## 4 Discussion
Since insulin plays an essential role in the entry of glucose into the cells, any disruptions in the transduction of insulin signals are associated with hyperglycemia due to cells' inability to absorb glucose [35]. The binding of insulin to receptor and post-receptor events, such as activation of the IRS-PI3K-Akt-PKC pathway, cause GLUT4 translocation to the membrane and subsequent glucose uptake into cells. Notably, a marked fall in body weight and a slight decline in food intake were observed in our experimental rats. A high-calorie diet might stimulate the release of hormones that promote satiety, such as cholecyst, glucagon-like peptide-1, and peptide YY [36], which may lead to a reduction in food intake. Moreover, the selective destruction of STZ to pancreatic \(\beta\)-cells diminishes insulin production [37]. Intense proteolysis and lipolysis due to insulin insufficiency make animals lose body weight. However, giving an HFD to T2 DM rats throughout the experiment did not alter calorie intake and visceral fat mass. Previous studies also showed a reduction in body weight without variation in retroperitoneal, epididymal, and perirenal lipid contents in animals given an HFD and STZ [38; 39]. Supplementation with the CCA extract for 12 weeks at the dose of 400 mg/kg BW could effectively diminish visceral fat accumulation in diabetic rats, despite an increase in calorie intake. There are a few previous reports which directly described the effect of a _C. carandas_ fruit extract on body weight and visceral fat weight. However, several studies demonstrate anthocyanin, a major flavonoid in the CCA extract, having such an effect. The reduction in body weight and white adipose tissue weight was observed in cyanidin-3-O-glucose-treated diabetic mice, which was accompanied by a decline in the size of adipocytes [40]. [PERSON] et al. reported that supplemental diets with an anthocyanin-rich blueberry extract markedly reduced body fat and body weight in obese HFD-fed C57 BL/6 mice [41]. The previous study suggested that Aronia fruits rich in anthocyanin phytochemicals suppressed hyperglycemia and the accumulation of visceral fats by inhibiting pancreatic lipase activity and/or intestinal lipid absorption [42]. As with visceral fat, CCA could also diminish serum lipid levels in diabetic rats. Dyslipidemia, strongly correlated with obese T2 DM individuals in several clinical reports, is characterized by the elevation of triglyceride, non-HDL cholesterol, and small dense LDL and HDL, as well as a reduction in HDL cholesterol [43]. Our study observed an anti-dyslipidemic effect of the CCA extract in the experimental diabetic animals after the 12-week intervention period. Researchers supposed that cyanidin-3-O-glucoside can inhibit intracellular de novo lipogenesis by inactivating the rate-limiting step of triglyceride synthesis, reducing hepatic steatosis in T2 DM [44]. Similarly, [PERSON] et al. found that a black rice anthocyanin extract normalized the increased body weight, serum cholesterol, and serum triglyceride in high-fat- and high-cholesterol-feeding mice [45]. Our in vitro study also confirmed the attenuation of insulin resistance observed in our in vivo study: the CCA extract treatment in mature adipocytes could alleviate the LPS-induced lipolysis, probably due to the presence of anthocyanin in CCA, which regulates FoxO1-mediated transcription of ATGL and thus inhibits adipocyte lipolysis [46]. In addition, decreased glucose uptake was also found in LPS-treated adipocytes. As mentioned earlier, incubation with the CCA extract exhibited improved glucose uptake into the mature adipocytes. Hence, CCA could probably upturn the LPS-induced inhibition of insulin signaling, consequently improving glucose disposal. Experiments in the 3T3-L1 cell line presented that cyanidin-3-O-glucose-treated preadipocytes were differentiated into smaller, insulin-sensitive adipocytes, thus enhancing glucose uptake and insulin signaling [47].