RESUMO
Liver plays a pivotal role in maintaining blood glucose levels through complex processes which involve the disposal, storage, and endogenous production of this carbohydrate. Insulin is the hormone responsible for regulating hepatic glucose production and glucose storage as glycogen, thus abnormalities in its function lead to hyperglycemia in obese or diabetic patients because of higher production rates and lower capacity to store glucose. In this context, two different but complementary therapeutic approaches can be highlighted to avoid the hyperglycemia generated by the hepatic insulin resistance: 1) enhancing insulin function by inhibiting the protein tyrosine phosphatase 1B, one of the main enzymes that disrupt the insulin signal, and 2) direct regulation of key enzymes involved in hepatic glucose production and glycogen synthesis/breakdown. It is recognized that medicinal plants are a valuable source of molecules with special properties and a wide range of scaffolds that can improve hepatic glucose metabolism. Some molecules, especially phenolic compounds and terpenoids, exhibit a powerful inhibitory capacity on protein tyrosine phosphatase 1B and decrease the expression or activity of the key enzymes involved in the gluconeogenic pathway, such as phosphoenolpyruvate carboxykinase or glucose 6-phosphatase. This review shed light on the progress made in the past 7 years in medicinal plants capable of improving hepatic glucose homeostasis through the two proposed approaches. We suggest that Coreopsis tinctoria, Lithocarpus polystachyus, and Panax ginseng can be good candidates for developing herbal medicines or phytomedicines that target inhibition of hepatic glucose output as they can modulate the activity of PTP-1B, the expression of gluconeogenic enzymes, and the glycogen content.
RESUMO
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.
RESUMO
Obesity predisposes to glucose intolerance and type 2 diabetes (T2D). This disease is often characterized by insulin resistance, changes in insulin clearance, and ß-cell dysfunction. However, studies indicate that, for T2D development, disruptions in glucagon physiology also occur. Herein, we investigated the involvement of glucagon in impaired glycemia control in monosodium glutamate (MSG)-obese mice. Male Swiss mice were subcutaneously injected daily, during the first 5 days after birth, with MSG (4 mg/g body weight [BW]) or saline (1.25 mg/g BW). At 90 days of age, MSG-obese mice were hyperglycemic, hyperinsulinemic, and hyperglucagonemic and had lost the capacity to increase their insulin/glucagon ratio when transitioning from the fasting to fed state, exacerbating hepatic glucose output. Furthermore, hepatic protein expressions of phosphorylated (p)-protein kinase A (PKA) and cAMP response element-binding protein (pCREB), and of phosphoenolpyruvate carboxykinase (PEPCK) enzyme were higher in fed MSG, before and after glucagon stimulation. Increased pPKA and phosphorylated hormone-sensitive lipase content were also observed in white fat of MSG. MSG islets hypersecreted glucagon in response to 11.1 and 0.5 mmol/L glucose, a phenomenon that persisted in the presence of insulin. Additionally, MSG α cells were hypertrophic displaying increased α-cell mass and immunoreactivity to phosphorylated mammalian target of rapamycin (pmTOR) protein. Therefore, severe glucose intolerance in MSG-obese mice was associated with increased hepatic glucose output, in association with hyperglucagonemia, caused by the refractory actions of glucose and insulin in α cells and via an effect that may be due to enhanced mTOR activation.