In vitro evaluation of hypoglycemic agents to target human islet amyloid polypeptide: a key protein involved in amyloid deposition and beta-cell loss

Abstract

Objectives: Deposition of islet amyloid has been associated with beta-cell death, thereby furthering diabetes progression. Several hypoglycemic agents, such as thiazolidinediones, biguanide and dipeptidyl peptidase-4 inhibitors, have been known to preserve beta-cell mass, possibly by direct inhibition of islet amyloid formation. The general objective of this study was to evaluate the impact of the major representatives of hypoglycemic agents on amyloid formation by using in vitro molecular screening approaches.

Methods: Ten prototypical representatives of hypoglycemic agents were evaluated for the inhibition of amyloid formation in vitro using thioflavin fluorescence assays, far-ultraviolet circular dichroism, photo-induced cross linking assays and cell viability assays.

Results: Glyburide, repaglinide and troglitazone showed the highest potency in delaying and reducing fibril formation. Troglitazone, a thiazolidinedione, was the most effective agent abrogating amyloid fibril formation. Troglitazone affected the secondary structures of incubated human islet amyloid polypeptide (hIAPP). The circular dichroism spectra showed a delayed transition to the beta sheet conformation. A photo-induced cross-linking-based oligomerization assay demonstrated that repaglinide supressed the formation of hIAPP oligomers, whereas glyburide and troglitazone were ineffective in inhibiting oligomerization. Cell toxicity induced by hIAPP was reduced by all 3 compounds.

Conclusion: This study provides new insights that could potentially identify new therapeutic strategies to impede the progression of pancreatic amyloidosis in human patients with type 2 diabetes.

Keywords: agents antiamyloïdogènes; antiamyloidogenic agents; diabète de type 2; hIAPP; hIAPP (human islet amyloid polypeptide); human islet amyloid polypeptide; polypeptide amyloïde d’îlots pancréatiques humains; repaglinide; répaglinide; troglitazone; type 2 diabetes.