Potential Roles of Stevia rebaudiana Bertoni in Abrogating Insulin Resistance and Diabetes: A Review

Abstract

Insulin resistance is a key factor in metabolic disorders like hyperglycemia and hyperinsulinemia, which are promoted by obesity and may later lead to Type II diabetes mellitus. In recent years, researchers have identified links between insulin resistance and many noncommunicable illnesses other than diabetes. Hence, studying insulin resistance is of particular importance in unravelling the pathways employed by such diseases. In this review, mechanisms involving free fatty acids, adipocytokines such as TNF α and PPAR γ and serine kinases like JNK and IKK β , asserted to be responsible in the development of insulin resistance, will be discussed. Suggested mechanisms for actions in normal and disrupted states were also visualised in several manually constructed diagrams to capture an overall view of the insulin-signalling pathway and its related components. The underlying constituents of medicinal significance found in the Stevia rebaudiana Bertoni plant (among other plants that potentiate antihyperglycemic activities) were explored in further depth. Understanding these factors and their mechanisms may be essential for comprehending the progression of insulin resistance towards the development of diabetes mellitus.

Figure 1

Manually derived and structured mechanisms of the insulin-signalling pathway in a normal state triggered by high glucose levels in the blood, prompting insulin binding and cascades of phosphorylation by ATP bindings, finally leading to the migration of GLUT4 from the cytoplasm to the cell membrane for extracellular glucose uptake. IR: insulin receptor; Y: tyrosine; S: serine; ATP: adenosine triphosphate; ADP: adenosine diphosphate; IRS1: insulin receptor substrate 1; PI3K: phosphoinositide kinase 3; PIP₂: phosphatidylinositol 4,5-bisphosphate; PIP₃: phosphatidylinositol 3,4,5-trisphosphate; PDK: PIP₃-dependent kinase; PKB/Akt: protein kinase B; GLUT4: glucose transporter 4.

Figure 2

The disruptions in the insulin-signalling pathway in an insulin-resistant state caused by elevated actions of TNF-α and FFA. IRS1 is no longer phosphorylated on its tyrosine residues but on serine residues, resulting in nonfunctional, inhibitory proteins. TNF-α also influences increased gene expressions of TNF-α but decreases PPARγ and GLUT4 expressions, resulting in lower levels of GLUT4 proteins. Glucose uptake is reduced, leading to hyperglycemia and hyperinsulinemia. IR: insulin receptor; Y: tyrosine; S: serine; ATP: adenosine triphosphate; ADP: adenosine diphosphate; IRS1: insulin receptor substrate 1; PI3K: phosphoinositide kinase 3; PIP₂: phosphatidylinositol 4,5-bisphosphate; TNF-α: tumour necrosis factor α; FFA: free fatty acid; IKK: a type of serine kinase; ROS: reactive oxygen species; PPARγ: peroxisome proliferator activator-receptor γ; GLUT4: glucose transporter 4.

Figure 3

Manually constructed flowchart summarising the factors leading to insulin resistance that will eventually result in many related diseases.