Microvascular actions of insulin : studies on the interaction with angiotensin II and on the postprandial state

Abstract

Background and aims Angiotensin II increases insulin-mediated glucose uptake in healthy individuals. The underlying mechanisms are undefined. Angiotensin II may increase glucose uptake through a direct effect on muscle cell insulin signaling or through increasing insulin delivery to muscle cells through effects on the microvasculature. Our objective was to determine whether angiotensin II increases insulinmediated glucose uptake through effects on insulin-induced capillary recruitment. Methods We examined the effects of angiotensin II on hyperinsulinemia-induced capillary density by measuring skin capillary density, capillary recruitment, and capillary density during venous congestion in 18 healthy subjects in the basal state, during systemic hyperinsulinemia, and during hyperinsulinemia with coinfusion of angiotensin II or phenylephrine (pressor control). In addition, whole-body glucose uptake and blood pressure were measured. Results Capillaroscopy data of 13 subjects were available for analysis. Compared with the basal state, hyperinsulinemia increased baseline capillary density (51.5±9.0 vs. 55.2±10.8 n/mm2, P<0.01), capillary recruitment (67.8±6.8 vs. 70.6±7.5 n/mm2, P < 0.05), and capillary density during venous congestion (78.5±12.0 vs. 80.3±12.0 n/mm2, P<0.01). Infusion of angiotensin II, but not phenylephrine, reduced insulin-induced capillary recruitment (69.3±8.6 vs. 65.2±8.0 n/mm2, P<0.05) and capillary density during venous congestion (79.7±15.3 vs. 73.9±12.1, P<0.05) while enhancing glucose uptake [2.40±0.7 vs. 2.68±0.6 (mg/kg/min per pmol/l) × 100, P<0.01)] (n=18). Conclusion Angiotensin II increases insulin-mediated glucose uptake in healthy individuals. This increase was probably not related to increases in microvascular perfusion because infusion of angiotensin II during hyperinsulinemia reduced insulin-mediated skin capillary recruitment. Additional studies are needed to investigate whether angiotensin II directly affects insulin delivery through increasing insulin transport across the microvasculature. InsulIn’s mIcrovascular actIons and angIotensIn II 45 Introduction Angiotensin II (AngII) is involved in the regulation of insulin-mediated glucose uptake.1,2 However, the effects of AngII appear to be complex and to differ between healthy individuals on the one hand and individuals with hypertension, obesity, or type 2 diabetes on the other.3–6 For example, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers, both of which decrease the effects of AngII, have been shown to increase insulin-mediated glucose uptake in individuals with hypertension, obesity, or type 2 diabetes,4,6-9 whereas, paradoxically, acutely raising AngII systemically in healthy individuals has been shown to increase insulin-mediated glucose uptake.3,10–12 On the other hand, studies with ACE inhibition in healthy non-obese subjects have demonstrated no increase13,14 or even a decrease15 in insulin-mediated glucose uptake. How AngII affects glucose metabolism remains to be defined. Two effects of insulin are crucial for stimulating glucose uptake in muscle. First, through its membrane receptor, insulin has direct effects on muscle cells. Second, insulin regulates its own delivery, and that of glucose, to muscle cells through actions on the microvasculature.16,17 Muscle microvasculature consists of nutritive capillary networks, which perfuse working muscle cells, and of nonnutritive networks, which are thought to be involved in thermoregulation.18,19 By relaxation of terminal arterioles connected to nutritive capillary networks, insulin can alter the distribution of muscle blood flow, resulting in enhanced access of glucose and insulin to muscle cells.16,17 Indeed, increasing or decreasing nutritive flow has been shown to result in parallel changes in insulin-mediated glucose uptake.20–23 Because microvascular perfusion appears to be crucial in the regulation of muscle glucose metabolism and AngII receptors are present in muscle microvasculature, the question thus arises whether vasoconstrictors such as AngII can affect insulin-mediated glucose uptake through influencing insulin-induced nutritive capillary recruitment. Possible effects of AngII on microvascular perfusion have been examined in animal studies. In a rat model in which the hind limb was perfused with perfusate, AngII infusion increased the number of perfused capillaries in muscle.19 In an in vivo rat study, AngII infusion increased muscle microvascular blood volume.24 However, in these studies, the effects of AngII were determined either in the absence of insulin19 or at fasting plasma insulin levels,24 whereas most glucose uptake takes place postprandially, i.e. during hyperinsulinemia. To date, there have been no studies (i.e. in humans or animals) where the effects of AngII on capillary recruitment during hyperinsulinemia have been determined. The present study was designed to determine, in healthy subjects, whether AngII infusion enhances insulin-induced capillary density and therefore insulin-mediated glucose uptake in healthy individuals, using skin capillary dynamics as a model for muscle microcirculation.22,25,26