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.
The onset of type 2 diabetes (T2D) is a consequence of the progressive loss of adequate β-cell insulin secretion, which frequently occurs under a background of insulin resistance. Currently, nearly 13 million Mexicans are living with diabetes. Moreover, due to poor socioeconomic conditions and the cultural idiosyncrasies of the Mexican population, the use of medicinal plants to treat T2D is a common practice in Mexico. In the Mexican state of Hidalgo, we found the traditional use of Calea urticifolia (CU) to treat this disease. To treat T2D, people drink an infusion made from the aerial part of the plant throughout the day. With the aim of investigating whether the infusion at a traditional dose produces a hypoglycemic effect in either the fasting or postprandial state, we measured the effect of the infusion in a hyperglycemic animal model (rats administered streptozotocin (STZ) and nicotinamide (NZ)) by conducting a glucose tolerance test and constructing a blood-glucose curve. We then analyzed whether the observed effect was related to the inhibition of glucose absorption in the gut or the inhibition of hepatic glucose output (HGO) in vivo and in vitro. Furthermore, we confirmed our findings by identifying the potential targets of the infusion via a network pharmacology analysis. Through high-performance liquid chromatography (HPLC) and thin layer chromatography (TLC), we detected a number of compounds in the extract and identified two of them. The plant extract produced a highly significant hypoglycemic effect under fasting conditions and a weak hypoglycemic effect following glucose or sucrose challenge. Although the plant extract blocked only 20% of the alpha-glucosidase enzyme activity in vitro, in the pyruvate tolerance test (which measures the liberation of hepatic glucose), it significantly reduced glucose levels. Furthermore, in vitro, the extract diminished the activity of the glucose-6-phosphatase complex by 90%. In addition, by conducting TLC, we detected the presence of chlorogenic acid and rutin, which have been reported to block HGO. The results presented here provide evidence of the hypoglycemic effect of the traditionally used C. urticifolia extract and demonstrate that this effect is associated with both a reduction in glucose synthesis via gluconeogenesis due to the phytochemical composition of the extract and a slight blockage of glucose absorption in the gut.
Type 2 diabetes is a worldwide prevalent disease that is due to a progressive loss of adequate β-cell insulin secretion, frequently against a background of insulin resistance. In Mexican traditional medicine, the therapeutic use of hypoglycemic plants to control the disease is a common practice among type 2 diabetic patients. In the present work, we examined the traditional use of the aerial parts of Eryngium longifolium and the rhizome of Alsophila firma, consumed by people use over the day (in fasting state) to control their blood glucose levels, therefore, we aimed to assess the acute hypoglycemic effect of both plants. First, basic phytochemical profiles of both plants were determined and, subsequently, acute toxicity tests were carried out. Then, in vivo hypoglycemic tests were performed in streptozotocin-nicotinamide (STZ-NA) induced hyperglycemic Wistar rats and finally the effect of the plants on three enzymes involved in glucose metabolism was assayed in vitro. Through HPLC-DAD chromatography, caffeic acid, chlorogenic acid, rosmarinic acid, isoflavones, and glycosylated flavonoids were identified in E. longifolium, while the possible presence of flavanones or dihydroflavonols was reported in A. firma. Both plants exhibited a statistically significant hypoglycemic effect, without a dose-dependent effect. Furthermore, they inhibited glucose 6-phosphatase and fructose 1,6-bisphosphatase in in vitro assays, which could be associated with the hypoglycemic effect in vivo. Thus, this study confirmed for the first time the traditional use of the aerial part of E. longifolium and the rhizome of A. firma as hypoglycemic agents in a hyperglycemic animal model. In addition, it was concluded that their ability to regulate hyperglycemia could involve the inhibition of hepatic glucose output, which mainly controls glucose levels in the fasting state.
Chronic hyperglycemia, the product of uncontrolled diabetes, leads to the appearance of vascular complications that can result in the premature death of diabetic patients. Consequently, pharmacological intervention with hypoglycemic agents could delay these complications and improve the quality of life of patients in the long term. Traditional Mexican medicine provides a great wealth of medicinal plants that are used for the treatment of type 2 diabetes, the most prevalent form of diabetes, accounting for nearly 90–95% of total cases. However, there is still a lack of studies that support their hypoglycemic effects, clarify their mechanisms of action, and report their long-term efficacy. Therefore, the aim of this study was to evaluate the chronic effects of the traditional extracts of some Mexican medicinal plants used by diabetic patients (Ageratina petiolaris (Moc. & Sessé ex DC.) R.M. King & H. Rob. (Asteraceae), Calea urticifolia (Mill.) DC. (Asteraceae), and Eryngium cymosum F.Delaroche (Apiaceae)) on hyperglycemia and hypertriglyceridemia. To achieve this goal, the aqueous extracts of these plants at their traditional doses were administered daily to streptozotocin-nicotinamide (STZ-NA) hyperglycemic Wistar rats for 42 days to assess their effects on nonfasting blood glucose (NFBG), glycated hemoglobin (HbA1c), and blood triglycerides (TG). The results showed that the A. petiolaris extract significantly reduced NFBG by 33% compared to its baseline (p = 0.0281). Besides, it prevented the increase in HbA1c by 2.63% (p = 0.0303) and diminished the AUC of TG (p = 0.0031) compared with the negative control. On the other hand, both C. urticifolia and E. cymosum prevented worsening of hyperglycemia by avoiding the significant increase in glucose levels seen in the negative control and the rise in HbA1c by 2.58% (p = 0.0156). These outcomes provide evidence for the first time of the antihyperglycemic effect of these Mexican medicinal plants, confirming their long-term efficacy in the control of chronic hyperglycemia.
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