Treatment of type 2 diabetes mellitus via reversing insulin resistance and regulating lipid homeostasis in�vitro and in�vivo using cajanonic acid A

Abstract

The present study investigated the effects of cajanonic acid A (CAA), extracted from the leaves of Cajanus cajan (L.) Millsp with a purity of 98.22%, on the regulatory mechanisms of glucose and lipid metabolism. HepG2 cells transfected with a protein-tyrosine phosphatase 1B (PTP1B) overexpression plasmid were established. The cells, induced with insulin resistance by dexamethasone (Dex) treatment, together with type 2 diabetes mellitus (T2DM) model rats and ob/ob mice, were used in the present study. The effects of CAA treatment on the differentiation of 3T3-L1 adipocytes were determined using Oil Red O. The expression levels of insulin signaling factors were detected via reverse transcription-quantitative polymerase chain reaction and western blot analyses. The results revealed that the overexpression of PTP1B contributed to insulin resistance, which was reversed by CAA treatment via inhibiting the activity of PTP1B and by regulating the expression of associated insulin signaling factors. The treatment of cell lines with Dex led to increased expression of PTP1B but decreased glucose consumption, and decreased tyrosine phosphorylation of insulin receptor, insulin receptor substrate 1, and phosphoinositide 3-kinase. Treatment with CAA not only reduced the fasting blood glucose levels and protected organs from damage, but also reduced the serum fasting levels of total cholesterol, triglycerides and low-density lipoprotein cholesterol in the T2DM rats. CAA treatment also inhibited adipocyte differentiation and decreased the mRNA levels of various adipogenic genes. Furthermore, CAA treatment restored the transduction of insulin signaling by regulating the expression of PTP1B and associated insulin signaling factors. Treatment with CAA also reduced the problems associated with hyperglycemia and hyperlipidemia. In conclusion, CAA may be used to cure T2DM via restoring insulin resistance and preventing obesity.

Soy husk extract improves physical and biochemical parameters of obese–diabetic rats through the regulation of PPARγ expression

“…Rosiglitazone Maleate eases type 2 diabetes by enhancing insulin sensitivity in peripheral tissues (Cox, ; Yang et al, ). Administration at 4 mg/kg BW has been proven to be effective in treating diabetes in rodent models (Sunil, Ignacimuthu, & Agastian, ).…”

“…Rosiglitazone Maleate eases type 2 diabetes by enhancing insulin sensitivity in peripheral tissues (Cox, 2004;Yang et al, 2018).…”

Pharmacokinetics, Tissue Distribution, and Excretion Study of Cajanonic Acid A in Rats by UPLC-MS/MS

“…CAA could also reduce blood glucose and led to weight loss in the leptin-deficient ob/ob mice and db/db type diabetic mice, showing the potential of CAA to treat obesity-associated diabetes [10][11][12]. In pharmacological mechanism studies, CAA could not only reverse PTP1B-mediated and/or dexamethasone-induced insulin resistance but also inhibit hormoneinduced adipogenesis by inhibiting PTP1B and down-regulating peroxisome proliferator-activated receptor-γ (PPARγ) [13][14][15]. Thus, CAA might avoid the side-effects caused by classical PPARγ activators, and could be a potential candidate and a good lead for the discovery of novel hypoglycemic drugs.…”

“…Twenty-four rats were randomly divided into 4 groups (low-dose, 15 mg/kg; medium-dose, 30 mg/kg; and 60 mg/kg high-dose oral group and intravenous group; 3 females and 3 males each group). The dose of CAA was determined based on the study of hypoglycemic activity of CAA in SD rats [10,13]. For intravenous administration (5 mg/kg), blood samples were collected into heparin tubes at 0 (before administration), 0.05, 0.15, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 20, 24 h after administration, and centrifuged immediately at 3000 g for 10 min to obtain plasma.…”

Cajanolactone A from Cajanus cajan Promoted Osteoblast Differentiation in Human Bone Marrow Mesenchymal Stem Cells via Stimulating Wnt/LRP5/β-Catenin Signaling

“…From this hydrophobic fraction, three new stilbenoids, cajanstilbene H, cajanonic acid A, and cajanolactone A, were discovered by us [14]. Among them, cajanstilbene H exhibited in vitro osteogenesis-promoting activity [15], while cajanonic acid A showed therapeutic potential in the treatment of type 2 diabetes [16]. In this study, we report our new findings that cajanolactone A promoted osteoblast differentiation in human bone marrow mesenchymal stem cells (hBMSCs) via stimulating Wnt/LRP5/β-catenin signaling, and is a promising anti-osteoporotic drug candidate.…”