Protective Effect of Jiang Tang Xiao Ke Granules against Skeletal Muscle IR via Activation of the AMPK/SIRT1/PGC‐1α Signaling Pathway

Abstract

The Jiang Tang Xiao Ke (JTXK) granule is a classic Chinese herbal formula that has been put into clinical use in the treatment of type 2 diabetes mellitus for decades. However, whether its ability to ameliorate skeletal muscle insulin resistance (IR) is through modulation of the AMPK/SIRT1/PGC-1α signaling pathway remains unknown. Therefore, we aimed to investigate the effects of JTXK granules on IR in skeletal muscle of high-fat diet-induced diabetic mice and C2C12 cells and analyze the underlying mechanisms. In the present study, we showed that JTXK granules attenuated body weight gain, reduced body fat mass, improved body lean mass, and enhanced muscle performance of diabetic mice. JTXK granules also improved glucose metabolism and skeletal muscle insulin sensitivity and partially reversed abnormal serum lipid levels, which might be related to the regulation of the AMPK/SIRT1/PGC-1α pathway, both in skeletal muscle tissue of diabetic mice and in C2C12 cells. Furthermore, drug-containing serum of JTXK granules was capable of enhancing glucose uptake and mitochondrial respiration in C2C12 cells, and AMPKα was proven to be closely involved in this process. Taken together, these results suggest that the JTXK granule ameliorates skeletal muscle IR through activation of the AMPK/SIRT1/PGC-1α signaling pathway, which offers a novel perspective of this formula to combat IR-related metabolic diseases.

Jiangtang Sanhao formula ameliorates skeletal muscle insulin resistance via regulating GLUT4 translocation in diabetic mice

“…Before Oral glucose tolerance test (OGTT) assay, mice were fasted overnight and then gavaged with 2 g/kg body weight of glucose dose ( Jung et al, 2018 ). To perform intraperitoneal insulin tolerance test (IPITT), mice were fasted from 9:00 a.m. to 2:00 p.m. before intraperitoneal injection of insulin (Actrapid; Novo Nordisk, Copenhagen, Denmark) at the dose of 0.5 U/kg body weight ( Bai et al, 2021 ). The glucose levels in mouse tail blood were measured at time points of 0, 30, 60, 90, and 120 min post gavage or injection.…”

“…Among them, the role of AMPK in promoting GLUT4 translocation by regulating mitochondrial function has been brought into the limelight. For example, AMPK may improve insulin sensitivity and GLUT4 translocation via stimulating peroxisome proliferator activated receptor-γ coactivator (PGC-1α), a mitochondrial biosynthesis-related gene ( Herzig and Shaw, 2018 ), and simultaneously affects a string of associated regulators accelerating mitochondrial synthesis ( Bai et al, 2021 ), such as peroxisome proliferator activated receptor α (PPARα), and silencing regulatory protein sirtuin1 (SIRT1). Therefore, mitochondrial dysfunction may bring about a huge impact on GLUT4 translocation, thereby aggravating IR through affecting glucose uptake, transport, and utilization.…”

“…Therefore, skeletal muscle was selected as the target tissue in this study. Moreover, the main active ingredients of JTSHF, such as ginsenoside Rb1 and the berberine, have been reported to improve the insulin sensitivity in skeletal muscle ( Tabandeh et al, 2017 ; Yu et al, 2018 ; Mi et al, 2019 ; Xu et al, 2020 ), with an acting mechanism of stimulating the expression or translocation of GLUT4 through activating the AMPK signaling pathway ( Kong et al, 2009 ; Bai et al, 2021 ). For example, a molecular docking study on berberine showed that berberine stimulated the Thr172 phosphorylation of AMPK through hydrophobic interaction with LysA29, an amino acid residue of AMPK, thereby activating the AMPK signaling pathway ( Li et al, 2021 ).…”

Nrf2 prevents diabetic cardiomyopathy via antioxidant effect and normalization of glucose and lipid metabolism in the heart

“…Abnormal fatty acid metabolism, especially elevated plasma triglyceride levels, is closely related to the occurrence and development of diabetes‐related cardiovascular disease (Oe et al, 2015; Shang & Rodrigues, 2021). While, AMPK‐Sirt1‐PGC‐1α signaling is associated with a decrease in plasma triglyceride levels in diabetes and obesity (Bai et al, 2021; Timmers et al, 2011; Wu et al, 2017). And in our study, we observed that Nrf2‐TG mice had reversed the diabetes‐induced inactivation of AMPK‐Sirt1‐PGC‐1α (Figure 5).…”

The role of Huidouba in regulating skeletal muscle metabolic disorders in prediabetic mice through AMPK/PGC-1α/PPARα pathway

“…The formation of such complexes appears to be necessary for complete transcriptional induction of PPARα gene targets [ 15 ]. One study found that in addition to PPARs, AMPK signaling also enhanced PGC-1α expression, induced glucose-consuming mitochondrial respiration, and increased glucose uptake in muscle cells (GLUT-4 upregulation), lowering blood glucose levels [ 16 ]. Moreover, studies have found that AMPK increases levels of GLUT4 to stimulate glucose uptake by muscle cells [ 17 ].…”