In summary, patients with type 2 diabetes exhibited impaired endothelium-dependent vasodilation in vivo, elevated serum triglycerides, decreased LDL size, and normal antioxidant capacity. Of these parameters, LDL size was significantly correlated with endothelial function.

Abstract-A total of 75 in vivo endothelial function tests (intrabrachial artery infusions of endothelium-dependent[acetylcholine] and -independent [sodium nitroprusside] vasoactive agents) were performed in 18 type 2 diabetic patients (aged 58Ϯ2 years, body mass index 28.5Ϯ0.6 kg/m 2 , and fasting plasma glucose 229Ϯ11 mg/dL) and 27 matched normal subjects. These tests were performed before and 6 months after combination therapy with insulin and metformin and before and 6 months after metformin therapy only. Before insulin therapy, blood flow responses to acetylcholine (15 g/min) were significantly blunted in type 2 diabetic patients (7.5Ϯ0.7 mL ⅐ dL Ϫ1 ⅐ min Ϫ1) compared with normal subjects (11.6Ϯ0.9 mL ⅐ dL Ϫ1 ⅐ min Ϫ1 , PϽ0.01). During insulin therapy, the acetylcholine response increased by 44% to 10.8Ϯ1.6 mL ⅐ dL Ϫ1 ⅐ min Ϫ1 (PϽ0.05). Insulin therapy also significantly increased the blood flow responses to both low and high doses of sodium nitroprusside. We conclude that insulin therapy improves endothelium-dependent and -independent vasodilatation. These data support the idea that insulin therapy has beneficial rather than harmful effects on vascular function.

. S.M. and A.S. contributed equally to this article. Abbreviations: DCCT, Diabetes Control and Complications Trial; E/I ratio, ratio of length of R-R intervals during expiration to inspiration; ETDRS, Early Treatment of Diabetic Retinopathy Study; HF, high frequency; HFnorm, normalized high frequency component; HRV, heart rate variability; LF, low frequency; LFnorm, normalized low frequency component; RMSSD, square root of the mean square of R-R interval differences; TP, total power; UAER, urinary albumin excretion rate; VLF, very low frequency.A OBJECTIVE -Frequency domain analysis of heart rate variability (HRV) is used to assess cardiovascular autonomic function. There are no prospective data on the sensitivity of its various components to glycemia or other diabetes-related risk factors compared with conventional tests and with other complications of diabetes. RESEARCH DESIGN AND METHODS -In 1985, possible risk factors of future complications were determined in 115 children with type 1 diabetes. In 1996, the presence of complications (HRV analysis, conventional tests of autonomic function, urinary albumin excretion rate [UAER], and retinopathy) were assessed in 83 of these patients (age 32 ± 1 years, duration of diabetes 22 ± 1 years). RESULTS -Poor glycemic control (measured as lifetime glycemic exposure or HbA 1c in 1985)was the most important independent predictor of decreases in all measures of absolute power of HRV (total power [TP] and very low frequency, low frequency [LF], and high frequency [HF] power) and square root of the mean square of R-R interval differences but not of changes of normalized measures or ratios (normalized HF and LF, LF/HF). Other significant independent predictors of autonomic dysfunction were late age of onset of diabetes, female sex, and high BMI. To examine the sensitivity of the various tests to glycemia, the patients were divided into tertiles based on lifetime glycemic exposure (A 1c months). Glycemic exposure in the tertiles averaged 194 ± 25 A 1c months (20 years of HbA 1c 0.8% above normal), 556 ± 19 A 1c months(20 years of HbA 1c 2.3% above normal), and 963 ± 30 A 1c months (20 years of HbA 1c 4% above normal). Tests of complications that were significantly abnormal in patients already in the lowest tertile and were correlated with glycemia were TP and severity of retinopathy. Of conventional tests, only the ratio of length of R-R intervals during expiration to inspiration (E/I ratio) was significantly related to glycemic exposure, but it required high glycemic exposure (20 years of HbA 1c 4% above normal) to be abnormal. UAER was significantly increased only in the highest tertile of glycemic exposure.CONCLUSIONS -TP and retinopathy score were much more sensitive to antecedent glycemia than conventional tests of autonomic function or UAER and were significantly abnor-

Abstract-Normal insulin action in vivo involves a decrease in stiffness of large arteries (a decrease in aortic pressure augmentation). We determined whether the ability of insulin to decrease arterial stiffness is altered in uncomplicated type 1 diabetes. Nine type 1 diabetic men (age 28Ϯ2 years, body mass index 24Ϯ1 kg/m 2 ) and 9 matched normal men were studied under normoglycemic hyperinsulinemic (sequential 2-hour insulin infusions of 1 [step 1] and 2 [step 2] mU ⅐ kg Ϫ1 ⅐ min Ϫ1) conditions. Central aortic pressure waveforms were synthesized from those recorded in periphery with applanation tonometry on the radial artery and a validated reverse transfer function to construct the central aortic pressure wave every 30 minutes. This allowed the determination of aortic augmentation (the pressure difference between the first and the second systolic peaks) and the augmentation index (augmentation divided by pulse pressure), as the measure of stiffness of large arteries. Whole-body glucose uptake was 44% (step 1) and 37% (step 2) lower (PϽ0.001) in the diabetic patients than in the normal subjects. At baseline, before the insulin infusion, augmentation averaged 0Ϯ1 and 2Ϯ1 mm Hg (NS) and the augmentation index was Ϫ1.5Ϯ4.5% and 4.0Ϯ3.7% (NS) in the normal and diabetic subjects, respectively. After 1 hour of hyperinsulinemia, the augmentation index had decreased significantly (PϽ0.01) to Ϫ9.5Ϯ4.8% in the normal subjects but remained at 4.4Ϯ4.2% in the diabetic patients. A significant decrease was not observed in the diabetic patients until 150 minutes (Ϫ1.2Ϯ4.1%, PϽ0.05 versus baseline). Whole-body glucose uptake was significantly inversely correlated with the change in the augmentation index during step 1 (rϭϪ0.61, PϽ0.01). Insulin resistance in type 1 diabetes involves a defect in the ability of insulin to decrease central aortic pressure. This defect could predispose these patients to premature stiffening of large arteries.

These data are consistent with idea that altered neurotransmission is an important determinant of vascular reactivity of diabetic blood vessels to nitrovasodilators in vivo.

Aims/hypothesis. Hyperglycaemia predicts microvascular complications but data on macrovascular disease are limited. We searched for predictors of carotid artery intima-media thickness in young adults with Type I (insulin-dependent) diabetes mellitus. Methods. A total of 71 children (F/M = 34/37) were followed after their diagnosis until they reached 32 ± 1 years of age, when duration of diabetes averaged 22 ± 1 years. Cardiovascular risk markers [lipids, blood pressure, smoking, urinary albumin excretion rate, lifetime glycaemic exposure (A 1c months), exercise habits, alcohol consumption, family history] were evaluated at age 21 ± 1 for the baseline examination and at age 32 ± 1 years for the follow-up examination years. During follow-up, intima-media thickness of common and internal carotid arteries and the carotid bulb were quantitated using a high-resolution B-mode ultrasound.Results. In univariate analysis, age, BMI, blood pressure, lifetime glycaemic exposure, a positive family history of Type II (non-insulin-dependent) diabetes mellitus, hypertension and cardiovascular disease were predictors of carotid intima-media thickness. In multivariate analysis, a positive family history of Type II diabetes predicted maximal (p < 0.05) and common (p < 0.005) carotid artery intima-media thickness, family history of hypertension predicted increases in maximal (p < 0.04), and far wall (p < 0.006) carotid artery intima-media thickness, and lifetime glycaemic exposure was an independent predictor of increased carotid bulb thickness (p < 0.03). Conclusion/interpretation. Positive family histories of Type II diabetes and hypertension are independent predictors of carotid intima-media thickness in patients with Type I diabetes, and could therefore predispose these patients to atherosclerosis [Diabetologia (2002) 45:711-718]

Background/aims-Recent studies have demonstrated marked renin and prorenin concentration gradients between ocular tissues and blood, and local expression of the renin-angiotensin system (RAS) in the eye. The authors determined whether serum total renin, which mostly consists of prorenin, is a marker of the activity and severity of diabetic retinopathy independent of other microvascular complications. Methods-Total renin concentrations (TRC) were measured with a time resolved immunofluorometric assay in 38 patients with IDDM (age 34 (SD 7) years, duration of disease 22 (7) years, serum creatinine 95 (15) µmol/l, urinary albumin excretion rate (UAER) 207 (829) µg/min, HbA 1c 8.5% (1.2%)), and in 13 matched normal subjects. All subjects were carefully characterised with respect to the presence and severity of retinopathy (RP score), nephropathy, and neuropathy using seven different tests of autonomic neuropathy. Results-Serum TRC was on average twofold higher in IDDM (396 (SE 211) ng/l) than in normal subjects (201 (88) ng/l, p<0.001). It was nearly twofold higher in patients with preproliferative or active proliferative retinopathy requiring careful follow up or therapy (TRC 596 (268) ng/l, n=11) compared with those with quiescent proliferative retinopathy after laser treatment (TRC 338 (183) ng/l, p<0.01, n=5); moderately severe non-proliferative retinopathy (337 (106) ng/l, p<0.01, n=13), no retinopathy, or only minimal nonproliferative retinopathy (270 (43) ng/l, p<0.001, n=9). In multiple linear regression analysis, RP score (p<0.01), but not the UAER or any index of autonomic neuropathy, was an independent determinant of serum TRC, and explained 32% of its variation (R=0.57, p<0.005). Conclusions-Serum TRC in patients with diabetic retinopathy is increased independent of renal function and autonomic neuropathy, especially in those with severe active changes requiring careful follow up or treatment. These findings support the idea that diabetic retinopathy is the most important determinant of serum TRC in patients with IDDM, and that TRC is produced when retinopathy is active. (Br J Ophthalmol 1998;82:939-944) The aspartyl protease renin is the rate liming enzyme in the formation of the vasoactive octapeptide angiotensin II.

Because of the outstanding importance of the glucocorticoid Dexamethasone (DEX) as supportive therapy in the management of brain tumours, the direct effect of DEX on tumour cell proliferation is of particular interest. Previous in vitro studies led to contradictory results. To characterise more precisely the influence of DEX, we investigated the glioblastoma multiforme (GM) cell lines A172, T98G and 86HG39. Cells were treated with DEX concentrations ranging from 5 x 10(-9) to 5 x 10(-5) M from 24 to 240h under different treatment conditions. Influence of DEX on glioma cell viability was assessed daily for 5 days by MTT-assay: (I) with continuous DEX incubation (acute treatment), (II) in a recultivation period without DEX after 5 days of DEX pre-incubation (pre-treatment), (III) with continuous DEX incubation after 5 days of DEX pre-incubation (combination treatment). DEX acute treatment led to strongly decreased proliferation of A172 cells, whereas T98G and 86HG39 cells remained uninfluenced. In opposite, a time-delayed inhibition of cell proliferation was observed in all three cell lines after DEX pre-treatment. Combination treatment induced a significant increase of the inhibitory effect in A172 and T98G cells. These data show a variable, partial time-dependent inhibitory effect of DEX on the proliferation of GM cells and may open new treatment strategies for malignant brain tumours.