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Muscle hypertrophic effect of inhaled beta₂ -agonist is associated with augmented insulin-stimulated whole-body glucose disposal in young men.

ABSTRACT: Rodent studies highlight enhancement of glucose tolerance and insulin sensitivity as potential clinically relevant effects of chronic beta₂ -agonist treatment. However, the doses administered to rodents are not comparable with the therapeutic doses used for humans. Thus, we investigated the physiological effects of prolonged beta₂ -agonist treatment at inhaled doses resembling those used in respiratory diseases on insulin-stimulated whole-body glucose disposal and putative mechanisms in skeletal muscle and adipose tissue of healthy men. Utilizing a randomized placebo-controlled parallel-group design, we assigned 21 healthy men to 4 weeks daily inhalation of terbutaline (TER; 4 mg × day^-1 , n = 13) or placebo (PLA, n = 8). Before and after treatments, we assessed subjects' whole-body insulin-stimulated glucose disposal and body composition, and collected vastus lateralis muscle and abdominal adipose tissue biopsies. Glucose infusion rate increased by 27% (95% CI: 80 to 238 mg × min^-1 , P = 0.001) in TER, whereas no significant changes occurred in PLA (95% CI: -37 to 195 mg × min^-1 , P = 0.154). GLUT4 content in muscle or adipose tissue did not change, nor did hexokinase II content or markers of mitochondrial volume in muscle. Change in lean mass was associated with change in glucose infusion rate in TER (r = 0.59, P = 0.03). Beta₂ -agonist treatment in close-to-therapeutic doses may augment whole-body insulin-stimulated glucose disposal in healthy young men and part of the change is likely to be explained by muscle hypertrophy. These findings highlight the therapeutic potential of beta₂ -agonists for improving insulin sensitivity. KEY POINTS: While studies in rodents have highlighted beta₂ -agonists as a means to augment insulin sensitivity, these studies utilized beta₂ -agonists at doses inapplicable to humans. Herein we show that a 4-week treatment period with daily therapeutic inhalation of beta₂ -agonist increases insulin-stimulated whole-body glucose disposal in young healthy lean men. This effect was associated with an increase of lean mass but not with changes in GLUT4 and hexokinase II or basal glycogen content in skeletal muscle nor GLUT4 content in abdominal adipose tissue. These findings suggest that the enhanced insulin-stimulated whole-body glucose disposal induced by a period of beta₂ -agonist treatment in humans, at least in part, is attributed to muscle hypertrophy. Our observations extend findings in rodents and highlight the therapeutic potential of beta₂ -agonists to enhance the capacity for glucose disposal and whole-body insulin sensitivity, providing important knowledge with potential application in insulin resistance.

SUBMITTER: Jessen S

PROVIDER: S-EPMC9310637 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLong chain omega-3 polyunsaturated fatty acids (ω-3PUFA) supplementation in animal models of diet-induced obesity has consistently shown to improve insulin sensitivity. The same is not always reported in human studies with insulin resistant (IR) subjects with obesity.ObjectiveWe studied whether high-dose ω-3PUFA supplementation for 3 months improves insulin sensitivity and adipose tissue (AT) inflammation in IR subjects with obesity.MethodsThirteen subjects (BMI = 39.3 ± 1.6 kg/m2) underwent 80 mU/m2·min euglycemic-hyperinsulinemic clamp with subcutaneous (Sc) AT biopsy before and after 3 months of ω-3PUFA (DHA and EPA, 4 g/daily) supplementation. Cytoadipokine plasma profiles were assessed before and after ω-3PUFA. AT-specific inflammatory gene expression was evaluated on Sc fat biopsies. Microarray analysis was performed on the fat biopsies collected during the program.ResultsPalmitic and stearic acid plasma levels were significantly reduced (P < 0.05) after ω-3PUFA. Gene expression of pro-inflammatory markers and adipokines were improved after ω-3PUFA (P < 0.05). Systemic inflammation was decreased after ω-3PUFA, as shown by cytokine assessment (P < 0.05). These changes were associated with a 25% increase in insulin-stimulated glucose disposal (4.7 ± 0.6 mg/kg ffm•min vs. 5.9 ± 0.9 mg/kg ffm•min) despite no change in body weight. Microarray analysis identified 53 probe sets significantly altered post- ω-3PUFA, with Apolipoprotein E (APOE) being one of the most upregulated genes.ConclusionHigh dose of long chain ω-3PUFA supplementation modulates significant changes in plasma fatty acid profile, AT, and systemic inflammation. These findings are associated with significant improvement of insulin-stimulated glucose disposal. Unbiased microarray analysis of Sc fat biopsy identified APOE as among the most differentially regulated gene after ω-3PUFA supplementation. We speculate that ω-3PUFA increases macrophage-derived APOE mRNA levels with anti-inflammatory properties.

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Muscle hypertrophic effect of inhaled beta₂ -agonist is associated with augmented insulin-stimulated whole-body glucose disposal in young men.

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Muscle hypertrophic effect of inhaled beta2 -agonist is associated with augmented insulin-stimulated whole-body glucose disposal in young men.

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Muscle hypertrophic effect of inhaled beta₂ -agonist is associated with augmented insulin-stimulated whole-body glucose disposal in young men.