## 4 Discussion
Rutin, one of the flavonoid glycosides found in fruits and vegetables, has been discovered to possess a stimulatory effect on glucose uptake by enhancing GLUT4 and insulin receptor kinases [48]. Since _C. carandas_ contains a high level of rutin, it is probable that it contributed to the antihyperglycemic effects of the CCA extract that we observed in our study. To investigate whether the antihyperglycemic effect of CCA is due to an improvement in insulin secretion, we assessed fasting insulin level and employed a homeostatic model (HOMA-\(\beta\)). The HOMA model is used to estimate the sensitivity of basal insulin and the function of \(\beta\)-cells from fasting plasma glucose and insulin levels [19]. The untreated T2 DM rats showed insignificantly lower plasma insulin levels and desperately worse HOMA-\(\beta\), indicating that pancreatic \(\beta\)-cells were in severe dysfunction and probably unable to secrete adequate insulin. The CCA-extract-treated rats exhibited proper control in glycemia, but neither CCA nor metformin enhanced the fasting plasma insulin levels and HOMA-\(\beta\), suggesting that the beneficial effect of the CCA extract on glycemic control is unrelated to the enhancement of insulin secretion. In contrast, [PERSON] and fellows (2019) claimed that the antidiabetic effect of the _C. carandas_ fruit extract hinged on the increase in insulin secretion; thereafter, they proved a possible mechanism of insulin secretagogue action with the closure of KATP channels in isolated islet \(\beta\)-cells [9]. The use of the HOMA to assess insulin sensitivity in subjects treated with insulin secretagogues has several drawbacks in result interpretation and needs further validation [49]. Nevertheless, the present study was unlikely to provide strong data to show that the CCA extract does not affect insulin secretion, since it did not investigate reliable parameters that reflect insulin production from the pancreas, such as C-peptide level, a marker of secretion [50], or parameters that reflect stimulated insulin secretion, such as insulin response curve and insulin sensitivity index (ISI) from an OGTT [51]. Remarkably, the histological study of the pancreas of diabetic rats treated with CCA showed that the severity of the degenerative changes in the islets of Langerhans was lower than that in the untreated diabetic rats. Hyperglycemia in diabetes was probably attenuated by supplementation with CCA, as a lower degree of hyperglycemia ameliorated \(\beta\)-cell damage progression. However, the antioxidative stress or anti-inflammation activity of the _C. carandas_ extract might be partly involved in these findings [13; 14]. Alternatively, the glucose-lowering effect of CCA supplements might be explained by other mechanisms. The results of this study revealed that improvement in insulin sensitivity might be a possible mechanism, and this conception was supported by the HOMA-IR index and the outcomes of the OGTT. Supplementation with the CCA extract showed an enhanced insulin sensitivity, the same as in the metformin-treated group. Metformin is a clinically common prescription in T2 DM, which can reduce insulin resistance and liver glucose production and therefore effectively control blood glucose levels [52]. [PERSON] and [PERSON] reviewed studies of treatment with metformin that can positively affect insulin sensitivity by reducing lipolysis and free fatty acids, as well as increase the metabolic clearance rate of glucose [53]. As results show in the present study, the efficacy of the CCA supplement was comparable with that of metformin in terms of insulin sensitivity enhancement. Insulin resistance is a pathological condition in which insulin-dependent cells, such as skeletal muscle and adipocytes, do not respond appropriately to normal plasma insulin levels [43]. The mechanisms that promote insulin resistance include decreased glucose uptake into skeletal muscles and adipose tissues as well as increased liver glucose production.