Approaches to Decrease Hyperglycemia by Targeting Impaired Hepatic Glucose Homeostasis Using Medicinal Plants

Abstract

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.

Keywords: PTP-1B inhibitors; hepatic glucose output; hyperglycemia; insulin resistance; medicinal plants; natural products.

FIGURE 1

PRISMA flowchart. PTP-1B: protein tyrosine phosphatase 1B; HGP: hepatic glucose production.

FIGURE 2

Impaired hepatic glucose homeostasis by insulin resistance. When insulin does not work properly either due to overexpression of PTP-1B or other factors, glucose production in liver is upregulated generating a hyperglycemic state. Both gluconeogenesis and glycogenolysis are enhanced due to poor insulin signaling, namely genetic expression of gluconeogenic enzymes is not repressed and enzymes related to glycogen metabolism are not adequately regulated. Akt functions: green color indicates positive regulation, red color indicates negative regulation, and blue color represents direct or indirect regulation by phosphorylation or allosterism. IR: insulin receptor; IRS: insulin receptor substrate; PI3K: phosphoinositide 3-kinase; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol 3,4,5-triphosphate; PDK: phosphoinositide-dependent kinase; Akt: protein kinase B; PTP-1B: protein tyrosine phosphatase 1B; PC: pyruvate carboxylase; OAA: oxalacetate; PEPCK: phosphoenolpyruvate carboxykinase; PK: pyruvate kinase; FBPase: fructose 1,6-bisphosphatase; PFK: phosphofructokinase; GS: glycogen synthase; GP: glycogen phosphorylase; PP1: protein phosphatase 1; GSK3: glycogen synthase kinase-3; GK: glucokinase; G6Pase: glucose 6-phosphatase; GLUT2: glucose transporter 2.