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

Bradley EA, Zhang L, Genders AJ, Richards SM, Rattigan S, Keske MA - Cardiovasc Diabetol (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Menzies Institute for Medical Research, University of Tasmania, Private Bag 23, Hobart, 7001, TAS, Australia. Eloise.Bradley@utas.edu.au.

ABSTRACT

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 (14)C-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.

No MeSH data available.


Related in: MedlinePlus

Changes in arterial blood lactate (∆BL) in response to saline (unfilled circle), insulin (filled circle), AICAR (unfilled square) and AICAR + insulin (filled square) treatments. Values are given as mean ± SE. Asterisk AICAR treated significantly different (p < 0.05) from corresponding untreated animals. Hash Insulin + AICAR treated significantly different (p < 0.05) from insulin treated animals. Cap symbol Insulin treated significantly different (p < 0.05) from saline treated animals. (Protocol A); 2-way repeated-measures ANOVA.
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Fig2: Changes in arterial blood lactate (∆BL) in response to saline (unfilled circle), insulin (filled circle), AICAR (unfilled square) and AICAR + insulin (filled square) treatments. Values are given as mean ± SE. Asterisk AICAR treated significantly different (p < 0.05) from corresponding untreated animals. Hash Insulin + AICAR treated significantly different (p < 0.05) from insulin treated animals. Cap symbol Insulin treated significantly different (p < 0.05) from saline treated animals. (Protocol A); 2-way repeated-measures ANOVA.

Mentions: We first determined whether AICAR infusion alters insulin levels achieved during clamps, to exclude the possibility that alterations in glucose handling result solely from altered plasma insulin concentration. Plasma insulin concentration was significantly elevated (twofold, p < 0.05) following insulin clamps (saline, 204 ± 28 pM; insulin, 410 ± 34 pM) but this was not affected by AICAR (AICAR, 234 ± 52 pM; insulin + AICAR, 425 ± 29 pM). Blood glucose concentration was also unaffected by AICAR infusion during insulin clamps, and was maintained at fasting levels with no differences between groups (saline, 3.49 ± 0.12 mM; insulin, 3.75 ± 0.12 mM; saline + AICAR, 3.41 ± 0.14 mM; insulin + AICAR, 3.41 ± 0.10 mM). However, blood lactate concentration significantly increased twofold (p < 0.05) with insulin (saline, 0.44 ± 0.04 mM; insulin, 0.87 ± 0.09 mM) and this was further enhanced with AICAR (AICAR, 3.52 ± 0.27 mM; insulin + AICAR, 2.46 ± 0.15 mM; Figure 2).Figure 2


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

Bradley EA, Zhang L, Genders AJ, Richards SM, Rattigan S, Keske MA - Cardiovasc Diabetol (2015)

Changes in arterial blood lactate (∆BL) in response to saline (unfilled circle), insulin (filled circle), AICAR (unfilled square) and AICAR + insulin (filled square) treatments. Values are given as mean ± SE. Asterisk AICAR treated significantly different (p < 0.05) from corresponding untreated animals. Hash Insulin + AICAR treated significantly different (p < 0.05) from insulin treated animals. Cap symbol Insulin treated significantly different (p < 0.05) from saline treated animals. (Protocol A); 2-way repeated-measures ANOVA.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4509722&req=5

Fig2: Changes in arterial blood lactate (∆BL) in response to saline (unfilled circle), insulin (filled circle), AICAR (unfilled square) and AICAR + insulin (filled square) treatments. Values are given as mean ± SE. Asterisk AICAR treated significantly different (p < 0.05) from corresponding untreated animals. Hash Insulin + AICAR treated significantly different (p < 0.05) from insulin treated animals. Cap symbol Insulin treated significantly different (p < 0.05) from saline treated animals. (Protocol A); 2-way repeated-measures ANOVA.
Mentions: We first determined whether AICAR infusion alters insulin levels achieved during clamps, to exclude the possibility that alterations in glucose handling result solely from altered plasma insulin concentration. Plasma insulin concentration was significantly elevated (twofold, p < 0.05) following insulin clamps (saline, 204 ± 28 pM; insulin, 410 ± 34 pM) but this was not affected by AICAR (AICAR, 234 ± 52 pM; insulin + AICAR, 425 ± 29 pM). Blood glucose concentration was also unaffected by AICAR infusion during insulin clamps, and was maintained at fasting levels with no differences between groups (saline, 3.49 ± 0.12 mM; insulin, 3.75 ± 0.12 mM; saline + AICAR, 3.41 ± 0.14 mM; insulin + AICAR, 3.41 ± 0.10 mM). However, blood lactate concentration significantly increased twofold (p < 0.05) with insulin (saline, 0.44 ± 0.04 mM; insulin, 0.87 ± 0.09 mM) and this was further enhanced with AICAR (AICAR, 3.52 ± 0.27 mM; insulin + AICAR, 2.46 ± 0.15 mM; Figure 2).Figure 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Menzies Institute for Medical Research, University of Tasmania, Private Bag 23, Hobart, 7001, TAS, Australia. Eloise.Bradley@utas.edu.au.

ABSTRACT

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 (14)C-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.

No MeSH data available.


Related in: MedlinePlus