Abstract
Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, amylin has long been related to IR. However the role of amylin in the vascular dysfunction associated to IR is not well addressed. Therefore, the aim of the study was to assess the effect of acute treatment with amylin on endothelium-dependent vasodilation of isolated mesenteric arteries from control (CR) and insulin resistant (IRR) rats and to evaluate the possible mechanisms involved. Five week-old male Wistar rats received 20% D-fructose dissolved in drinking water for 8 weeks and were compared with age-matched CR. Plasmatic levels of glucose, insulin and amylin were measured. Mesenteric microvessels were dissected and mounted in wire myographs to evaluate endothelium-dependent vasodilation to acetylcholine. IRR displayed a significant increase in plasmatic levels of glucose, insulin and amylin and reduced endothelium-dependent relaxation when compared to CR. Acute treatment of mesenteric arteries with r-amylin (40 pM) deteriorated endothelium-dependent responses in CR. Amylin-induced reduction of endothelial responses was unaffected by the H2O2 scavenger, catalase, but was prevented by the extracellular superoxide scavenger, superoxide dismutase (SOD) or the NADPH oxidase inhibitor (VAS2870). By opposite, amylin failed to further inhibit the impaired relaxation in mesenteric arteries of IRR. SOD, or VAS2870, but not catalase, ameliorated the impairment of endothelium-dependent relaxation in IRR. At concentrations present in insulin resistance conditions, amylin impairs endothelium-dependent vasodilation in mircrovessels from rats with preserved vascular function and low levels of endogenous amylin. In IRR with established endothelial dysfunction and elevated levels of amylin, additional exposure to this peptide has no effect on endothelial vasodilation. Increased superoxide generation through NADPH oxidase activity may be a common link involved in the endothelial dysfunction associated to insulin resistance and to amylin exposure in CR.
Highlights
Amylin, named islet amyloid polypeptide (IAPP), is a 37 aminoacids peptide that is cosecreted with insulin by the pancreatic β-cells in response to glucose, free fatty acid and food intake [1,2]
The present results suggest that elevated levels of amylin could contribute to the impairment of endothelium-dependent vasodilation observed in insulin resistance through generation of superoxide anions
This is based on the fact that the impairment of endothelial vasodilation in mesenteric microarteries from insulin resistant rats is associated with increased concentration of serum amylin
Summary
Named islet amyloid polypeptide (IAPP), is a 37 aminoacids peptide that is cosecreted with insulin by the pancreatic β-cells in response to glucose, free fatty acid and food intake [1,2]. An association between insulin resistance and amylin is supported by studies showing elevated levels of this hormone in patients with impaired glucose regulation [7] and in insulin resistant elderly women [8]. Insulin resistance has been proposed to play a major role in CVD [12,13,14,15] This is probably related to the impairment of endothelium-dependent vascular function associated with insulin resistance, an alteration documented in different distrcits of human and animal vasculature [16,17,18,19,20,21,22,23]. We have previously proposed that amylin may interfere with endothelial vasodilation in rat arteries [27], the role of amylin in vascular dysfunction associated with insulin resistance has not been addressed
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