Abstract
Polyphenolic compounds are thought to show considerable promise for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM). This review addresses evidence from in vitro, in vivo, and clinical studies for the antidiabetic effects of certain polyphenolic compounds. We focus on the role of cytotoxic human amylin (hA) aggregates in the pathogenesis of T2DM, and how polyphenols can ameliorate this process by suppressing or modifying their formation. Small, soluble amylin oligomers elicit cytotoxicity in pancreatic islet β-cells and may thus cause β-cell disruption in T2DM. Amylin oligomers may also contribute to oxidative stress and inflammation that lead to the triggering of β-cell apoptosis. Polyphenols may exert antidiabetic effects via their ability to inhibit hA aggregation, and to modulate oxidative stress, inflammation, and other pathways that are β-cell-protective or insulin-sensitizing. There is evidence that their ability to inhibit and destabilize self-assembly by hA requires aromatic molecular structures that bind to misfolding monomers or oligomers, coupled with adjacent hydroxyl groups present on single phenyl rings. Thus, these multifunctional compounds have the potential to be effective against the pleiotropic mechanisms of T2DM. However, substantial further research will be required before it can be determined whether a polyphenol-based molecular entity can be used as a therapeutic for type 2 diabetes.
Highlights
Type 2 diabetes mellitus (T2DM) is a disorder of blood glucose regulation, characterized by hyperglycemia, insulin resistance, pancreatic amyloid deposition, and β-cell dysfunction (Ashcroft and Rorsman, 2012)
T2DM was considered as predominantly a disease caused by insulin resistance and therapies focused on lowering blood glucose levels
In recent years there has been a paradigm shift, from a glucose-centric to a β-cell-centric view of T2DM (Saisho, 2020). This evolution recognizes that T2DM occurs only when β-cell function has failed
Summary
Type 2 diabetes mellitus (T2DM) is a disorder of blood glucose regulation, characterized by hyperglycemia, insulin resistance, pancreatic amyloid deposition, and β-cell dysfunction (Ashcroft and Rorsman, 2012). Accumulating evidence suggests that the molecular scaffold of polyphenols implicated in the suppression of cytotoxicity (including multiple phenol rings and hydroxyl functional groups) enables their wide range of activities These include their ability to inhibit the aggregation of amyloidogenic peptides, oxidative stress, inflammation, and modulate various signaling pathways. HA oligomers can induce release of pro-inflammatory cytokines These cytokines, such as interleukin (IL)-1β, tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ), impair insulin secretion by RIN-m5F β-cells, trigger ROS production, and cause mitochondrial dysfunction; impairing mitochondrial membrane potential and leading to apoptosis (Zhang et al, 2011). Multiple mechanisms are implicated in hAinduced β-cell dysfunction and activation of apoptosis in vitro, including direct membrane disruption, receptor-mediated apoptosis and induction of cellular stress and inflammation, it remains to be seen if all these play in vivo roles. The ability of various polyphenolic compounds to inhibit hA aggregation in vitro has been investigated extensively and are TABLE 1 | Summary table of in vitro studies of polyphenolic compounds shown to inhibit human amylin (hA) fibril formation in biophysical studies
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