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  • In conclusion we demonstrated that in

    2023-01-21

    In conclusion, we demonstrated that, in the skeletal muscle of rats with T1DM, CRBN levels increased and AMPK, Akt, GLUT4, PGC-1α, and FNDC5 levels decreased, resulting in increased fasting glucose levels. Aerobic exercise training decreased levels of CRBN, which was possibly mediated by AMPK, Akt, GLUT4, PGC-1α, and FNDC5 protein levels. These results suggested an important mechanism for the aerobic exercise-induced regulation of glucose levels in the skeletal muscle of rats with TIDM (Fig. 4).
    Author contributions
    Conflicts of interest
    Acknowledgements This work was supported by the National Research Foundation of Korea, and the funding was granted by the Ministry of Education of Korea (2010-0020224).
    Introduction AMP-activated protein kinase (AMPK) is an energy sensing serine/threonine kinase, often implicated in diabetes mellitus, with the primary purpose of regulating cellular metabolic functions. These metabolic functions include glucose and lipid homeostasis, adipokine driven regulation of food intake, and body weight [1], [2], [3]. When activated, AMPK phosphorylates many downstream targets that lead to the inhibition of pathways that consume energy, such as fatty glucose transporter synthesis, cholesterol synthesis, and gluconeogenesis [4], [5], [6]. In order for AMPK to be activated it is necessary to have both an increase in the intracellular AMP:ATP ratio and phosphorylation of Thr172 on the α-subunit of the molecule [1], [2], [3], [4], [5]. There are a vast number of known, upstream AMPK activators of physiological, hormonal, natural, and pharmacological origin, however much less is known about factors that inhibit AMPK. To date, two sites of phosphorylation have been shown to inhibit AMPK activity, at Ser485 of the α1 subunit and Ser491 of the α2 subunit [7], [8], [9]. As summarized by Saha et al., in 2014, the current known mechanisms of phosphorylation here are by the molecules Akt (primarily at Ser485), protein kinase A (PKA), p70S6K (primarily at Ser491), and protein kinase Cμ/protein kinase D1 (PKCμ/PKD1), and in some circumstances by autophosphorylation [4]. Thiazolidinediones (TZDs) are a class of antidiabetic drugs including troglitazone, rosiglitazone, and pioglitazone, that have been shown to lower serum glucose and insulin levels, decrease triglyceride levels, and initiate other positive metabolic changes in patients with T2D [10]. It was initially posited that TZDs work primarily as ligands for the peroxisome proliferator activated receptor γ (PPARγ) however subsequent studies trying to gain a more in-depth understanding of the drugs' actions have shown that the PPARγ-mediated mechanism does not account for all the effects of TZDs and there must be an un-accounted for PPARγ-independent mechanism of action [11], [12]. It was first theorized that AMPK might be implicated in TZDs' antidiabetic effects when a study showed that they, along with another antidiabetic drug, Metformin, was found to strongly activate the AMPK pathway, leading to beneficial downstream metabolic effects [13]. The same year Le Brasseur et al. demonstrated that, not only do TZDs directly affect AMPK activity, but also that the abundance of PPARγ has no correlation with noted AMPK change [12]. These findings and many more support the aforementioned PPARy-independent mechanism of action and identify the missing link as AMPK. Despite this correlation between TZDs and AMPK, the complete mechanism of action has yet to be fully elucidated. Furthermore, there has been little, if any, research on changes in p-AMPK Ser485/491 phosphorylation, a potential new target for regulating AMPK activity. In this study we sought to determine the effects of Troglitazone on AMPK at the site of activation (Thr172) and inhibition activation (Ser485) as well as overall downstream activity of the molecule in cultured hepatocytes. We then examined potential mediators of this inhibitory phosphorylation in order to gain a better understanding of the kinase(s) responsible for the changes in phosphorylation. In addition, we compared our results with the other two TZDs, rosiglitazone and pioglitazone, to determine if they would have the same effects, as well as repeating our initial experiment on C2C12 skeletal muscle cells in order to determine if our results were in part cell specific.