## 3 Effect of PS on Components of MetS
### Effect of PS on Hyperglycaemia or Diabetes  
Populations with MetS are five times more likely to develop type 2 diabetes (T2 DM) [74; 75]. The main abnormality that connects the metabolic and hemodynamic disturbances found in MetS is impaired insulin-mediated glucose uptake [76; 77]. Insulin resistance is linked to prediabetes, defined as an elevated plasma glucose level (hyperglycaemia) above the normal range but below the clinical diabetes threshold [78]. Hyperglycaemia in prediabetes can cause oxidative stress and upregulation of proinflammatory factors, leading to impaired insulin receptor signalling in insulin-sensitive target tissues. Ultimately, T2 DM and insulin resistance will occur [78; 79]. Streptozoticin (STZ) is an antibiotic currently used to reliably induce both insulin-dependent and non-insulin-dependent diabetes mellitus (DM) by inducing beta cell death via DNA alkylation [80]. The STZ-induced DM is a low-cost and fast-onset experimental model applied in many rodent strains [81]. Although high-dose STZ severely impairs insulin secretion, emulating type 1 DM, low-dose STZ has been shown to cause a mild impairment of beta cell insulin secretion similar to late-stage T2 DM [82; 83]. [PERSON] et al. [84] reported that the aqueous leaf extract of PS (125 mg/kg/day for 28 days) increased body  
Figure 2: Protective effect of PS supplementation against obesity: current knowledge and future area of investigation. List of abbreviations: PS, _Piper sarnutosum_; 11 HSD-1, 11B-hydroxsteroid dehydrogenase type 1; CEBP-\(\alpha\), -\(\beta\), CCAAT/enhancer-binding protein; PPAR-\(\gamma\), peroxisome proliferatorator activator receptor-gamma; increase; +, in combination with. weight, and decreased fasting blood glucose and urine glucose levels in STZ-induced DM rats. A short-term treatment of the PS aqueous leaf extract (125 and 250 mg/kg/day for 7 days) did not lower the fasting plasma glucose level of STZ-induced diabetic rats [85]. This could be attributed to the short treatment duration, which was insufficient to produce any therapeutic effects. [PERSON] et al. [86] reported increased inflammatory cells infiltration, Bowman's capsule size, and glomerular membrane thickness in the kidney of STZ-induced DM rats. This suggests that hyperglycaemia due to DM causes kidney damage, leading to renal failure in rats. Some renal complications in DM include diabetic nephropathy, proteinuria, hypertension, and cardiovascular risks [87]. The aqueous leaf extract of PS (125 mg/kg/day for 28 days) reduced these degenerative renal changes in STZ-induced DM rats, suggesting that PS supplementation prevented renal failure due to DM. However, it did not change the body weight, fasting blood glucose, kidney weight index, and glomerular area in a renal corpuscle of DM rats [86]. There were a few shortcomings in the studies examined. Some studies measured fasting blood glucose as an index of the glycaemic status of the animals, which might not be accurate. It should be supported by the oral glucose tolerance test, insulin level, and homeostasis model assessment of insulin resistance, which are stronger predictors of T2 DM. At the very least, a combination of fasting plasma glucose and glycated haemoglobin (HbA1c) would be adequate to indicate DM accurately [88]. On the other hand, STZ does not produce hyperinsulinemia associated with early stage T2 DM. According to [PERSON] [89], a combination of a high-fat diet (HFD) and STZ is a better model to recapitulate DM progression in humans. Otherwise, a high-carbohydrate high-fat diet without STZ would also reproduce the hyperinsulinemia state in early DM, but the successful establishment of MetS would take 12-16 weeks [90]. Apart from that, PS alone fails to lower blood glucose levels in two studies [85; 86]. Thus, future research should explore combining PS with a conventional T2 DM medication such as metformin. Furthermore, only one study examined the effects of PS on renal complications due to DM (diabetic nephropathy).