Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats

Abstract

prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats. Am J Physiol Endocrinol Metab 311: E640 -E648, 2016. First published July 19, 2016 doi:10.1152/ajpendo.00205.2016.-Muscle microvasculature critically regulates endothelial exchange surface area to facilitate transendothelial delivery of insulin, nutrients, and oxygen to myocytes. Insulin resistance blunts insulin-mediated microvascular recruitment and decreases muscle capillary density; both contribute to lower microvascular blood volume. Glucagon-like peptide 1 (GLP-1) and its analogs are able to dilate blood vessels and stimulate endothelial cell proliferation. In this study, we aim to determine the effects of sustained stimulation of the GLP-1 receptors on insulin-mediated capillary recruitment and metabolic insulin responses, small arterial endothelial function, and muscle capillary density. Rats were fed a high-fat diet (HFD) for 4 wk with or without simultaneous administration of liraglutide and subjected to a euglycemic hyperinsulinemic clamp for 120 min after an overnight fast. Insulin-mediated muscle microvascular recruitment and muscle oxygenation were determined before and during insulin infusion. Muscle capillary density was determined and distal saphenous artery used for determination of endothelial function and insulin-mediated vasodilation. HFD induced muscle microvascular insulin resistance and small arterial vessel endothelial dysfunction and decreased muscle capillary density. Simultaneous treatment of HFD-fed rats with liraglutide prevented all of these changes and improved insulin-stimulated glucose disposal. These were associated with a significantly increased AMPK phosphorylation and the expressions of VEGF and its receptors. We conclude that GLP-1 receptor agonists may exert their salutary glycemic effect via improving microvascular insulin sensitivity and muscle capillary density during the development of insulin resistance, and early use of GLP-1 receptor agonists may attenuate metabolic insulin resistance as well as prevent cardiovascular complications of diabetes.

Effect of liraglutide on dietary lipid‐induced insulin resistance in humans

“…9 Studies in rats showed that fatty acid-induced microvascular dysfunction can be partially restored with liraglutide. 29 In the present study, insulin-induced vasodilation of adipose tissue arterioles was markedly impaired after the SFA diet, and this impairment appeared to be partially abrogated after liraglutide treatment. These data are very consistent with our previous ex vivo studies, which showed that GLP-1R agonists could directly blunt impairment of arterial vasodilation induced by VLDL hydrolysis products.…”

“…Exposure to fatty acids impairs both microvascular function and skeletal muscle glucose utilization . Studies in rats showed that fatty acid‐induced microvascular dysfunction can be partially restored with liraglutide . In the present study, insulin‐induced vasodilation of adipose tissue arterioles was markedly impaired after the SFA diet, and this impairment appeared to be partially abrogated after liraglutide treatment.…”

“…We have also previously shown that endothelial cell AMPK activation played a critical role in the vascular effects of GLP‐1R agonists . Previous studies also showed increased AMPK activation with GLP‐1R agonists in various cell types, including skeletal muscle . In vivo studies in rats showed that the protective effect of liraglutide against high‐fat‐diet‐induced insulin resistance was associated with increased AMPK phosphorylation after an insulin clamp .…”

“…16 Previous studies also showed increased AMPK activation with GLP-1R agonists in various cell types, 16,30 including skeletal muscle. 29 In vivo studies in rats showed that the protective effect of liraglutide against high-fat-diet-induced insulin resistance was associated with increased AMPK phosphorylation after an insulin clamp. 29 Consistent with these findings, in the present study, AMPK phosphorylation was higher after liraglutide in the post-IST skeletal muscle biopsy, indicating a role for AMPK activation in the glucose-lowering effect of liraglutide.…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Colin et al showed that myocytes from obese, nondiabetic Zucker rates were significantly enlarged and depleted of lipid droplets with exendin‐4 treatment, secondary to modulation of oxidative stress; Takada et al showed improved mitochondrial function and exercise capacity in mice receiving exendin‐4 . Exenatide was reported to prevent sarcoma‐induced cachexia in a mouse model, while liraglutide was shown to improve skeletal muscle capillary density in an animal model of insulin resistance, indicating a protective role against metabolic insulin resistance at the skeletal muscle level . Exenatide has also been shown to increase irisin, a myokine that is commonly induced by exercise, in patients with T2D .…”