Amyloid‐induced β‐cell dysfunction and islet inflammation are ameliorated by 4‐phenylbutyrate (PBA) treatment

Abstract

Human islet amyloid polypeptide (hIAPP) aggregation is associated with β-cell dysfunction and death in type 2 diabetes (T2D). we aimed to determine whether treatment with chemical chaperone 4-phenylbutyrate (PBA) ameliorates hIAPP-induced β-cell dysfunction and islet amyloid formation. Oral administration of PBA in hIAPP transgenic (hIAPP Tg) mice expressing hIAPP in pancreatic β cells counteracted impaired glucose homeostasis and restored glucose-stimulated insulin secretion. Moreover, PBA treatment almost completely prevented the transcriptomic alterations observed in hIAPP Tg islets, including the induction of genes related to inflammation. PBA also increased β-cell viability and improved insulin secretion in hIAPP Tg islets cultured under glucolipotoxic conditions. Strikingly, PBA not only prevented but even reversed islet amyloid deposition, pointing to a direct effect of PBA on hIAPP. This was supported by calculations uncovering potential binding sites of PBA to monomeric, dimeric, and pentameric fibrillar structures, and by assays showing inhibition of hIAPP fibril formation by PBA. Collectively, these results uncover a novel beneficial effect of PBA on glucose homeostasis by restoring β-cell function and preventing amyloid formation in mice expressing hIAPP in β cells, highlighting the therapeutic potential of PBA for the treatment of T2D.-Montane, J., de Pablo, S., Castaño, C., Rodríguez-Comas, J., Cadavez, L., Obach, M., Visa, M., Alcarraz-Vizán, G., Sanchez-Martinez, M., Nonell-Canals, A., Parrizas, M., Servitja, J.-M., Novials, A. Amyloid-induced β-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment.

Pre-structured hydrophobic peptide β-strands: A universal amyloid trap?

“…Recently however, a new small molecule has been shown to inhibit hAM amyloidogenesis as well as decrease the toxicity related to hAM aggregation. Montane et al demonstrated that 4-phenylbutyrate (PBA) ( Table 1), a drug that is currently used to treat urea-cycle disorders and cystic fibrosis, is capable of restoring the glucose metabolism of transgenic mice that overexpress hAM [120]. The tests show that PBA is able to restore the function of β-cells and prevent the death of β-cells in transgenic mice.…”

Cationic Carbosilane Dendritic Systems as Promising Anti‐Amyloid Agents in Type 2 Diabetes

“…The covalent combination of both fragments may promote synergisms between the two different therapeutic agents. [14,20] For this purpose, as ystematic strategy has been designed that allowst he functionalization of carbosilane wedges with 4-PBA at the focal point and ammonium groups at the surface, because both have been shown to be interesting anti-amyloid agents. [14] Also, the choice of two dendritic wedges with differentf ocal points, hydroquinone (from dendron II)a nd 4-PBA,t os tudy their anti-amyloid capacity will establish whether there is a synergistic effect between fragments with anti-amyloid activity (4-PBA and the cationic charges on the dendritic surface).…”

“…Quaternization of the amino groups withM eI was confirmed by displacement to lowf ield of signals close to the nitrogen atom in the 1 HNMR spectra corresponding to the neutralp recursors (see Figure 2f or the 1 HNMR spectrum of dendritic wedge 15.). The cationic dendritic wedges ArCO 2 G n (SNMe 3 I) m (n = 1, m = 2( 13); n = 2, m = 4 (14); n = 3, m = 8( 15)) were obtained as yellow water-soluble solids in excellent yields.…”

“…[13] Some studies have demonstrated that PBA treatmenti nm iceo verexpressing the amyloidogenic human IAPP (hIAPP) in pancreatic b cells prevents and reverses pancreatic islet amyloid formation in hIAPP transgenic islets cultured ath igh glucose concentrations. [14] The interaction between nanotechnology and medicine provides an opportunity to carry out new treatments or improve existing ones, to drive the design andu se of such nanoscopic systemsa sd rug delivery or anti-amyloid agentsp er se. [15] In this sense, dendrimerso rd endritic systems, due to their unique properties, such as their monodisperse structure and high multifunctionalizationc apacity,h ave provedt ob ei deal systems.…”

Discovery of N‐(2‐(Benzylamino)‐2‐oxoethyl)benzamide analogs as a novel scaffold of pancreatic β‐cell protective agents against endoplasmic reticulum stress

“…Recent reports of chemical chaperons such as 4-phenyl butyrate (PBA; Engin & Hotamisligil, 2010;Montane et al, 2017) and tauroursodeoxycholic acid (TUDCA; Engin & Hotamisligil, 2010;Engin et al, 2013;Montane et al, 2017;Ramalho, Viana, Low, Steer, & Rodrigues, 2008; see Figure 1) have shown effect on ER stress modulation and antidiabetic activity in T2D animal models. However, because of their low efficacy, large dose is needed for any therapeutic treatment, which makes it unlikely that these agents can be used for the treatment for human patients due to the increased toxicity (Lee et al, 2016;Liu, Lee, Salazar Hernandez, Mazitschek, & Ozcan, 2015).…”