Chitinase enzyme activity in CSF is a powerful biomarker of Alzheimer disease.

OBJECTIVE: DNA damage accumulation in brain is associated with the development of Alzheimer disease (AD), but newly identified protein markers of DNA damage have not been evaluated in the diagnosis of AD and other forms of dementia. METHODS: Here, we analyzed the level of novel biomarkers of DNA damage and telomere dysfunction (chitinase activity, N-acetyl-glucosaminidase activity, stathmin, and EF-1α) in CSF of 94 patients with AD, 41 patients with non-AD dementia, and 40 control patients without dementia. RESULTS: Enzymatic activity of chitinase (chitotriosidase activity) and stathmin protein level were significantly increased in CSF of patients with AD and non-AD dementia compared with that of no dementia control patients. As a single marker, chitinase activity was most powerful for distinguishing patients with AD from no dementia patients with an accuracy of 85.8% using a single threshold. Discrimination was even superior to clinically standard CSF markers that showed an accuracy of 78.4% (ß-amyloid) and 77.6% (tau). Combined analysis of chitinase with other markers increased the accuracy to a maximum of 91%. The biomarkers of DNA damage were also increased in CSF of patients with non-AD dementia compared with no dementia patients, and the new biomarkers improved the diagnosis of non-AD dementia as well as the discrimination of AD from non-AD dementia. CONCLUSIONS: Taken together, the findings in this study provide experimental evidence that DNA damage markers are significantly increased in AD and non-AD dementia. The biomarkers identified outperformed the standard CSF markers for diagnosing AD and non-AD dementia in the cohort investigated.

Protein array analysis of oligomerization-induced changes in alpha-synuclein protein-protein interactions points to an interference with Cdc42 effector proteins.

Aggregation of alpha-synuclein may contribute to neuropathology in Parkinson's disease patients and in transgenic animal models. Natively unfolded alpha-synuclein binds to various proteins and conformational changes due to alpha-synuclein misfolding may alter physiological interactions. In the present study, we used protein arrays spotted with 5000 recombinant human proteins for a large scale interaction analysis of monomeric versus oligomeric alpha-synuclein. Monomeric alpha-synuclein bound to arrayed cAMP regulated phosphoprotein 19 and binding appears to be disrupted by alpha-synuclein oligomerization. Incubation with recombinant alpha-synuclein oligomers lead to the identification of several GTPase activating proteins and Cdc42 effector proteins as binding partners. Protein database searches revealed a Cdc42/Rac interactive binding domain in some interactors. To demonstrate in vivo relevance, we analyzed brainstem protein extracts from alpha-synuclein(A30P) transgenic mice. Pull-down assays using beads conjugated with a Cdc42/Rac interactive binding domain lead to an enrichment of endogenous alpha-synuclein oligomers. Cdc42 effector proteins were also co-immunoprecipitated with alpha-synuclein from brainstem lysates and were colocalized with alpha-synuclein aggregates in brain sections by double immunostaining. By two-dimensional gel electrophoretic analysis of synaptosomal fractions from transgenic mouse brains we detected additional isoforms of septin 6, a downstream target of Cdc42 effector proteins. Small GTPases have recently been identified in a genetic modifier screen to suppress alpha-synuclein toxicity in yeast. Our data indicate that components of small GTPase signal transduction pathways may be directly targeted by alpha-synuclein oligomers which potentially leads to signaling deficits and neurodegeneration.

Serum concentrations of retinol-binding protein 4 in women with and without gestational diabetes.

AIMS/HYPOTHESIS: Pregnancy is characterised by temporarily increased insulin resistance. Gestational diabetes occurs when pancreatic beta cell function is unable to compensate for this insulin resistance. Retinol-binding protein 4 (RBP4) could be related to insulin resistance. We hypothesised that RBP4 is elevated in gestational diabetes. METHODS: Serum RBP4, transthyretin and retinol were cross-sectionally measured in 42 women with gestational diabetes and 45 pregnant controls. Of these, 20 women with and 22 without gestational diabetes were included in an additional longitudinal study. RBP4 was determined by enzyme immunometric assay (EIA) and western blot. RESULTS: Women with gestational diabetes had lower RBP4 EIA and western blot levels than controls (median 6.8 [interquartile range, 3.9-14.3] vs 11.3 [7.8-19.9] microg/ml, p < 0.001 and 25.1 [21.7-29.6] vs 26.6 [23.5-32.2] microg/ml, p = 0.026). Transthyretin and the RBP4:transthyretin molar ratio were comparable between the groups. Serum retinol was lower (p < 0.001) and the RBP4 Western blot level: retinol molar ratio was higher in women with gestational diabetes (p = 0.044). RBP4 was not associated with the glucose or homeostasis model assessment of insulin resistance (HOMA-IR), but in gestational diabetes the RBP4:retinol molar ratio correlated with blood glucose and negatively with 2 h post-load insulin. The RBP4:transthyretin ratio correlated with HOMA-IR and fasting insulin in controls. In women with gestational diabetes RBP4 EIA and western blot levels increased after delivery. Retinol increased in both groups, while transthyretin and the RBP4:transthyretin ratio were not altered after parturition. CONCLUSIONS/INTERPRETATION: RBP4 measured by two different techniques is not elevated, but the RBP4:retinol molar ratio is higher and correlates with fasting blood glucose in women with gestational diabetes. Thus, the RBP4:retinol ratio and the RBP4:transthyretin ratio are more informative than RBP4 levels alone when assessing insulin-glucose homeostasis during pregnancy.

High prevalence of abnormal circadian blood pressure regulation and impaired glucose tolerance in adults with hypopituitarism.

Patients with hypopituitarism have an increased mortality from cardiovascular events. Reduced nocturnal blood pressure decline (non-dipping) and impaired glucose tolerance are considered as cardiovascular risk factors. To evaluate the role of these risk factors in patients with hypopituitarism we determined the 24-hour blood pressure regulation and glucose tolerance status in hypopituitary patients with and without growth hormone (GH) deficiency. Sixty-one hypopituitary subjects 5 +/- 3 years after brain surgery because of macroadenoma, 61 patients with type 2 diabetes mellitus (T2DM), and 20 healthy controls were included. Forty-four hypopituitary patients were GH deficient and 28 of these on GH treatment. Non-dipping was observed in 41 % (n = 7) of hypopituitary subjects with normal GH release, in 46 % (n = 13) of patients on GH therapy, and in 69 % (n = 11) of untreated GH deficient patients. Untreated GH deficient patients had a higher systolic night/day ratio (1.00 +/- 0.03) compared to non GH deficient (0.92 +/- 0.02; p < 0.02) and GH treated hypopituitary patients (0.93 +/- 0.01; p < 0.02). The rate of non-dipping in hypopituitarism was comparable to that in T2DM. Pathologic glucose tolerance was diagnosed in 30 % of the hypopituitary patients. The prevalence of non-dipping was independent of glucose metabolism in hypopituitary patients. All controls had normal night time blood pressure fall and glucose metabolism. The high prevalence of nocturnal non-dipping and glucose intolerance detected in this cohort might contribute to the increased cardiovascular risk of hypopituitary patients.

Circulating ADMA concentrations are elevated in hypopituitary adults with and without growth hormone deficiency.

BACKGROUND: Cardiovascular mortality is increased in patients with hypopituitarism. Elevated concentrations of the endogenous NO synthase antagonist asymmetrical dimethylarginine (ADMA) may be related to the development of atherosclerosis and are associated with cardiovascular risk. We studied the concentrations of ADMA in hypopituitary patients with and without growth hormone deficiency (GHD) and in healthy subjects. MATERIALS AND METHODS: Plasma from 44 patients with hypopituitarism with (n = 30) and without GHD (n = 14) and from 25 age- and sex-matched healthy controls was taken for analysis of L-arginine, ADMA, symmetrical dimethylarginine (SDMA) and clinical parameters. Further plasma from 10 hypopituitary patients was examined before and after treatment with 9 g of oral L-arginine for 14 days. RESULTS: Asymmetrical dimethylarginine was significantly higher in the hypopituitary patients than in the controls (0.63 +/- 0.12 vs. 0.51 +/- 0.15 micromol L(-1); P < 0.005). L-arginine and the L-arginine/ADMA ratios were lower in the subjects with hypopituitarism (53 +/- 18 vs. 90 +/- 29 micromol L(-1) and 87 +/- 31 vs. 185 +/- 59; both P < 0.0001). Symmetrical dimethylarginine was comparable between the patients and the controls. L-arginine and dimethylarginines were associated with 2-h stimulated glucose levels in a glucose tolerance test (r = 0.33; P < 0.05), but not other cardiovascular risk factors. Oral L-arginine supplementation normalized the reduced L-arginine/ADMA ratio in the hypopituitary patients. CONCLUSION: Asymmetrical dimethylarginine is elevated in patients with hypopituitarism independent of GHD and traditional risk factors. This might contribute to the increased cardiovascular morbidity in hypopituitary patients.

[Angiotensin II type-1 receptor antagonists and diabetes mellitus]. / Angiotensin-II-Typ-1-Rezeptor-Antagonisten und Diabetes mellitus.

Arterial hypertension is a major risk factor for microangiopathic diabetic complications and associated with an increased cardiovascular morbidity and mortality. An intensified antihypertensive treatment reduces microangiopathic complications and cardiovascular morbidity and mortality in diabetic patients. Even in normotensive type 1 and type 2 diabetic patients, the treatment with ACE inhibitors may prevent the later development of diabetic nephropathy. Treatment with ACE inhibitors increases the concentrations of bradykinin, which is responsible for the side effects such as cough and urticaria in some patients. On the other hand, bradykinin may have beneficial intrarenal effects decreasing the intraglomerular pressure. The novel angiotensin II receptor type 1 antagonists do not influence the bradykinin concentrations and seem to be tolerated by patients suffering from chronic cough with ACE inhibitor therapy. It is still unclear whether the different intrarenal effects are of clinical relevance in the long-term treatment of diabetic patients. In studies with diabetic animals the nephroprotective effects of ACE inhibitors and angiotensin II type 1 receptor antagonists are comparable. It was shown that glucose and lipid metabolism is not influenced by treatment with angiotensin II type 1 receptor antagonists. Further compared to Felodipine the reduction of urinary albumin excretion rate (UAER) was more pronounced by Losartane in Chinese type 2 diabetic patients. Short-term studies directly comparing the renal effects of ACE inhibitors with AT II type 1 receptor antagonists revealed similar reduction of blood pressure and albumin excretion rate in patients with diabetic nephropathy, so a combination of both substances might be useful. Data from ongoing long-term trials are still missing. Further, it is unknown whether different phenotypes of the ACE gene (DD, II polymorphism) require different therapeutic options. In conclusion, treatment with angiotensin II receptor antagonists is well-tolerated and has no adverse effects on metabolic control in diabetic patients. The beneficial effect on microangiopathic complications however has to be proven in randomized long-term studies in direct comparison with ACE inhibitors, which were clearly shown to delay the development and progression of diabetic nephropathy.

Growth hormone replacement therapy is not associated with retinal changes.

GH and/or growth factors are thought to play a role in the pathogenesis of diabetic retinopathy. In addition, the occurence of retinal changes mimicking diabetic retinopathy in two GH-deficient (GHD) patients receiving GH replacement therapy (GHRT) has recently been reported. The present study was performed to evaluate whether this was a coincidence or whether GHRT might regularly induce retinal changes. Sixty-one GHD patients on GHRT with a mean age of 42.5 +/-17.3 yr were examined by one ophthalmologist (AR). The mean duration of GHRT was 8.4 +/- 3.7 yr in childhood onset and 3.5 +/- 2.1yr in adult onset patients. Plasma insulin-like growth factor I concentrations were 76.4 +/- 49.6 ng/mL before GHRT and 244.3 +/- 119.2 ng/mL while receiving GHRT with a dose of 1.7 +/- 0.7 IU/day. After pupil dilatation with tropicamide, fundus examinations of both eyes were performed using a Volk 90 diopter fundus lens with a slit lamp (Haag Streit, Bern, Switzerland). In none of the patients were vascular or retinal changes like macular edema, microaneurysms, hemorrhages, hard exsudates, cotton wool spots, preproliferative signs, or proliferations found. The optic discs were also normal in all patients. We conclude, therefore, that long-term GHRT can be administered safely in GHD patients without an increased risk of retinal changes.

Initial urinary albumin excretion determines the progression of microalbuminuria in patients with type-2 diabetes and normotensive blood pressure values despite improved metabolic control.

Persistent increased urinary albumin excretion rate (UAER) is associated with increased cardiovascular mortality in type-2 diabetes, however, there are no conclusive data about the progression of advanced UAER in these patients. The present study has investigated the effect of metabolic intervention on the progression in UAER in relation to initial UAER levels. A total of 20 patients with type-2 diabetes and secondary failure to sulfonylurea were observed during 1 year (age, 60 +/- 8 years; HbA1c, 10.8 +/- 1.4%; and duration of diabetes, 17 +/- 10 years) and divided into two groups: group 1 (n = 10; UAER: 51 +/- 35 mg/24 h); and group 2 (n = 10; UAER: 191 +/- 175 mg/24 h). Despite a significant improvement of metabolic control by insulin treatment in both groups (HbA1c: group 1: 11 +/- 1.5 vs. 7.9 +/- 1.2%; group 2: 10.6 +/- 0.9 vs. 9.1 +/- 1.3%, P < 0.001), a progression of UAER was observed in group 2 (191 +/- 175 vs. 331 +/- 237 mg/24 h, P < 0.02), but not in group 1 (51 +/- 35 vs. 41 +/- 24 mg/24 h). Still serum creatinine levels remained normal in all patients during the observation period. The 24 h blood pressure (RR) values in the two groups remained normal under antihypertensive therapy throughout the study (group 1: RR syst: 130 vs. 136 mmHg; RR diast: 80 vs. 81 mmHg, mean arterial pressure (MAD): 89 vs. 93 mmHg; group 2: RR syst: 139 vs. 134 mmHg; RR diast: 78 vs. 75 mmHg, MAD: 97 vs. 90 mmHg). The data shows that in type-2 diabetic patients with normotensive blood pressure values the initial urinary albumin excretion levels determine the progression of UAER. When metabolic control is improved incipient UAER remains constant, but advanced UAER shows progression.

Renal and metabolic effects of 1-year treatment with ramipril or atenolol in NIDDM patients with microalbuminuria.

UNLABELLED: The clinical importance of selection of different antihypertensive drugs for the treatment of diabetic patients is still unclear. Thus we performed a randomised, controlled study in 105 hypertensive non-insulin-dependent diabetic (NIDDM) patients with microalbuminuria over 1 year. Patients received either the angiotensin converting enzyme (ACE) inhibitor ramipril (2.5-5.0 mg/day; in addition 24% of patients also received felodipine) or the beta blocking agent atenolol (50-100 mg/day; in addition 24% of patients also received hydrochlorothiazide). Blood pressure, metabolic control, lipid levels and albumin excretion rate were studied during the follow-up. After 1 year an almost identical fall (p < 0.001) in blood pressure was observed with ramipril (170/100 vs 150/ 85 mmHg, median) and atenolol (180/100 vs 150/ 80 mmHg, median). With ramipril a reduction of total cholesterol (6.3 vs 5.9 mmol/l), of LDL cholesterol (3.8 vs 3.6 mmol/l) and HDL cholesterol (1.3 vs 1.2 mmol/l) was found, whereas triglycerides slightly increased (1.8 vs 2.0 mmol/l). With atenolol a similar reduction of total cholesterol (6.3 vs 5.9 mmol/l), LDL cholesterol (3.8 vs 3.7 mmol/l) and HDL cholesterol (1.4 vs 1.2 mmol/l) and an increase of triglycerides (1.4 vs 1.7 mmol/l) was noted. Metabolic control of the patients was maintained with both ramipril and atenolol treatment. With ramipril treatment urinary albumin creatinine ratio (14.4 vs 13.8 mg/mmol) and creatinine clearance (82 vs 84 ml/min) were constant, but with atenolol an increase of albumin creatinine ratio (13.9 vs 19 mg/mmol, p < 0.001) and a slight decrease of creatinine clearance (80 vs 66 ml/min, p < 0.05, not significant after Bonferroni correction) was observed. IN CONCLUSION: 1-year treatment of NIDDM patients with ramipril or atenolol does not influence metabolic control, the changes in serum lipids were similar. Despite almost identical blood pressure reduction in both groups the albumin creatinine ratio was constant under ramipril, but increased under atenolol treatment.

Nondipping of nocturnal blood pressure is related to urinary albumin excretion rate in patients with type 2 diabetes mellitus.

Although cardiovascular and cerebrovascular morbidity and mortality in type 2 diabetic patients is closely related to urinary albumin excretion rate (UAER), the causative mechanisms are not yet identified. The aim of our study was to define the circadian variation of blood pressure (BP) in 72 type 2 diabetic patients (mean age 60 years, mean diabetes mellitus duration: 12 years) in comparison with 41 nondiabetic controls with essential hypertension (mean age 58 years) by using ambulatory blood pressure measurement. Thirty diabetic patients had normal UAER (< 30 mg/24 h), 27 had microalbuminuria (30 to 300 mg/24 h), and 15 had persistent proteinuria (> 300 mg/24 h). Systolic blood pressure during both nighttime and daytime was significantly elevated in type 2 diabetic patients with macroalbuminuria compared to controls and patients with normal UAER. During nighttime even type 2 diabetic patients with microalbuminuria had significantly elevated systolic blood pressure compared to controls with essential hypertension. We also observed a correlation of nocturnal blood pressure to UAER (systolic: r = 0.32, P < .007 and diastolic: r = 0.24, P < .04). Nondipping (defined as a reduction of nocturnal BP < 10%) was observed in 80% of the macroalbuminuric, 74% of the microalbuminuric, but only in 43% of the normoalbuminuric type 2 diabetic patients and in 37% of the controls (P < .04). Since a loss of circadian variation of BP is closely related to vascular complications in nondiabetics, our findings may indicate an important relationship between nondipping of BP and the high morbidity and mortality rate in diabetic patients with increased UAER.

Pulmonary dysfunction in type 1 diabetes in relation to metabolic long-term control and to incipient diabetic nephropathy.

UNLABELLED: The available data on pulmonary function in type 1 diabetes are still conflicting. Recently, restrictive alterations of pulmonary function were demonstrated in type 1 diabetic patients with end-stage renal failure (diabetic nephropathy), whereas patients with kidney failure from other causes had normal pulmonary function test results. In this study, the prevalence and nature of pulmonary dysfunction in type 1 diabetes and the relationship of pulmonary function tests to incipient diabetic nephropathy and metabolic long-term control were analyzed. Pulmonary function tests were performed in long-standing type 1 diabetic patients (n = 39) with normal serum creatinine levels (< 1.3 mg/dl) and the results compared with those of healthy control (n = 44). The patients were divided into those with a normal urinary albumin excretion rate (AER; n = 21, < 30 mg/day) and those with microalbuminuria (n = 18, AER 30-300 mg/day). We found a significant reduction of the following pulmonary function tests (performed by standardized spirometry and wholebody plethysmography) as compared with controls (C) in diabetic patients with microalbuminuria (M) and in diabetic patients with normoalbuminuria (N): total lung capacity (TLC; % predicted: M 89.6, p < 0.004; N 98.5, p = NS; C 101.1), vital capacity (VC; % predicted: M 83.7, p < 0.001; N 90.2, p < 0.03; C 97.3), forced expiratory volume in 1 s (FEV1; % predicted: M 81.2, p < 0.002; N 88.8, p < 0.02; C 93.8), and diffusing capacity of the lung for CO (DLCO; % predicted: M 83.4, p < 0.04; N 92.4, p = NS; C 95.6). We also found a slight increase of the airway resistance (kPa/l/s: M 0.22, p < 0.03; N 0.2, p = NS; C 0.18). The differences in TLC (% predicted) between diabetic patients with normo- and microalbuminuria were significant (p < 0.04). Further a close relation of pulmonary function tests to metabolic long-term control (mean values of repeated HbA1c measurements) was observed: TLC (% predicted: M r= -0.61, p < 0.007, N p = NS), VC (% predicted: M r = -0.57, p < 0.01; N r= -0.59, p < 0.005), and FEV1 (% predicted: M r = -0.50, p < 0.03; N r= -0.62, p < 0.003). IN CONCLUSION: pulmonary dysfunction in long-standing type 1 diabetic patients is more pronounced in patients with increased AER. Typical features of restrictive pulmonary defects, namely a reduction of TLC (% predicted) plus DLCO (% predicted) were observed predominantly in patients with incipient diabetic nephropathy. The clear correlation of pulmonary function tests with HbA1c measurements stresses the importance of optimal metabolic long-term control in type 1 diabetes.

Enhanced serum levels of thiobarbituric-acid-reactive substances in diabetes mellitus.

PURPOSE: To investigate whether serum levels of lipid peroxides measured as thiobarbituric-acid-reactive substances (TBARS) differ in type I and type II diabetic patients, whether serum levels correlate with late sequelae of diabetes, and whether serum levels of free vitamin E correlate with levels of lipid peroxidation by-products. PATIENTS AND METHODS: The relationship among lipids, glycosylated hemoglobin A1c (HbA1c), lipid peroxides measured as TBARS, and free vitamin E was determined in 158 patients. Fifteen of the 77 patients with type I diabetes and 39 of the 81 patients with type II diabetes had clinically apparent peripheral vascular disease or coronary artery disease, or both. RESULTS: Compared with control subjects, serum levels of TBARS were found to be significantly elevated (P < 0.001) in diabetic patients, and type II diabetic patients had significantly higher levels (P < 0.001) than type I patients. Both type I and type II diabetic patients with good metabolic control (HbA1c < 6.5%) had significantly lower (P < 0.005) TBARS levels than patients with poor metabolic control, but all groups had higher levels than the control group. Type II patients with angiopathy had significantly higher levels of TBARS than patients without angiopathy. Free vitamin E levels in control subjects and diabetic patients did not differ statistically. CONCLUSION: Serum levels of TBARS were significantly increased in all patients suffering from diabetes mellitus, whereby TBARS levels did not depend on the total amount of circulating lipids. It can be suggested that the enhanced lipidperoxidation is contributed to an increased formation of free radicals in diabetes mellitus.

Hypomagnesemia in type II diabetes: effect of a 3-month replacement therapy.

OBJECTIVE: To investigate the effects of long-term high-dose oral magnesium (Mg) therapy (30 mmol/day) in patients with type II diabetes. Low plasma magnesium levels have been reported in type II diabetes and are associated with insulin resistance and diabetic late complications. RESEARCH DESIGN AND METHODS: Forty patients with type II diabetes and hypomagnesemia were observed in a randomized double-blind placebo-controlled trial for 3 months (body mass index: 28 +/- 4 kg/m2; HbA1c: 7.4 +/- 0.8%). Plasma and urine magnesium and metabolic control parameters were determined, and side effects were considered, especially with regard to patients' compliance. RESULTS: A significant increase in plasma magnesium levels was observed after 3 months of treatment (Mg: 0.73 +/- 0.8 vs. 0.81 +/- 0.1 mmol/l), reaching magnesium levels of the control group (0.88 +/- 0.8 mmol/l; NS); metabolic control, however, was not altered (HbA1c: 7.2 +/- 0.7 vs. 7.4 +/- 0.9%). Six months after the end of the trial, plasma magnesium declined to pretreatment levels (Mg: 0.73 +/- 0.07 mmol/l). The prevalence of side effects was high at the beginning and was reduced significantly during treatment. CONCLUSIONS: We conclude that oral magnesium replacement therapy corrects hypomagnesemia after a minimum treatment period of 3 months. These observations might be important for the prevention of diabetic late complications.

Effects of captopril treatment versus placebo on renal function in type 2 diabetic patients with microalbuminuria: a long-term study.

We evaluated the renal effect of long-term antihypertensive treatment (12 months) with the angiotensin-converting enzyme inhibitor captopril compared to placebo in 15 type 2 diabetic patients with microalbuminuria. The patients were randomly allocated to captopril (n = 9) or placebo (n = 6). After 1-year therapy no significant decrease in blood pressure was demonstrated with captopril (139 +/- 17/80 +/- 9 versus 138 +/- 13/76 +/- 6 mmHg) or placebo (138 +/- 9/75 +/- 6 versus 135 +/- 14/79 +/- 10 mmHg). Only in a small hypertensive subgroup (n = 4) treated with captopril did we find a significant reduction in blood pressure (154 +/- 2/88 +/- 1 versus 142 +/- 7/78 +/- 5 mmHg, P < 0.05). The urinary albumin excretion rate did not change significantly either in the captopril group (95.6 mg/24 h, 25th percentile 138.4, 75th percentile 25.1; versus 127.8 mg/24 h, 25th percentile 29.3, 75th percentile 222) or in the placebo group (99.2 mg/24 h, 25th percentile 58.5, 75th percentile 125.8; versus 120.9 mg/24 h, 25th percentile 62.1, 75th percentile 179.7). There were also no alterations in renal blood flow or filtration rate. In the hypertensive subgroup treated with captopril a reduction in urinary albumin excretion rate after 3 and 6 months of treatment was observed (captopril 73.4 versus 24 and 41 mg/24 h, P < 0.05), but not after 12 months. Triglyceride and cholesterol levels remained constant before and after treatment while glycosylated hemoglobin decreased significantly after 12 months captopril (7.8 +/- 0.9 versus 6.9 +/- 0.7 mg%, P < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Haemostatic abnormalities persist despite glycaemic improvement by insulin therapy in lean type 2 diabetic patients.

Diabetes mellitus is associated with disturbances of the hemostatic system, which might contribute to the development of diabetic vascular disease. We investigated the effect of metabolic improvement by insulin therapy on the haemostatic system in 61 patients with type 2 diabetes mellitus and secondary sulfonylurea failure compared with 45 healthy control subjects matched for age, sex and BMI. Median age was 65, median diabetes duration 10 years. Median HbA1c (10%) and fructosamine (4.0 mM) levels were elevated before induction of therapy and decreased significantly within 6 months of insulin treatment to 7.5% and 3.0 mM, respectively (p < 0.0001). Compared with control subjects, median plasma levels of fibrinogen (317 vs 286 mg/dl), coagulation factor VII activity (1.1 vs 0.89 U/l), von Willebrand factor (1.6 vs 1.3 U/l), D-dimer (105 vs 86 micrograms/l), protein C:Ag (1.24 vs 0.95 U/l), total protein S:Ag (1.15 vs 0.91 U/l), and antithrombin III activity (1.17 vs 1.08 U/l) were significantly elevated. Levels of free protein S were not different from control values. No significant decline of coagulation parameters could be recorded during insulin therapy. Patients with diabetic vasculopathy had higher levels of D-dimer than those without (133 vs 76 micrograms/l before, 109 vs 88 micrograms/l during therapy), whereas the other haemostatic parameters were not different. Our data indicate a significant activation of the coagulation system in diabetic patients with secondary failure to sulfonylurea drugs, with signs of a prethrombotic state and endothelial cell disturbance.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term treatment with nifedipine reduces urinary albumin excretion and glomerular filtration rate in normotensive type 1 diabetic patients with microalbuminuria.

The aim of the present study was to investigate the renal effects of long-term treatment with the calcium channel blocker nifedipine in normotensive type 1 diabetic patients with microalbuminuria. In a randomized, double-blind trial, 15 type 1 diabetic patients were treated with either nifedipine (n = 8; dosage 30 mg/day) or placebo (n = 7) for 12 months. At baseline and after 6 and 12 months of therapy, the albumin excretion rate (UAER, radioimmunoassay), glomerular filtration rate (GFR, chromium 51 ethylenediamine tetra-acetic acid clearance) and renal plasma flow (RPF, iodine 125 hippuran clearance) were determined. Nifedipine treatment caused a significant reduction of UAER after 6 and 12 months (median, Q1/Q3 in mg/24 h): baseline 84 (65/163); 6 months 35 (23/90), P < 0.02; 12 months 39 (15/79), P < 0.05). GFR was significantly decreased by nifedipine treatment (baseline 157 +/- 15, 6 months 122 +/- 8, 12 months 111 +/- 47 ml/min; P < 0.05, mean +/- SEM), whereas RPF remained constant. Nifedipine treatment did not influence systolic (baseline 121 +/- 7, 12 months 124 +/- 2 mmHg, mean +/- SEM) or diastolic (baseline 72 +/- 2, 12 months 74 +/- 3 mmHg) arterial blood pressure. With placebo treatment no significant alterations of UAER, GFR, RPF and arterial blood pressure were observed. Metabolic control was constant throughout the whole study period. Thus, 1 year's treatment with nifedipine reduces the UAER and GFR in normotensive type 1 diabetic patients without influencing the systemic arterial blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoprotein (a) levels and atherogenic lipid fractions in relation to the degree of urinary albumin excretion in type 2 diabetes mellitus.

The relationship between serum lipids, apolipoprotein levels including apolipoprotein (a) to albumin excretion rate (AER) in 52 (17 male, 35 female) type 2 diabetic patients was studied. Patients were classified in groups as follows: (1) patients with normal AER (< 30 mg/24 h); (2) patients with microalbuminuria (AER 30-300 mg/24 h), and (3) patients with macroalbuminuria (AER > 300 mg/24 h). Apolipoprotein B levels were significantly (p < 0.05) elevated in the patients with macroalbuminuria compared to the normoalbuminuric group. Further, we observed a significant correlation between total cholesterol, low-density lipoprotein cholesterol, as well as apolipoprotein B levels to the degree of AER. No correlation between apolipoprotein (a) levels and AER, which is in contrast to recently published data for type 1 diabetic patients, was found. Systolic blood pressure was significantly higher (p < 0.002) in the patients with micro- and macroalbuminuria compared to the group with normal albumin excretion, whereas no relationship between diastolic blood pressure and albuminuria was found. We conclude that elevated increased atherogenic lipid fractions in addition to systolic hypertension may contribute to an increased cardiovascular risk in type 2 diabetic patients with proteinuria.

Apolipoprotein (a) levels in patients with type 1 diabetes mellitus are unrelated to metabolic control or vascular disease.

Increased serum levels of lipoprotein (a) have been found to be an independent risk factor for coronary heart disease. The major protein constituents of lipoprotein (a) are apolipoprotein B 100 und apolipoprotein (a) (apo(a)). We determined the serum levels of apo(a) and several lipid (cholesterol, HDL- and LDL-cholesterol, triglycerides, apolipoproteins A, A1 and B) and glycaemic (HbA1c, fasting blood glucose) parameters in 40 patients with type 1 diabetes mellitus and in 103 age- and sex-matched control subjects. The median serum levels of apo(a) were significantly increased in the type 1 diabetic patients (142.7 vs. 80.0 U/L; P = 0.03), whilst HDL, LDL-cholesterol, and apolipoprotein A, A1 and B levels were lower (P < 0.01). No significant correlation was found between parameters of metabolic control and apo(a) levels. After subdivision of the diabetic patients according to different stages of diabetic nephropathy (DN), determined by urinary albumin excretion, significant relationships were found between DN and triglycerides (P = 0.04), LDL (P = 0.03) and apolipoprotein B (P = 0.008, Kruskal-Wallis test) levels. Apo(a) levels were significantly higher than normal values in patients without DN (P < 0.05), but unrelated to the degree of DN. Patients with diabetic macroangiopathy had significant higher levels of cholesterol (P = 0.0001), triglycerides (P = 0.026), LDL (P = 0.0003), and apoB (P = 0.002) than patients without. Apo(a) levels were unrelated to diabetic macroangiopathy. The significantly elevated levels of apo(a) even in patients without DN or macroangiopathy are noteworthy.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombogenic factors are related to urinary albumin excretion rate in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients.

Parameters of haemostasis, endothelial cell markers and lipid peroxide levels were studied in 64 Type 1 (insulin-dependent) and 94 Type 2 (non-insulin-dependent) diabetic patients according to their urinary albumin excretion rate in comparison with age-matched control subjects. We determined plasma levels of fibrinogen (Clauss' method), coagulation factor VII:activity (clotting assay), factor VII antigen, protein C and S antigen, von Willebrand factor antigen, D-dimer concentration (ELISA), and lipid peroxide levels (thiobarbituric acid) in relation to urinary albumin excretion rate (RIA). Significant positive correlations were found between urinary albumin excretion rate and plasma fibrinogen (p < 0.005, p < 0.02), factor VII activity (p < 0.0002, p < 0.002), factor VII antigen (p < 0.0001, p < 0.001), protein C (p < 0.003, p < 0.05), and lipid peroxides (p < 0.02, p < 0.004) in Type 1 as well as in Type 2 diabetes. Von Willebrand factor (p < 0.001) and protein S (p < 0.0005) correlated with albuminuria only in patients with Type 1 diabetes. Although most of the haemostatic abnormalities are already found in normoalbuminuric patients, the significant positive correlations to urinary albumin excretion indicate that endothelial cell damage and coagulation disorders deteriorate with the progression of diabetic nephropathy.