Enhancement of insulin-mediated rat muscle glucose uptake and microvascular perfusion by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside.

Eloise A Bradley,Stephen Rattigan,Amanda J Genders,Michelle A Keske,Lei Zhang,Stephen M Richards

doi:10.1186/s12933-015-0251-y

Abstract

BackgroundInsulin-induced microvascular recruitment is important for optimal muscle glucose uptake. 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, an activator of AMP-activated protein kinase), can also induce microvascular recruitment, at doses that do not acutely activate glucose transport in rat muscle. Whether low doses of AICAR can augment physiologic insulin action is unknown. In the present study we used the euglycemic hyperinsulinemic clamp to assess whether insulin action is augmented by low dose AICAR.MethodsAnesthetized rats were studied during saline infusion or euglycemic insulin (3 mU/kg/min) clamp for 2 h in the absence or presence of AICAR for the last hour (5 mg bolus followed by 3.75 mg/kg/min). Muscle glucose uptake (R’g) was determined radioisotopically with 14C-2-deoxyglucose and muscle microvascular perfusion by contrast-enhanced ultrasound with microbubbles.ResultsAICAR did not affect blood glucose, or lower leg R’g, although it significantly (p < 0.05) increased blood lactate levels and augmented muscle microvascular blood volume via a nitric oxide synthase dependent pathway. Insulin increased femoral blood flow, whole body glucose infusion rate (GIR), R’g, hindleg glucose uptake, and microvascular blood volume. Addition of AICAR during insulin infusion increased lactate production, further increased R’g in Type IIA (fast twitch oxidative) and IIB (fast twitch glycolytic) fiber containing muscles, and hindleg glucose uptake, but decreased R’g in the Type I (slow twitch oxidative) fiber muscle. AICAR also decreased GIR due to inhibition of insulin-mediated suppression of hepatic glucose output. AICAR augmented insulin-mediated microvascular perfusion.ConclusionsAICAR, at levels that have no direct effect on muscle glucose uptake, augments insulin-mediated microvascular blood flow and glucose uptake in white fiber type muscles. Agents targeted to endothelial AMPK activation are promising insulin sensitizers, however, the decrease in GIR and the propensity to increase blood lactate cautions against AICAR as an acute insulin sensitizer.

Highlights

Insulin-induced microvascular recruitment is important for optimal muscle glucose uptake. 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, an activator of AMP-activated protein kinase), can induce microvascular recruitment, at doses that do not acutely activate glucose transport in rat muscle
The phosphorylation and activation of endothelial nitric oxide synthase (eNOS) can occur by other kinase pathways and we have reported that activation of AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide1-β-d-ribofuranoside (AICAR) increases nitric oxide (NO) synthesis and muscle microvascular perfusion [25]
Blood glucose concentration was unaffected by AICAR infusion during insulin clamps, and was maintained at fasting levels with no differences between groups

Summary

Introduction

Insulin-induced microvascular recruitment is important for optimal muscle glucose uptake. 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, an activator of AMP-activated protein kinase), can induce microvascular recruitment, at doses that do not acutely activate glucose transport in rat muscle. 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, an activator of AMP-activated protein kinase), can induce microvascular recruitment, at doses that do not acutely activate glucose transport in rat muscle. Inhibition of PI3K by wortmannin in rats in vivo leads to loss of insulin-mediated microvascular recruitment in muscle suggesting this pathway is important [24]. The phosphorylation and activation of eNOS can occur by other kinase pathways and we have reported that activation of AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide1-β-d-ribofuranoside (AICAR) increases NO synthesis and muscle microvascular perfusion [25]. There have been no studies examining whether AMPK activation by AICAR improves the ability of insulin to increase microvascular perfusion in skeletal muscle. In the present study we have examined the acute effect of AICAR on muscle glucose uptake in vivo during a physiologic insulin infusion. The dose of AICAR used was sufficient to cause microvascular recruitment but not stimulate muscle glucose uptake alone [25]

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