantly increased in patients with type 2 diabetes compared with nondiabetic control subjects (median [5th-95th percentile]: AGEs 7.4 [4.4-10.9] vs. 4.2 [1.6-6.4] U/ml, P < 0.0001; CML 15.6 [5.6-29.9] vs. 8.6 [4.4-25.9] U/ml, P < 0.0001). The median level of AGEs but not CML was significantly increased in patients with type 2 diabetes and CHD compared with patients without CHD (8.1 [6.4-10.9] vs. 7.1 [3.5-9.8] U/ml, P = 0.03). There were significant positive correlations between serum levels of AGEs and CML in both patients and control subjects. CONCLUSIONS: Levels of AGEs and CML were significantly increased in patients with type 2 diabetes compared with nondiabetic control subjects, and levels of AGEs but not CML were significantly higher in patients with type 2 diabetes and CHD than in patients without diabetes. These results may indicate a role for non-CML AGEs in the development of macrovascular disease in patients with type 2 diabetes.

Severity of glomerulopathy predicts long-term urinary albumin excretion rate in patients with type 1 diabetes and microalbuminuria.

OBJECTIVE: To investigate whether the degree of glomerular structural lesions in young patients with type 1 diabetes and microalbuminuria was associated with urinary albumin excretion rate (AER) 6 years later and whether the AER level was influenced by blood glucose control, blood pressure, or glomerular filtration rate (GFR). RESEARCH DESIGN AND METHODS: There were 17 young adults with type 1 diabetes and microalbuminuria, 8 men and 9 women with mean age 20 years (95% CI: 18-22) and duration of diabetes of 11 years (10-13), who participated in a 6-year prospective study. Kidney biopsies (measurements of basement membrane thickness [BMT] and mesangial and matrix volume fractions) and GFR were performed at baseline. AER and HbA1c were measured at least three times a year and blood pressure once a year. RESULTS: In a multivariate analysis, baseline BMT and mean 6-year HbA1c contributed significantly to AER at the end of the study (R2 = 0.69, P < 0.01). When mesangial volume fraction replaced BMT as the independent variable, this parameter and AER at baseline predicted the AER at 6 years (R2 = 0.55, P < 0.55). Mesangial volume fraction and BMT (in separate analysis) contributed significantly to change in AER during the study. During the study, neither AER (30 micrograms/min [19-40] to 16 micrograms/min [7-90]) nor blood pressure (96 mmHg [92-102] to 95 mmHg [91-98]) changed significantly in the group. However, HbA1c was reduced from 10.3 (9.6-11.0) to 8.4% (7.8-9.1) (P < 0.01). CONCLUSIONS: In young patients with microalbuminuria, the long-term urinary AER was predicted by the degree of glomerular structural changes and associated with blood glucose control, but not with blood pressure or GFR.

The advanced glycation end product Nepsilon-(carboxymethyl)lysine is increased in serum from children and adolescents with type 1 diabetes.

OBJECTIVE: To investigate whether children and adolescents with type 1 diabetes have increased serum levels of the glycoxidation product Nepsilon-(carboxymethyl)lysine (CML) at an early stage of the disease. RESEARCH DESIGN AND METHODS: The serum levels of CML in 38 patients with type 1 diabetes aged 14+/-3.2 (mean+/-SD) years were compared with those in 26 control subjects aged 16+/-1.7 years. The mean duration of diabetes was 5+/-4.7 years, ranging from 0.5 to 15 years. The mean levels of HbA1c were 10.3+/-2.5% in the patient group. The serum levels of CML were measured using a monoclonal anti-CML antibody in a fluoremetric immunoassay. Serum protein levels of advanced glycation end products (AGEs) were assayed using a polyclonal antibody from rabbit immunized with AGE-RNase (pAGE). RESULTS: The serum levels of CML and pAGE were significantly increased in the patient group versus the control group: 1.08 (0.45-2.97) U/ml CML (median 10-90 percentiles) vs. 0.70 (0.36-1.79) U/ml CML, P < 0.03, and 6.6 (5.1-9.9) U/ml pAGE vs. 5.5 (3.7-8.2) U/ml AGEs, P < 0.01. A significant relationship between CML and pAGE was found in the IDDM group, r = 0.76, P < 0.001. The CML levels were not associated with the HbAlc levels (n = 23, r = -0.02, NS), cholesterol levels (n = 21, r = 0.07, NS), age, sex, or diabetes duration. CONCLUSIONS: Serum levels of CML are increased in patients with type 1 diabetes. This increase precedes the development of micro- and macrovascular complications.

Hydroperoxides in plasma are reduced by intensified insulin treatment. A randomized controlled study of IDDM patients with microalbuminuria.

OBJECTIVE: An association between reactive oxygen species and diabetic micro- and macrovascular complications has been proposed. In the present study, we have examined the effect of an improved blood glucose control on plasma levels of hydroperoxides in patients with IDDM. RESEARCH DESIGN AND METHODS: Subjects included 30 young IDDM patients with microalbuminuria who were randomized to receive either continuous subcutaneous insulin infusion (CSII) by a portable insulin pump (n = 15) or conventional insulin treatment (CIT) (n = 15) for 24 months. Plasma levels of hydroperoxides were measured by the ferrous oxidation with Xylenol Orange, version 2 (FOX2) assay. This method measures total lipid hydroperoxides and, unlike other methods, does not suffer from extraction losses. RESULTS: The mean HbA1c level was lower in the CSII group at the end of the study than in the CIT group: (mean [95% CI]) 8.6 (8.1-9.1) vs. 9.6 (9.0-10.3)%, respectively (P < 0.002). The level of plasma hydroperoxides was very similar at the start of the study but was significantly lower in the CSII group compared with the CIT group at the end of the study: 2.9 (2.1-3.7) vs. 4.3 (3.2-5.4) mumol/l, respectively (P < 0.02). In the CSII group, hydroperoxides were reduced by 31% from baseline (P < 0.001), whereas there was no change in levels of hydroperoxides in the CIT group. Mean hydroperoxide levels correlated with mean HbA1c during the study (r = 0.39, P < 0.04). Hydroperoxide levels were associated with the levels of microalbuminuria (r = 0.45, P < 0.02). CONCLUSIONS: This study provides support for the hypothesis that hyperglycemia is an important factor in the generation of hydroperoxides, and, thus, reactive oxygen species, in the circulation of IDDM patients.

Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes.

OBJECTIVE: Impairment of left ventricular diastolic function, possibly caused by increased collagen cross-linking of the cardiac muscle, is common in patients with type 1 diabetes even without coronary artery disease. Advanced glycation end products (AGEs) cross-link tissue collagen and are found within myocardial fibers. The aim of this study was to examine for a possible association between circulating AGEs and left ventricular cardiac function. RESEARCH DESIGN AND METHODS: Left ventricular diastolic and systolic function were assessed by M-mode and Doppler echocardiography in 52 patients with type 1 diabetes, age 40 +/- 13 (mean +/- SD) years, diabetes duration 17 +/- 13 years, and HbA1c 8.3 +/- 1.1%. Serum levels of AGEs and N epsilon-(carboxymethyl)lysine (CML) were measured by newly developed competitive immunoassays. RESULTS: A positive correlation was found between serum levels of AGEs and isovolumetric relaxation time (IVRT), r = 0.46 (P < 0.0008), and left ventricular diameter during diastole, r = 0.37 (P < 0.008). The systolic parameters did not correlate with serum levels of AGEs. Stepwise regression analysis showed that 21% of the IVRT variation could be explained by serum levels of AGEs (F = 11.4, P < 0.002), whereas serum levels of CML, HbA1c, albumin excretion rate, diabetes duration, and mean arterial blood pressure were of no importance. AGE levels were significantly increased in men compared with women (P < 0.03) and present or former smokers (P < 0.04). CONCLUSIONS: Increased serum levels of AGEs, unlike serum levels of CML, are associated with heart stiffness in patients with type 1 diabetes, possibly mediated by the cross-linking properties of AGEs.