Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes

Jose M Castellano, Angeles Guinda, Teresa Delgado, Mirela Rada, Jose A Cayuela, Jose M Castellano, Angeles Guinda, Teresa Delgado, Mirela Rada, Jose A Cayuela

Abstract

Oleanolic acid (OA), a natural component of many plant food and medicinal herbs, is endowed with a wide range of pharmacological properties whose therapeutic potential has only partly been exploited until now. Throughout complex and multifactorial mechanisms, OA exerts beneficial effects against diabetes and metabolic syndrome. It improves insulin response, preserves functionality and survival of β-cells, and protects against diabetes complications. OA may directly modulate enzymes connected to insulin biosynthesis, secretion, and signaling. However, its major contributions appear to be derived from the interaction with important transduction pathways, and many of its effects are consistently related to activation of the transcription factor Nrf2. Doing that, OA induces the expression of antioxidant enzymes and phase II response genes, blocks NF-κB, and represses the polyol pathway, AGEs production, and hyperlipidemia. The management of type 2 diabetes requires an integrated approach, which includes the early intervention to prevent or delay the disease progression, and the use of therapies to control glycemia and lipidemia in its late stages. In this sense, the use of functional foods or drugs containing OA is, undoubtedly, an interesting path.

Figures

FIG. 1.
FIG. 1.
Chemical structures of OA and related natural triterpenes with antidiabetic effects.
FIG. 2.
FIG. 2.
OA increases insulin biosynthesis and secretion and improves glucose tolerance. It also promotes β-cell survival and proliferation. Actions of OA on pancreatic β-cells involve multitargeted mechanisms. a: Increase of acetylcholine release and activation of M3 muscarinic receptors. b: Enhancement of the glucagon-like peptide-1 (GLP)-1 release by agonist action on the TGR-5 receptors. c: Alleviation of the oxidative stress. d: Stimulation of the Src-homology phosphotyrosyl phosphatase 2 activity and PKB/Akt pathway. e: Improvement of the β-cell survival and proliferation.
FIG. 3.
FIG. 3.
OA and related triterpenoids improve insulin sensitivity in peripheral tissues through a multiple mechanism. f: Stimulation of IR autophosphorylation. g: Inhibition of PTP1B/TCPTP activities. h: Stimulation of the PI3K/AKT pathway. i: Activation of LKB1/AMPK. j: Inhibition of GSK3. k: Stimulation of glycogenesis and inhibition of gluconeogenesis. l: Improvement of the antioxidant defenses. m: Inhibition of the proinflammatory cytokine production. n: Repression of polyol pathway and AGE formation. o: Amelioration of hyperlipidemia. GP, glycogen phosphorylase; GS, glycogen synthase; mtROS, mitochondrial ROS; VAMP, vesicle-associated membrane protein.
FIG. 4.
FIG. 4.
Diabetes is now considered a phenotype of mitochondrial dysfunction. Hyperglycemia and hyperlipidemia provoke overproduction of superoxide and ROS, which contribute to impair insulin signaling, β-cell failure, and other pathologies associated with diabetes.
FIG. 5.
FIG. 5.
A unifying hypothesis of the OA antidiabetic action. OA exerts its activity mainly through indirect mechanisms, stimulating stress-induced pathways in which the transcription factor Nrf2 plays a protagonist role. In this scheme, OA is a potent inducer of antioxidant enzymes and other phase II response genes, as well as a repressor of NF-κB.

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