GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans

Subaran, Sharmila C.; Sauder, Matthew A.; Chai, Weidong; Jahn, Linda; Fowler, Dale; Aylor, Kevin W.; Basu, Ananda; Liu, Zhenqi

doi:10.1042/cs20130708

Cited by 67 publications

(71 citation statements)

References 44 publications

(59 reference statements)

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“…These actions contribute up to 40% of insulin-mediated glucose disposal and are impaired in the insulin-resistant states (43). Our current observation, together with our prior reports that GLP-1 acutely recruits muscle microvasculature in both insulin-sensitive and -resistant states (10,13,15,40), strongly suggests that muscle microvasculature is a therapeutic target of GLP-1 and its analogs. However, although liraglutide can directly stimulate endothelial cell NO production (19) and exenatide can acutely increase capillary perfusion in humans (37), it does not appear that the increase in insulin-mediated microvascular recruitment in HFD-fed rats was secondary to an acute, direct action of liraglutide, as the last dose of liraglutide was given 24 h before insulin clamp and tissue harvest, and in rodents the half-life of liraglutide is only ϳ4 h (39).…”

Section: Discussionsupporting

confidence: 62%

“…Indeed, GLP-1 increases coronary blood flow and myocardial uptake of glucose in the Langendorff-perfused rat heart during low-flow ischemia (49) and myocardial glucose uptake in dogs with cardiomyopathy (31) and regulates muscle glucose uptake independent of its ability to enhance insulin secretion (3). Recently, we have shown that acute GLP-1 infusion increases muscle microvascular recruitment and glucose use independent of insulin secretion (10,40), likely via protein kinase A-mediated endothelial nitric oxide synthase (eNOS) activation (10,15). Importantly, GLP-1's microvascular action is preserved in both acute and chronic insulinresistant states (13).…”

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confidence: 99%

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

Chai

Aylor

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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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.

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Section: Discussionsupporting

confidence: 62%

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confidence: 99%

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

Chai

Aylor

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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“…There seems to be general agreement among these studies that all dosage levels of insulin enhance MBV in healthy young individuals. Insulin‐stimulated MBF was also consistently increased in skeletal muscle of lean, healthy individuals . Nevertheless, a paradoxical reduction in MFV was shown by Coggins et al .…”

Section: Insulin Action On Resistance Vessels and Capillariesmentioning

confidence: 86%

Skeletal Muscle Vascular Function: A Counterbalance of Insulin Action

et al. 2015

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Insulin is a vasoactive hormone that regulates vascular homeostasis by maintaining balance of endothelial-derived NO and ET-1. Although there is general agreement that insulin resistance and the associated hyperinsulinemia disturb this balance, the vascular consequences for hyperinsulinemia in isolation from insulin resistance are still unclear. Presently, there is no simple answer for this question, especially in a background of mixed reports examining the effects of experimental hyperinsulinemia on endothelial-mediated vasodilation. Understanding the mechanisms by which hyperinsulinemia induces vascular dysfunction is essential in advancing treatment and prevention of insulin resistance-related vascular complications. Thus, we review literature addressing the effects of hyperinsulinemia on vascular function. Furthermore, we give special attention to the vasoregulatory effects of hyperinsulinemia on skeletal muscle, the largest insulin-dependent organ in the body. This review also characterizes the differential vascular effects of hyperinsulinemia on large conduit vessels versus small resistance microvessels and the effects of metabolic variables in an effort to unravel potential sources of discrepancies in the literature. At the cellular level, we provide an overview of insulin signaling events governing vascular tone. Finally, we hypothesize a role for hyperinsulinemia and insulin resistance in the development of CVD.

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“…While endothelial cells express GIP receptors (41), neither the underlying mechanism nor the clinical relevance of these findings is known. Interestingly, GLP-1 has been shown to increase forearm blood flow as measured by venous occlusion plethysmography (7) and both brachial artery diameter and blood flow (35), as well as microvascular perfusion measured by ultrasound Doppler (34), during euglycemic conditions. In our study, however, we found no effects of GLP-1 on hemodynamic variables.…”

Section: Discussionmentioning

confidence: 99%

Direct effect of incretin hormones on glucose and glycerol metabolism and hemodynamics

Karstoft

Mortensen

Knudsen

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Karstoft K, Mortensen SP, Knudsen SH, Solomon TP. Direct effect of incretin hormones on glucose and glycerol metabolism and hemodynamics. Am J Physiol Endocrinol Metab 308: E426-E433, 2015. First published January 6, 2015; doi:10.1152/ajpendo.00520.2014.-The objective of this study was to assess the insulin-independent effects of incretin hormones on glucose and glycerol metabolism and hemodynamics under euglycemic and hyperglycemic conditions. Young, healthy men (n ϭ 10) underwent three trials in a randomized, controlled, crossover study. Each trial consisted of a two-stage (euglycemia and hyperglycemia) pancreatic clamp (using somatostatin to prevent endogenous insulin secretion). Glucose and lipid metabolism was measured via infusion of stable glucose and glycerol isotopic tracers. Hemodynamic variables (femoral, brachial, and common carotid artery blood flow and flow-mediated dilation of the brachial artery) were also measured. The three trials differed as follows: 1) saline [control (CON)], 2) glucagon-like peptide (GLP-1, 0.5 pmol·kg Ϫ1 ·min Ϫ1 ), and 3) glucosedependent insulinotropic polypeptide (GIP, 1.5 pmol·kg Ϫ1 ·min Ϫ1 ). No between-trial differences in glucose infusion rates (GIR) or glucose or glycerol kinetics were seen during euglycemia, whereas hyperglycemia resulted in increased GIR and glucose rate of disappearance during GLP-1 compared with CON and GIP (P Ͻ 0.01 for all). However, when normalized to insulin levels, no differences between trials were seen for GIR or glucose rate of disappearance. Besides a higher femoral blood flow during hyperglycemia with GIP (vs. CON and GLP-1, P Ͻ 0.001), no between-trial differences were seen for the hemodynamic variables. In conclusion, GLP-1 and GIP have no direct effect on whole body glucose metabolism or hemodynamics during euglycemia. On the contrary, during hyperglycemia, GIP increases femoral artery blood flow with no effect on glucose metabolism, whereas GLP-1 increases glucose disposal, potentially due to increased insulin levels. pancreatic clamp; glucose disposal; glucose-dependent insulinotropic polypeptide; glucagon-like peptide-1; hyperglycemia; glucose effectiveness; glucose kinetics; somatostatin; hemodynamics IT IS WELL ESTABLISHED that the incretin hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), stimulate insulin secretion from pancreatic beta cells (18). It is also well known that the incretin effect on insulin secretion is glucose-dependent, such that both GLP-1 and GIP more greatly augment insulin secretion when plasma glucose is in the hyperglycemic range (19,38,39). Moreover, GLP-1 and GIP receptors are expressed extrapancreatically. For example, GLP-1 receptors have been identified by us and others in rat/human skeletal muscle, in muscle cell lines and primary human muscle cells (10,16,40), in human adipose tissue (23), and in human hepatocytes (17), although this has recently been questioned (30). GIP receptors have been identified in the endothelium (41) and in adipose tissue (32)....

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GLP-1 at physiological concentrations recruits skeletal and cardiac muscle microvasculature in healthy humans

Cited by 67 publications

References 44 publications

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

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

Skeletal Muscle Vascular Function: A Counterbalance of Insulin Action

Direct effect of incretin hormones on glucose and glycerol metabolism and hemodynamics

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