Impaired cardiac autonomic function in women with prior gestational diabetes mellitus.

BACKGROUND: Cardiac autonomic neuropathy is a common dysfunction in manifest diabetes mellitus and is associated with duration of diabetes and/or an inadequate glycaemic control. Heart rate variability (HRV) reflects autonomic heart function. The aim of the present study was to investigate whether in women with prior gestational diabetes (GD; pre-type 2 diabetes) alterations of cardiac autonomic function can be observed after delivery in relation to insulin sensitivity and glycaemic control. MATERIALS AND METHODS: Forty-eight healthy women with prior GD were consecutively admitted to the study. HRV was analysed by both time, as well as frequency, domain methods using 24-h Holter monitoring. In addition, 20 women with normal glucose tolerance during and after pregnancy were investigated as control subjects. All women underwent a frequently sampled intravenous glucose tolerance test (FSIGT) for measurement of insulin sensitivity. RESULTS: Time domain analysis (standard deviation of normal RR intervals; SDNN) showed a reduced HRV in 25 out of the 48 (52%) women with prior GD. Frequency domain analysis revealed that in these 25 subjects both low and high frequency components of power spectral density (reflecting mainly sympathetic respectively parasympathetic activity) were reduced, indicating that sympathetic as well as parasympathetic functional impairment may be assumed. However, a relative predominance of the sympathetic over parasympathetic cardiac function was observed. The impairment of cardiac autonomic function (reduced SDNN) was correlated with HbA1c values and the 2-h blood glucose concentration (oral glucose tolerance test) but not with insulin sensitivity. CONCLUSION: The present results demonstrate that in 52% of the women examined who had prior GD, an impairment of cardiac sympathetic as well as parasympathetic function was present, which related to glycaemic control, but not to insulin sensitivity. This infers that functional autonomic changes could be an early prognostic indicator in pre-type 2 diabetes.

Free fatty acids do not acutely increase asymmetrical dimethylarginine concentrations.

Concentrations of asymmetrical dimethylarginine (ADMA) and free fatty acids (FFAs) are elevated in insulin resistance which is associated with impaired vascular function. We hypothesized that FFAs could alter vascular tone by affecting ADMA concentrations. Plasma FFA levels were increased in seventeen healthy male volunteers by Intralipid/heparin infusion; hemodynamic and biochemical parameters were measured after 90 minutes. Plasma collected before and during Intralipid/heparin or equivalent synthetic FFAs was incubated with human umbilical vein endothelial cells (HUVECs) in vitro. Intralipid/heparin infusion resulted in an approximately seven-fold increase in plasma FFA levels to 1861 +/- 139 micromol/l, which was paralleled by increased systemic blood pressure and forearm blood flow. Intralipid/heparin did not affect ADMA (baseline mean 0.59 [95 % confidence interval [CI]: 0.54; 0.64] and 0.56 [CI: 0.51; 0.59] after 90 minutes), but slightly decreased SDMA (from 0.76, [CI: 0.70; 0.83] to 0.71 [CI: 0.64; 0.74], p < 0.05), and had no effect on ADMA/SDMA ratio. There was no correlation between ADMA and FFA concentrations or forearm blood flow. Incubation of HUVECs with FFA-rich plasma or synthetic FFAs induced an ADMA release after 24 hours, but not after 90 minutes. Acutely increased FFA levels caused hemodynamic effects but did not affect ADMA. Prolonged elevation of FFA levels might influence vascular function by increasing ADMA levels.

Effect of a nifedipine induced reduction in blood pressure on the association between ocular pulse amplitude and ocular fundus pulsation amplitude in systemic hypertension.

BACKGROUND: The ocular pressure/volume relation, which is described by the Friedenwald equation, forms the basis of intraocular pressure (IOP) measurement with Schiotz tonometry and measurement of pulsatile ocular blood flow (POBF) with pneumotonometry. Changes in intraocular volume during the cardiac cycle are caused by arterial inflow and venous outflow and are accompanied by changes in IOP. The relation between volume and pressure changes is dependent on the elastic properties of the eye coats as described by the ocular rigidity coefficient. Previous studies indicate that there is a vascular contribution to ocular rigidity and that the volume/pressure relationship may depend on the mean arterial pressure. METHODS: The effect of a nifedipine induced reduction in systemic blood pressure on pulse amplitude (PA) as assessed with pneumotonometry and fundus pulsation amplitude (FPA), as measured with laser interferometry was investigated in 16 untreated patients with moderate to severe systemic hypertension (mean arterial pressure 123 (SD 12) mm Hg). RESULTS: The ratio between PA and FPA was taken as a measure of the ocular rigidity coefficient. Nifedipine reduced mean arterial pressure by 17.3% and increased pulse rate by 11.0% (p<0.001 each). Whereas PA was significantly reduced after administration of nifedipine (-15.6%; p<0.001), FPA remained unchanged. Accordingly, the ratio of PA/FPA was reduced from 0.86 mm Hg/mum to 0.73 mm Hg/mum after administration of nifedipine. CONCLUSION: These data are in keeping with previous animal experiments indicating a blood pressure dependent vascular component to the rigidity of the eye coats in vivo. This needs to be taken into account for measurement of IOP with Schiotz tonometry and POBF with pneumotonometry.

Brain energy metabolism during hypoglycaemia in healthy and type 1 diabetic subjects.

AIMS/HYPOTHESIS: This study aimed to examine brain energy metabolism during moderate insulin-induced hypoglycaemia in Type 1 diabetic patients and healthy volunteers. METHODS: Type 1 diabetic patients (mean diabetes duration 13 +/- 2.5 years; HbA1c 6.8 +/- 0.3%) and matched controls were studied before, during (0-120 min) and after (120-240 min) hypoglycaemic (approximately 3.0 mmol/l) hyperinsulinaemic (1.5 mU x kg(-1) min(-1)) clamp tests. Brain energy metabolism was assessed by in vivo 31P nuclear magnetic resonance spectroscopy of the occipital lobe (3 Tesla, 10-cm surface coil). RESULTS: During hypoglycaemia, the diabetic patients showed blunted endocrine counter-regulation. Throughout the study, the phosphocreatine:gamma-ATP ratios were lower in the diabetic patients (baseline: controls 3.08 +/- 0.29 vs diabetic patients 2.65 +/- 0.43, p<0.01; hypoglycaemia: 2.97 +/- 0.38 vs 2.60 +/- 0.35, p<0.05; recovery: 3.01 +/- 0.28 vs 2.60 +/- 0.35, p<0.01). Intracellular pH increased in both groups, being higher in diabetic patients (7.096 +/- 0.010 vs. 7.107 +/- 0.015, p<0.04), whereas intracellular magnesium concentrations decreased in both groups (controls: 377 +/- 33 vs 321 +/- 39; diabetic patients: 388 +/- 47 vs 336 +/- 68 micromol/l; p<0.05). CONCLUSIONS/INTERPRETATION: Despite a lower cerebral phosphocreatine:gamma-ATP ratio in Type 1 diabetic patients at baseline, this ratio does not change in control or diabetic patients during modest hypoglycaemia. However, both groups exhibit subtle changes in intracellular pH and intracellular magnesium concentrations.

Free fatty acids exert a greater effect on ocular and skin blood flow than triglycerides in healthy subjects.

BACKGROUND: Free fatty acids (FFAs) and triglycerides (TGs) can cause vascular dysfunction and arteriosclerosis. Acute elevation of plasma FFA and TG concentration strongly increase ocular and skin blood flow. This study was designed to discriminate whether FFA or TG independently induce hyperperfusion by measuring regional and systemic haemodynamics. METHODS: In a balanced, randomized, placebo-controlled, double-blind, three-way, crossover study nine healthy subjects received either Intralipid (Pharmacia and Upjohn, Vienna, Austria) with heparin, Intralipid alone or placebo control. Pulsatile choroidal blood flow was measured with laser interferometry, retinal blood flow and retinal red blood cell velocity with laser Doppler velocimetry, and skin blood flow with laser Doppler flowmetry during an euglycaemic insulin clamp. RESULTS: A sevenfold increase of FFA during Intralipid/heparin infusion was paralleled by enhanced choriodal, retinal, and skin blood flow by 17 +/- 4%, 26 +/- 5% (P < 0.001), and 47 +/- 19% (P = 0.03) from baseline, respectively. In contrast, a mere threefold increase of FFA by infusion of Intralipid alone did not affect outcome parameters, despite the presence of plasma TG levels of 250-700 mg dL(-1); similar to those obtained during combined Intralipid/heparin infusion. Systemic haemodynamics were not affected by drug infusion. CONCLUSIONS: Present findings demonstrate a concentration-dependent increase in ocular and skin blood flow by FFA independently of elevated TG plasma concentrations. As vasodilation of resistance vessels occur rapidly, FFA may play a role in the development of continued regional hyperperfusion and deteriorate microvascular function.

Acute exercise has no effect on ghrelin plasma concentrations.

Exercise is a potent, dose-dependent stimulus of growth hormone (GH) secretion. The hypothalamic peptides, GH-releasing hormone (GHRH) and somatostatin are regarded as major regulators of this stimulation. The role of the stomach-derived peptide ghrelin, which has been shown to exert strong GH releasing effects, has not been fully characterized yet. We therefore studied GH and ghrelin plasma concentrations in response to graded levels of exercise in eight healthy young volunteers. After determination of their individual maximal exercise capacity, all individuals underwent a treadmill exercise at 50 %, 70 %, and 90 % of maximum oxygen consumption (VO (2)max) on different days. Maximal GH response to exercise was observed after 40 minutes at 50 % VO (2)max and after 20 minutes at 70 and 90 % VO (2max). GH serum concentrations increased significantly at all three exercise intensities (GH peak concentrations were 5.8 +/- 2.3 ng/ml, 12.0 +/- 3.2 ng/ml, and 9.8 +/- 4.7 ng/ml, respectively). In contrast, ghrelin plasma concentrations remained unchanged at all three workloads. Assuming that the sensitivity of the GH neuroendocrine/metabolic regulation of GH is unaltered, ghrelin does not participate in the regulation of the GH response to exercise in healthy males.

Effect of systemic vitamin C on free fatty acid-induced lipid peroxidation.

OBJECTIVES: Plasma malondialdehyde (MDA), a reactive product of lipid peroxidation, may be influenced by anti-oxidant therapy. The aim of the present study was to investigate if elevated MDA as induced by increased free fatty acids (FFA) correlates with endothelial function and is affected by high doses of vitamin C. METHODS: The study design was randomised, placebo-controlled, double blind, 2-way cross over. Plasma MDA concentrations and forearm blood flow (FBF) responses to intra-arterial acetylcholine (ACh) and glyceryl trinitrate were assessed during co-administration of vitamin C or placebo in the presence of increased plasma FFA by Intralipid/heparin infusion in 10 healthy male subjects. RESULTS: The seven-fold rise in plasma FFA was associated with an increase in plasma MDA concentrations (r=0.7, p<0.001) and decreased FBF responses to ACh (r=-0.4, p<0.01). Co-administration of vitamin C restored the impaired reactivity of FBF to ACh but had no effect on elevated MDA concentrations. CONCLUSIONS: Anti-oxidant vitamin C improves lipid-induced impairment of endothelium-dependent vasodilation, but does not alter MDA formation or breakdown.

ANP but not BNP reflects early left diastolic dysfunction in type 1 diabetics with myocardial dysinnervation.

OBJECTIVE: We investigated whether plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) reflect impaired diastolic relaxation or its improvement after ACE inhibition. METHODS: 7 long-term Type 1 diabetic patients with normal systolic but impaired diastolic function and with sympathetic myocardial dysinnervation and 10 controls were included. Exercise tolerance and maximal O 2 uptake were evaluated by bicycle exercise prior to the study. ANP, BNP and norepinephrine/epinephrine (NE/E) were determined at baseline and at 80 % .VO2 max workload and after recovery, before and following 12 weeks of treatment with fosinopril (10 mg/d). RESULTS: Isovolumetric relaxation time (IVRT) and A/E wave ratio were increased by 26.7 +/- 11.5 % and 54.4 +/- 26.1 % in diabetic patients as compared to controls, respectively (p < 0.02). After 12 weeks of fosinopril treatment, no differences in IVRT or A/E wave ratio were detectable between groups. ANP was enhanced in Type 1 diabetes as compared to controls (baseline: 9.2 +/- 3.0 vs. 4.5 +/- 1.1; exercise: 22.4 +/- 7.7 vs. 7.9 +/- 1.2; recovery: 20.3. +/- 4.6 vs. 9.5 +/- 2.0 fmol/ml, p < 0.02). Fosinopril treatment abolished any differences between groups. BNP plasma levels did not differ between groups and no exercise dependent changes were observed. NE- and E-increase was greater at 80 % .VO2 max work load in Type 1 diabetes than in controls (p < 0.05). Again, fosinopril abolished differences between groups. CONCLUSION: In Type 1 diabetes, impaired diastolic function is associated with elevated ANP and catecholamine plasma levels that are normalized after ACE inhibition. Thus, ANP but not BNP appears to be a sensitive biochemical marker for early diastolic dysfunction in Type 1 diabetes.

Endothelin ETA receptor-subtype specific antagonism does not mitigate the acute systemic or renal effects of exogenous angiotensin II in humans.

BACKGROUND: Angiotensin II (Ang II) is assumed to play a pathophysiological role in a variety of vascular diseases. Animal studies indicate that these effects are partly attributed to stimulation of endothelin-1 (ET-1) release. The aim of the present study was to investigate whether the acute effects of Ang II on systemic and renal haemodynamics in healthy subjects can be influenced by endothelin ET(A)-receptor blockade. DESIGN: The study design was balanced, randomized, placebo-controlled, double blind, two-way cross-over, in 10 healthy male subjects. METHODS: Subjects received stepwise increasing intravenous doses of Ang II (0.65, 1.25, 2.5, 5 ng kg(-1) min(-1) for 15 min per dose level) in the presence or absence of BQ-123 (60 microg min(-1)), a specific ETA-receptor antagonist. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate and inulin plasma clearance method, respectively. Renal vascular resistance (RVR) was calculated from mean arterial pressure (MAP) and renal plasma flow. RESULTS: Ang II decreased RPF by 34% and GFR by 9% and increased RVR by 94% and MAP by 27% (ANOVA, P < 0.001 vs. baseline, for all parameters). BQ-123 did not alter these renal and systemic haemodynamic responses to a significant degree. In addition, BQ-123 had no significant haemodynamic effect under baseline conditions. CONCLUSIONS: Short-term increase of circulating Ang II levels causes systemic and renal pressor effects, which are not mitigated by endothelin ETA-receptor blockade. This suggests that the pressor response to Ang II cannot be accounted for by the acute release of vasoactive ET-1.

The renal and systemic hemodynamic effects of a nitric oxide-synthase inhibitor are reversed by a selective endothelin(a) receptor antagonist in men.

There is evidence for an interaction between nitric oxide (NO) and endothelin (ET) at the level of the renal vasculature. We hypothesized that acute renal effects of systemic NO synthase inhibition (NG-monomethyl-l-arginine, L-NMMA) may be blunted by coadministration of a specific ET(A) receptor antagonist (BQ-123) in healthy humans. Fifteen healthy young male subjects participated in this randomized, double-blind, placebo-controlled 3-way crossover study. These sodium-repleted volunteers received L-NMMA alone, or BQ-123 alone, or L-NMMA with a subsequent coinfusion of BQ-123. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined with the PAH and inulin clearance method, respectively. Mean arterial pressure (MAP) and pulse rate were measured noninvasively at baseline and every 15 min after the start of the study period. L-NMMA alone reduced RPF (-22%, P < 0.001) and GFR (-8%, P < 0.009) and increased MAP (+10%, P < 0.001). BQ-123 alone did not affect these parameters. However, coinfusion of BQ-123 blunted the effects of L-NMMA on RPF (P < 0.001), GFR (P < 0.001), and MAP (P = 0.006). Peripheral and renal hemodynamic effects of acute systemic NO synthase inhibition are at least partially reversed by ET(A) receptor blockade with BQ-123. This indicates a functional antagonism between specific ET(A) receptor antagonist and NO synthase inhibitors at the level of the renal vasculature.

Free fatty acids/triglycerides increase ocular and subcutaneous blood flow.

Elevated plasma free fatty acids (FFA) induce skeletal muscle insulin resistance and impair endothelial function. The aim of this study was to characterize the acute hemodynamic effects of FFA in the eye and skin. A triglyceride (Intralipid 20%, 1.5 ml/min)/heparin (bolus: 200 IU; constant infusion rate: 0.2 IU. kg(-1). min(-1)) emulsion or placebo was administered to 10 healthy subjects. Measurements of pulsatile choroidal blood flow with laser interferometry, retinal blood flow with the blue field entoptic technique, peak systolic and end diastolic blood velocity (PSV, EDV) in the ophthalmic artery with Doppler sonography, and subcutaneous blood flow with laser Doppler flowmetry were performed during an euglycemic somatostatin-insulin clamp over 405 min. Plasma FFA/triglyceride elevation induced a rise in pulsatile choroidal blood flow by 25 +/- 3% (P < 0.001) and in retinal blood flow by 60 +/- 23% (P = 0.0125). PSV increased by 27 +/- 8% (P = 0.001), whereas EDV was not affected. Skin blood flow increased by 149 +/- 38% (P = 0.001). Mean blood pressure and pulse rate remained unchanged, whereas pulse pressure amplitude increased by 17 +/- 5% (P = 0.019). Infusion of heparin alone had no hemodynamic effect in the eye or skin. In conclusion, FFA/triglyceride elevation increases subcutaneous and ocular blood flow with a more pronounced effect in the retina than in the choroid, which may play a role for early changes of ocular perfusion in the insulin resistance syndrome.

Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans.

Carbon dioxide is an important regulator of vascular tone. Glibenclamide, an inhibitor of ATP-sensitive potassium channel (K(ATP)) activation, significantly blunts vasodilation in response to hypercapnic acidosis in animals. We investigated whether glibenclamide also alters the cerebral and ocular vasodilator response to hypercapnia in humans. Ten healthy male subjects were studied in a controlled, randomized, double-blind two-way crossover study under normoxic and hypercapnic conditions. Glibenclamide (5 mg po) or insulin (0.3 mU. kg(-1). min(-1) iv) were administered with glucose to achieve comparable plasma insulin levels. In control experiments, five healthy volunteers received glibenclamide (5 mg) or nicorandil (40 mg) or glibenclamide and nicorandil in a randomized, three-way crossover study. Mean blood flow velocity and resistive index in the middle cerebral artery (MCA) and in the ophthalmic artery (OA) were measured with Doppler sonography. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. Forearm blood flow was measured with venous occlusion plethysmography. Hypercapnia increased ocular fundus pulsation amplitude by +18.2-22.3% (P < 0. 001) and mean flow velocity in the MCA by +27.4-33.3% (P < 0.001), but not in the OA (2.1-6.5%, P = 0.2). Forearm blood flow increased by 78.2% vs. baseline (P = 0.041) after nicorandil administration. Glibenclamide did not alter hypercapnia-induced changes in cerebral or ocular hemodynamics and did not affect systemic hemodynamics or forearm blood flow but significantly increased glucose utilization and blunted the nicorandil-induced vasodilation in the forearm. This suggests that hypercapnia-induced changes in the vascular beds under study are not mediated by activation of K(ATP) channels in humans.