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Cited by 54Metabolism, Diabetes, and CancerAdipose Tissue and MetabolismPancreatic function and diabetes

Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity

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Kalinovich, Anastasia, Dehvari, Nodi, Åslund, Alice, van Beek, Sten, Halleskog, Carina, Olsen, Jessica, Forsberg, Elisabete, Zacharewicz, Evelyn +7 more·2020·Diabetologia
DOI 10.1007/s00125-020-05171-yPMC PMC7351816
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Abstract

Abstract Aims/hypothesis Chronic stimulation of β2-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of β2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of β2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect. Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen. Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment, p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg−1 day−1 (40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%, p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%, p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 ± 0.31%/min in comparison with 0.15 ± 0.36%/min in control mice, p < 0.05) and drastically reduced hepatic steatosis (by 40%, p < 0.01) and glycogen (by 23%, p < 0.05). Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective β2-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans.

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  • Prolonged treatment with low dose of β2-adrenoceptor agonists can further enhance whole-body insulin sensitivity, immensely reduce hepatic glycogen levels, and lower blood glucose levels.

    “Prolonged treatment with the low dose of β 2-adrenoceptor agonists can further enhance whole-body insulin sensitivity, immensely reduce hepatic glycogen levels, and lower blood glucose levels (32).”

    From The progression of secondary diabetes: A review of modeling studies (2022) · cites this paper as [32]

    The Results (pages not provided) report that prolonged low-dose clenbuterol improved whole-body insulin sensitivity and reduced liver glycogen by 23% in mice with diet-induced obesity. They also report lower fasting blood glucose after prolonged treatment, but that result came from a higher-dose regimen. The claim therefore overstates the glycogen reduction as “immense” and combines findings from different doses without limiting them to mice. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Long period effect of low-dose epinephrine can improve insulin sensitivity in vivo.

    “the updated biological findings indicate that the long period effect of low-dose epinephrine can improve insulin sensitivity and reduce blood glucose level in vivo (31–33).”

    From The progression of secondary diabetes: A review of modeling studies (2022) · cites this paper as [32]

    The Discussion reports improved whole-body insulin sensitivity after prolonged low-dose clenbuterol treatment, and the Results identify the subjects as mice. The cited paper does not establish that low-dose epinephrine has the same effect; clenbuterol is a different agent. Page numbers were not provided in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Long period effect of low-dose epinephrine can reduce blood glucose level in vivo.

    “the updated biological findings indicate that the long period effect of low-dose epinephrine can improve insulin sensitivity and reduce blood glucose level in vivo (31–33).”

    From The progression of secondary diabetes: A review of modeling studies (2022) · cites this paper as [32]

    The Results section reports that four days of clenbuterol treatment reduced fasting blood glucose by 21% in mice, with benefits persisting for up to 42 days. The cited paper tested low-dose clenbuterol, not low-dose epinephrine, so it does not establish the claimed effect for epinephrine. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Low dose of β2-adrenoceptor agonists can improve glucose tolerance in diet-induced obese mice within 4 days of treatment.

    “Moreover, experiments have shown low dose of β 2-adrenoceptor agonists can improve glucose tolerance in diet-induced obese mice within 4 days of treatment.”

    From The progression of secondary diabetes: A review of modeling studies (2022) · cites this paper as [32]

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Authors
Kalinovich, A., Dehvari, N., Åslund, A., van Beek, S., Halleskog, C., Olsen, J., Forsberg, E., Zacharewicz, E., Schaart, G., Rinde, M., Sandström, A., Berlin, R., Östenson, C.-G., Hoeks, J., & Bengtsson, T.
Affiliations
  • Stockholm University (SE)
  • Atrogi (Sweden) (SE)
  • Maastricht University (NL)
  • Karolinska University Hospital (SE)
Corresponding author
Bengtsson, Tore
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2020-05-29
Volume
63
Issue
8
Pages
1603-1615
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-020-05171-y
PMC
PMC7351816
OpenAlex
W3031579337
Cited by
54
References
52
Citations by year
2026: 7 · 2025: 7 · 2024: 9 · 2023: 11 · 2022: 5 · 2021: 15
FWCI
2.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetologia (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
  • Diabetesfonden
  • Magnus Bergvalls Stiftelse
  • Vetenskapsrådet
  • Stiftelsen Olle Engkvist Byggmästare
  • Carl Tryggers Stiftelse för Vetenskaplig Forskning
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
beta2-adrenergic agonists, clenbuterol, diet-induced obesity, glucose uptake, skeletal muscle, glucose homeostasis, insulin sensitivity, insulin resistance, hepatic steatosis, liver glycogen, glucose tolerance, diabetes treatment, hepatic lipid metabolism, hepatic glucose metabolism, hepatic gluconeogenesis
MeSH terms
Animals, Clenbuterol, Fatty Liver, Glucose, Homeostasis, Insulin Resistance, Male, Mice, Inbred C57BL, Obesity, Muscle, Skeletal, Mice, Adrenergic beta-2 Receptor Agonists

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