Forearm vascular control during acute hyperglycemia in healthy humans

Abstract

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...

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

“…Other laboratories have reached opposite conclusions. Houben et al [16], with the use of a very similar protocol (local hyperglycaemia of about 15 mmol/l), failed to find differences in forearm microvessel and resistance vessel reactivity to ACh, SNP, norepinephrine or NO synthase inhibition, despite extending the study time to 24 h. More recently, Reed et al [21], using a very elegant study design, also concluded that in healthy participants, when the insulin response is prevented, neither 6 h of moderate hyperglycaemia (2 mmol/l above fasting values) nor glycaemic excursions reproducing the OGTT response of IGT patients are capable of depressing the forearm vascular response to ACh or SNP. Similar findings were reported by Strey et al [20] and Gudmundsson et al [9], who measured the forearm vascular response before and after a mixed meal in healthy participants and before and after improvement of metabolic control in patients with type 2 diabetes.…”

“…3), is unlikely to be due to hyperglycaemia itself, since the studies using either local or systemic hyperglycaemia have not reported this effect. It may also be unrelated to hyperinsulinaemia, since neither isolated local hyperinsulinaemia [27] nor intravenous insulin infusion [21] have been shown to affect the vascular response to SNP; however, no study to date has evaluated this response after glucose ingestion. The smaller and less persistent decline in maximal response to SNP observed when glucose was given intravenously (fasting, 651±111; 60 min, 510±88; 120 min, 545±90; 180 min, 671±121%) vs orally (fasting, 760±127; 60 min, 631±89; 120 min, 545± 90; 180 min, 549±71%) suggests that factors related to gastro-intestinal stimulation are involved.…”

“…With regard to the acute effect of hyperglycaemia on endothelium-dependent vasodilatation (EDV), conflicting results have been reported in vivo in humans, with some describing a neutral or a very mild and short-lasting effect [16][17][18][19][20][21] and others a negative impact [22][23][24][25][26]. Part of this heterogeneity can be ascribed to differences in the vascular district investigated (large, small or micro-vessels), the experimental technique adopted and the stimulus applied.…”

“…Thus, isolated hyperglycaemia whether systemic (glucose clamp + somatostatin) or local (perfused forearm), hyperglycaemia with hyperinsulinaemia (oral glucose) or hyperglycaemia in combination with hyperlipidaemia (meal test) in participants with different degrees of glucose tolerance have all been tested. For small vessels (resistance arteries and the microcirculation), the balance of evidence indicates that while hyperglycaemia has a neutral [16,21] or only a modest negative effect on EDV [5], hyperinsulinaemia exerts a consistent positive action [27][28][29]. The question of how glucose tolerance status may modulate the vascular response to physiological combinations of hyperinsulinaemia and hyperglycaemia has not been examined.…”

Efeitos da ingestão de glicose sobre a circulação materno-fetal

“…No estudo de Eicke et al 18 , também não se demonstrou redução da velocidade de fl uxo pós-prandial neste mesmo leito vascular, embora avaliando pacientes fora do período gestacional. Estudos mais recentes que utilizaram a infusão intravenosa de glicose também em indivíduos não gestantes não puderam demonstrar alteração doplervelocimétrica, mesmo avaliando vasos de menor diâmetro, tais como na artéria braquial 19 , na artéria da retina em estudo realizado em animal 20 ou mesmo nas artérias coronárias 21 , o que faz concluir que a forma aguda ou moderada de hiperglicemia não é capaz de alterar a resposta vascular.…”