Bradley, EA and Zhang, L and Genders, AJ and Richards, SM and Rattigan, S and Keske, MA, Enhancement of insulin-mediated rat muscle glucose uptake and microvascular perfusion by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, Cardiovascular Diabetology, 14, (1) Article 91. ISSN 1475-2840 (2015) [Refereed Article]
© 2015 Bradley et al. Licenced under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/
Background: 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 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.
Methods: Anesthetized 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.
Results: AICAR 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.
Conclusions: AICAR, 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.
|Item Type:||Refereed Article|
|Keywords:||muscle, insulin, glucose, microcirculation, microbubbles|
|Research Division:||Medical and Health Sciences|
|Research Group:||Clinical Sciences|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Author:||Bradley, EA (Miss Eloise Bradley)|
|Author:||Richards, SM (Dr Stephen Richards)|
|Author:||Rattigan, S (Professor Stephen Rattigan)|
|Author:||Keske, MA (Dr Michelle Keske)|
|Web of Science® Times Cited:||2|
|Deposited By:||Menzies Institute for Medical Research|
|Downloads:||74 View Download Statistics|
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