We sought to examine further the potential role of nitric oxide (NO) in the neurally mediated cutaneous vasodilation in nonacral skin during body heating in humans. Six subjects were heated with a water-perfused suit while cutaneous blood flow was measured by using laser-Doppler flowmeters placed on both forearms. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) was given selectively to one forearm via a brachial artery catheter after marked cutaneous vasodilation had been established. During body heating, oral temperature increased by 1.1 +/- 0.1 degreesC while heart rate increased by 30 +/- 6 beats/min. Mean arterial pressure stayed constant at 84 +/- 2 mmHg. In the experimental forearm, cutaneous vascular conductance (CVC; laser-Doppler) decreased to 86 +/- 5% of the peak response to heating (P < 0.05 vs. pre-L-NMMA values) after L-NMMA infusion. In some subjects, L-NMMA caused CVC to fall by approximately 30%; in others, it had little impact on the cutaneous circulation. CVC in the control arm showed a similar increase with heating, then stayed constant while L-NMMA was given to the contralateral side. These results demonstrate that NO contributes modestly, but not consistently, to cutaneous vasodilation during body heating in humans. They also indicate that NO is not the only factor responsible for the dilation.

Evidence for the existence of sympathetic vasodilator nerves in human skeletal muscle is controversial. Manoeuvres such as contralateral ischaemic handgripping to fatigue that cause vasoconstriction in the resting forearm evoke vasodilatation after local α‐adrenergic receptor blockade, raising the possibility that both constrictor and dilator fibres are present. The purpose of this study was to determine whether this dilatation is neurally mediated. Ten subjects (3 women, 7 men) performed ischaemic handgripping to fatigue before and after acute local anaesthetic block of the sympathetic nerves (stellate ganglion) innervating the contralateral (resting) upper extremity. Forearm blood flow was measured with venous occlusion plethysmography in the resting forearm. In control studies there was forearm vasoconstriction during contralateral handgripping to fatigue. During contralateral handgripping after stellate block, blood flow in the resting forearm increased from 6.1 ± 0.7 to 18.7 ± 2.2 ml dl−1 min−1 (P < 0.05). Mean arterial pressure measured concurrently increased from ≈90 to 130 mmHg and estimated vascular conductance rose from 6.5 ± 0.7 to 14.0 ± 1.5 units, indicating that most of the rise in forearm blood flow was due to vasodilatation. Brachial artery administration of β‐blockers (propranolol) and the nitric oxide (NO) synthase inhibitor NG‐monomethyl‐L‐arginine (L‐NMMA) after stellate block virtually eliminated all of the vasodilatation to contralateral handgrip. Since vasodilatation was seen after stellate block, our data suggest that sympathetic dilator nerves are not responsible for limb vasodilatation seen during sympathoexcitation evoked by contralateral ischaemic handgripping to fatigue. The results obtained with propranolol and L‐NMMA suggest that β‐adrenergic mechanisms and local NO release contribute to the dilatation.

Aims/hypothesis. The aim of this study was to determine whether rapid conversion to inactive and potentially antagonistic peptides could alter the response to GLP-1. Methods. We evaluated the ability of exendin-4, a GLP-1 analogue resistant to degradation by dipeptidyl peptidase IV, to modulate insulin-induced stimulation of glucose uptake and suppression of glucose production in eight healthy subjects during infusion of GLP-1 (1.2 pmol·kg -1 ·min -1 ), exendin-4 (0.12 pmol·kg -1 · min -1 ), or saline. Glucose was clamped at 5.3 mmol/l and insulin was infused to progressively increase insulin concentrations to about 65, 190 and 700 pmol/l, respectively. Endogenous insulin secretion was inhibited with somatostatin to ensure comparable portal insulin concentrations while glucagon and growth hormone were maintained at basal concentrations. Results. Glucose, insulin, C-peptide, glucagon and growth hormone concentrations did not differ on the three occasions. In contrast, cortisol concentrations were greater during both exendin-4 (25.1±4.4 mmol/l per 7 h; p<0.01) and GLP-1, (17.0±2.0 mmol/l 7 h; p<0.05) than saline (13.5±1.5 mmol/l per 7 h). While insulin-induced stimulation of glucose disappearance at the highest insulin concentrations tended to be greater and insulin-induced suppression of glucose production lower in the presence of exendin-4 or GLP-1 than saline, the differences were not significant. Conclusion/interpretation. Exendin-4 and GLP-1 increase cortisol secretion in human subjects. However, neither alters insulin action in non-diabetic human subjects. These data also suggest that the lack of an effect of GLP-1 on insulin action is not likely to be explained by rapid degradation to inactive or antagonistic peptides. [Diabetologia (2002[Diabetologia ( ) 45:1410[Diabetologia ( -1415 Keywords GLP-1, exendin-4, insulin action, glucose production, cortisol secretion. [11,12] and the liver [13]. GLP-1 (7-36) can increase glucose uptake in each of these tissues with its effects being additive to those of insulin [12,14,15,16]. In contrast, results from in vivo studies have been less consistent. GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21] GLP-1 (7-36) is actively being evaluated as a therapy for diabetes mellitus. GLP-1 (7-36) increases insulin secretion, decreases glucagon secretion and delays gastric emptying [1,2,3,4,5,6,7]. In vitro data suggest it might also enhance insulin action. Although controversial, GLP-1 receptors, to which Exendin-4

The vascular endothelium is a site of pathological changes in patients with diabetes mellitus that may be related to severe chronic hyperglycemia. However, it is unclear whether transient hyperglycemia alters vascular function in an otherwise healthy human forearm. To test the hypothesis that acute, moderate hyperglycemia impairs endothelium-dependent forearm vasodilation, we measured vasodilator responses in 25 healthy volunteers (11 F, 14 M) assigned to one of three protocols. In protocol 1, glucose was varied to mimic a postprandial pattern (i.e., peak glucose ϳ11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance. Protocol 2 involved 6 h of mild hyperglycemia (ϳ7 mmol/l). Protocol 3 involved 6 h of euglycemia. Glucose concentration was maintained with a variable systemic glucose infusion. Insulin concentrations were maintained at ϳ65 pmol/l by means of a somatostatin and "basal" insulin infusion. Glucagon and growth hormone were replaced at basal concentrations. Forearm blood flow (FBF) was calculated from Doppler ultrasound measurements at the brachial artery. In each protocol, FBF dose responses to intrabrachial acetylcholine (ACh) and sodium nitroprusside (NTP) were assessed at baseline and at 60, 180, and 360 min of glucose infusion. Peak endothelium-dependent vasodilator responses to ACh were not diminished by hyperglycemia in any trial. For example, peak responses to ACh during protocol 2 were 307 Ϯ 47 ml/min at euglycemic baseline and 325 Ϯ 52, 353 Ϯ 65, and 370 Ϯ 70 ml/min during three subsequent hyperglycemic trials (P ϭ 0.46). Peak endothelium-independent responses to NTP infusion were also unaffected. We conclude that acute, moderate hyperglycemia does not cause short-term impairment of endothelial function in the healthy human forearm. endothelial function; vasodilation; postprandial hyperglycemia IN THE LAST 20 YEARS, the endothelium has emerged as a major site of vascular regulation and disease (20,22). Endothelial dysfunction is a recognized consequence of exposure to most traditional cardiovascular risk factors, including hyperglycemia due to diabetes mellitus (15). In diabetes mellitus, microand macrovascular disease are common complications (13a, 21, 22); indeed, macrovascular disease is the most common cause of death in affected patients.The effects of acute episodes of hyperglycemia on vascular function, independent of the chronic changes seen in the diabetic endothelium, are less well defined. Numerous studies to date have attempted to determine whether a single exposure to acute hyperglycemia can impair vasodilation in diabetic and healthy humans. In diabetics and those at risk for developing diabetes mellitus, there appears to be an adverse effect of acute hyperglycemia on forearm blood flow (FBF) (14,19). Studies performed by Clarkson et al. (7), Anastasiou et al. (1), and Caballero et al. (4) all conclude that diabetics, or those at risk for diabetes, including individuals with impaired glucose tolerance or a history of gestational diabetes, have impaired flow...

The authors identified several errors after their paper had been printed: 1. C-peptide values were inadvertently converted to nmol/l from ng/ml by multiplying by 0.331 twice. Correct values require division of reported values by 0.331. 2. Fig. 2: the Y-axis for growth hormone should be labelled as µg/l. 3. The mean growth hormone concentration at 0 min on the saline study day was incorrectly plotted. The correct value was 2.34 µg/l +/-1.64. 4. Fig. 2: the Y-axis for cortisol should be labelled as nmol/l