Harnessing phytochemicals to combat diabetes: Insights into molecular pathways and therapeutic advances
Putri Cahaya Situmorang, Cut Fatimah Zuhra, Anisa Lutfia, Khatarina Meldawati Pasaribu, Rini Hardiyanti, Alexander Patera Nugraha
Abstract
Diabetes mellitus (DM) is a multifactorial metabolic disorder characterized by insulin resistance, pancreatic beta-cell dysfunction, oxidative stress, and chronic inflammation. It is influenced by various molecular pathways, including phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), glycolysis, hexosamine, diacylglycerol/protein kinase C (DAG/PKC), polyol, and advanced glycation end-products (AGEs). These pathways regulate glucose metabolism, insulin signaling, lipid homeostasis, and inflammatory responses. Single-target therapies often fail to provide comprehensive treatment, making a multi-pathway approach more effective. Several natural compounds exhibit multi-target effects, such as quercetin and anthocyanin, which enhance the PI3K/Akt pathway and inhibit AGEs formation. Epigallocatechin-3-gallate (EGCG) suppresses the hexosamine and polyol pathways, reducing insulin resistance and vascular complications. Luteolin and myricitrin regulate DAG/PKC signaling, minimizing inflammation and endothelial dysfunction. A multi-pathway strategy using natural compounds offers promising therapeutic potential for effective and sustainable DM management. Phytochemicals derived from plants, including alkaloids, flavonoids, tannins, terpenes, terpenoids, and phenols, are investigated in vitro, in vivo and in silico models for their antidiabetic potential. These compounds modulate key pathways involved in diabetes phatophysiology, such as the polyol, hexosamine, DAG-PKC. AGEs, glycolysis, PI3K/Akt and apoptosis pathways. Through their effects on glucagon secretion activity, phytochemicals contribute to glycemic control, offering therapeutic alternatives to conventional drugs. • The Multi-target phytochemicals modulate multiple pathways to enhance glucose control. • The antihyperglycemic action through the modulation of Glycolysis, DAG, PKC, Polyol, AGEs and PI3K pathway. • Quercetin and EGCG activate PI3K/Akt, inhibit AGEs formation, and reduce oxidative stress. • A multi-pathway approach is more effective than single-target therapy in combating insulin resistance. • Future strategies should optimize phytochemical combinations to enhance therapeutic efficacy