Abstract
This study investigated the effects of Tiliacora triandra (Colebr.) Diels aqueous extract (TTE) on hepatic glucose production in hepatocellular carcinoma (HepG2) cells and type 2 diabetic (T2DM) conditions. HepG2 cells were pretreated with TTE and its major constituents found in TTE, epicatechin (EC) and quercetin (QC). The hepatic glucose production was determined. The in vitro data were confirmed in T2DM rats, which were supplemented daily with 1000 mg/kg body weight (BW) TTE, 30 mg/kg BW metformin or TTE combined with metformin for 12 weeks. Results demonstrate that TTE induced copper-zinc superoxide dismutase, glutathione peroxidase and catalase genes, similarly to EC and QC. TTE decreased hepatic glucose production by downregulating phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and increasing protein kinase B and AMP-activated protein kinase phosphorylation in HepG2 cells. These results correlated with the antihyperglycemic, antitriglyceridemic, anti-insulin resistance, and antioxidant activities of TTE in T2DM rats, similar to the metformin and combination treatments. Consistently, impairment of hepatic gluconeogenesis in T2DM rats was restored after single and combined treatments by reducing PEPCK and G6Pase genes. Collectively, TTE could potentially be developed as a nutraceutical product to prevent glucose overproduction in patients with obesity, insulin resistance, and diabetes who are being treated with antidiabetic drugs.
Highlights
Type 2 diabetes mellitus (T2DM) refers to a group of metabolic diseases defined by hyperglycemia and insulin resistance [1]
A high level of EC was detected at 1.37 ± 0.025 mg/g extract, whereas QC and gallic acid were found at minimal levels of 0.134 ± 0.001 and 0.053 ± 0.007 mg/g extract, respectively
Similar to the general characteristics of T2DM, these results show that T2DM rats exhibited glucose intolerance, represented by a significant area under the curve (AUC), whereas T2DM rats treated with TTE, metformin, or the combination treatment had a significantly decreased AUC when compared with T2DM rats (Figure 5A,B)
Summary
Type 2 diabetes mellitus (T2DM) refers to a group of metabolic diseases defined by hyperglycemia and insulin resistance [1]. Pancreatic β-cells oversecrete insulin, but it is not able to regulate glucose metabolism due to the presence of insulin resistance; this results in elevated blood glucose levels in T2DM [2]. The key enzymes involved in the regulation of gluconeogenesis are known, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [6]. The expression of these enzymes is highly regulated by glucagon and insulin in correlation with maintaining blood glucose levels [7]. PEPCK and G6Pase, are thought to be the rate-limiting enzymes for gluconeogenesis and have been implicated as potential targets to reduce hepatic glucose production and blood glucose levels in T2DM. Activation of AMP-activated protein kinase (AMPK) by metformin, the first-line drug for T2DM, is able to suppress hepatic gluconeogenesis in T2DM rats [12]
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