Hepatic Glucose Output Inhibition by Mexican Plants Used in the Treatment of Type 2 Diabetes

Abstract

De novo hepatic glucose production or hepatic gluconeogenesis is the main contributor to hyperglycemia in the fasting state in patients with type 2 diabetes (T2D) owing to insulin resistance, which leads to at least twice as much glucose synthesis compared to healthy subjects. Therefore, control of this pathway is a promising target to avoid the chronic complications associated with elevated glucose levels. Patients with T2D in the rural communities of Mexico use medicinal plants prepared as infusions that are consumed over the day between meals, thus following this rationale (consumption of the infusions in the fasting state), one approach to understanding the possible mechanism of action of medicinal plants is to assess their capacity to inhibit hepatic glucose production. Furthermore, in several of these plants, the presence of phenolic acids able to block the enzyme glucose-6-phosphatase (G6Pase) is reported. In the present work, extracts of Ageratina petiolaris, Bromelia karatas, Equisetum myriochaetum, Rhizophora mangle, and Smilax moranensis, which are Mexican plants that have been traditionally used to treat T2D, were assayed to evaluate their possible hepatic glucose output (HGO) inhibitory activity with a pyruvate tolerance test in 18-h fasted STZ-NA Wistar rats after oral administration of the extracts. In addition, the in vitro effects of the extracts on the last HGO rate-limiting enzyme G6Pase was analyzed. Our results showed that four of these plants had an effect on hepatic glucose production in the in vivo or in vitro assays. A. petiolaris and R. mangle extracts decreased glucose output, preventing an increase in the blood glucose levels and sustaining this prevented increase after pyruvate administration. Moreover, both extracts inhibited the catalytic activity of the G6Pase complex. On the other hand, even though S. moranensis and B. karatas did not exhibit a significant in vivo effect, S. moranensis had the most potent inhibitory effect on this enzymatic system, while the E. myriochaetum extract only inhibited hepatic glucose production in the pyruvate tolerance test. Because of the traditional method in which diabetic patients use plants, hepatic glucose production inhibition seems to be a mechanism that partially explains the common hypoglycemic effect. However, further studies must be carried out to characterize other mechanisms whereby these plants can decrease HGO.

Glucose-6-Phosphatase and α-Glucosidase Inhibitors from Smilax moranensis Roots Identified by Affinity-Directed Fractionation

“…These two key enzymes involved in the control of the homeostatic regulation of blood glucose levels with reduction of postprandial glycemic peaks (Ghosh et al 2002). The hypoglycemic effect on rats of the ethanol/water extract has been previously reported (Andrade-Cetto 2011; Romo-Pérez et al 2019;Mata-Torres et al 2020) and 3-O-caffeoyl-quinic acid, 5-O-caffeoyl-quinic acid, and trans-resveratrol were isolated, which may potentially be involved in this effect (Romo-Pérez et al 2019). Smilax moranensis is native to Mexico, known as sarsaparilla, corresponding to a complex of species of the Smilax genus used in traditional medicine since pre-Columbian times.…”

“…G6Pase catalyzes the terminal reaction of glycogenolysis and gluconeogenesis, the two glucose-producing pathways in the liver of humans and higher animals (Arion et al 1997). G6Pase is widely held to be a significant factor in the abnormally high rates of hepatic glucose production observed in the diabetic state (Mata-Torres et al 2020).…”

“…In Mexico, medicinal plants have traditionally played an important role (Mata-Torres et al 2020); besides, the renewed worldwide interest in the use of herbal medicines under the belief of their lack of toxicity and their low cost has led to the use of phytopharmaceuticals for the treatment of hyperglycemia. However, very few traditional medicinal plants have been studied to verify their hypoglycemic properties, toxicity, and abundance to ensure a safe source of the medicinal plants.…”

Molecules Isolated from Mexican Hypoglycemic Plants: A Review

“…Although in the international literature, polyphenols like kaempferol or caffeic acid have been related to the blockage of the enzyme G6Pase, from Mexican plants, chlorogenic acid a well-characterized inhibitor of the G6Pase T1 translocase system [ 19 ]; thus, it can block HGO, has been reported. ρ -Coumaric acid ( 3 ) inhibits fructose-1,6-bisphosphatase, which also leads to the block of HGO; however, this mechanism has not been explored in molecules isolated from Mexican plants.…”

Antioxidant and Antiproliferative Activity of the Ethanolic Extract of Equisetum myriochaetum and Molecular Docking of Its Main Metabolites (Apigenin, Kaempferol, and Quercetin) on β-Tubulin

“…In vivo tests of the aqueous extract of E. myriochaetum showed an inhibitory effect on the production of hepatic glucose at 120 min with 324 mg/dL during the pyruvate tolerance test when using metformin as a hypoglycemic control [14]. This evidence suggests the biological potential hypoglycemia of these species as a whole; however, E. myriochaetum has been hardly studied as a reservoir of additional bioactive chemical compounds, such as antiproliferative agents, even when some related Equisetum species showed this potential [15,16].…”