Mitigation of Insulin Resistance by Natural Products from a New Class of Molecules, Membrane-Active Immunomodulators

Abstract

Insulin resistance (IR), accompanied by an impaired cellular glucose uptake, characterizes diverse pathologies that include, but are not limited to, metabolic disease, prediabetes and type 2 diabetes. Chronic inflammation associated with deranged cellular signaling is thought to contribute to IR. The key molecular players in IR are plasma membrane proteins, including the insulin receptor and glucose transporter 4. Certain natural products, such as lipids, phenols, terpenes, antibiotics and alkaloids have beneficial effects on IR, yet their mode of action remains obscured. We hypothesized that these products belong to a novel class of bioactive molecules that we have named membrane-active immunomodulators (MAIMs). A representative MAIM, the naturally occurring medium chain fatty acid ester diethyl azelate (DEA), has been shown to increase the fluidity of cell plasma membranes with subsequent downstream effects on cellular signaling. DEA has also been shown to improve markers of IR, including blood glucose, insulin and lipid levels, in humans. The literature supports the notion that DEA and other natural MAIMs share similar mechanisms of action in improving IR. These findings shed a new light on the mechanism of IR mitigation using natural products, and may facilitate the discovery of other compounds with similar activities.

Marine-Derived Phosphoeleganin and Its Semisynthetic Derivative Decrease IL6 Levels and Improve Insulin Signaling in Human Hepatocellular Carcinoma Cells

“…Indeed, a key tool in enabling the advancement of knowledge of biological processes and at the same time providing a basis for new drug discovery are small organic molecules, which can be used as “probe molecules” to both understand and treat diseases. In this view, marine NPs, in particular, are now emerging as novel lead structures for identifying and designing potential drugs against IR and its associated complications, such as T2D, obesity, metabolic syndrome, and cardiovascular complications [ 16 , 39 , 40 ]. As reported above, PE acts as an insulin-sensitizing agent on HepG2 cells moving within the cell’s cytoplasm, where it can inhibit PTP1B and enhance the insulin signaling pathway [ 19 ].…”