Ameliorating Prediabetes Symptoms via Aerobic Exercise Combined with Green Coffee and Chlorogenic Acid Intake by Targeting MondoA-TXNIP/ARRDC4-GLUT4 Axis inHigh Fat Diet-Induced Prediabetic Mice

Abstract Background and Aim: Type 2 diabetes (T2D) begins with prediabetes (PD), whose primary cause is insulin resistance (IR) in the muscle, liver, and adipose tissues, followed by hyperinsulinemia induced by beta (β)-cells and their destruction. As metabolic balance and homeostasis in the human body heavily depend on skeletal muscles, metabolic syndrome (MetS), hepatic steatosis (HS), and T2D may all occur by skeletal muscle failure. Improving understanding of the molecular mechanisms of muscle energy homeostasis and IR may accordingly help in discovering novel methods for combating metabolic disorders, like T2D. In this way, MondoA, an essential glucose-responsive transcription factor regulated by nutrients, such as glucose 6-phosphate (G6P), can reduce the increased amount of glucose inside the cell and prevent more glucose from entering the cell by amplifying the expression of two insulin pathway suppressors, viz, thioredoxin-interacting protein (TXNIP) and arrestin domain containing protein 4 (ARRDC4), under normal conditions. Against this background, the main objective of the present study was to examine the effects of aerobic exercise (Exe) alone and in combination with green coffee (GC) and chlorogenic acid (CGA) intake on the MondoA activity and the expression of its target genes in the skeletal muscles of a high-fat diet (HFD)-induced PD mouse model. Materials and Methods To develop PD, the C57 black 6 (C57BL/6) mice recruited in this study received an HFD for 12 weeks. Upon confirming the PD induction, the animals were given Exe, GC, CGA, or their combination for 10 weeks. Afterward, the metabolic data, i.e., fasting blood sugar (FBS), glucose tolerance test (GTT), the homeostatic model assessment for IR (HOMA-IR) index, plasma insulin levels, together with the cellular localization of MondoA and glucose transporter type 4 (GLUT4), as well as the TXNIP and ARRDC4 expression in the myocytes from various groups were evaluated. Results After administering the treatments in this study, the results established a downward trend in the TXNIP and ARRDC4 expression, a drop in the presence of MondoA in the cell nucleus, and a rise in GLUT4 in the muscle cell membrane. Conclusion By reducing the MondoA activity in the cell nucleus and expanding the presence of GLUT4 in the cell membrane, Aerobic exercise alone and in combination with green coffee and chlorogenic acid intake may be thus useful in lowering blood sugar and improving PD conditions in mice.