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Inhibition of Human Amylin Aggregation and Cellular Toxicity by Lipoic Acid and Ascorbic Acid

Sarah Kassem Azzam1, Hyunwoo Jang2, Myung Chul Choi2

  • 1Department of Biomedical Engineering , Khalifa University of Science and Technology , P.O. Box 127788, Abu Dhabi , United Arab Emirates.

Molecular Pharmaceutics
|May 1, 2018
PubMed

Insights

Lipoic acid and ascorbic acid inhibit amylin aggregation, a key factor in type 2 diabetes mellitus (T2DM). These antioxidants protect pancreatic beta cells from toxic amylin aggregates, offering a potential therapeutic strategy for T2DM.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Medicine

Background:

  • Protein aggregation, implicated in over 30 degenerative diseases like Alzheimer's and type 2 diabetes mellitus (T2DM), involves islet amyloid deposits in T2DM.
  • Amylin aggregation is linked to reduced pancreatic beta-cell mass, a critical factor in T2DM pathogenesis.

Purpose of the Study:

  • To investigate the inhibitory effects of lipoic acid and ascorbic acid on amylin aggregation and subsequent beta-cell toxicity.
  • To elucidate the molecular mechanisms underlying the interaction between these inhibitors and amylin.

Main Methods:

  • Amylin aggregation inhibition was quantified using fluorescence assays and transmission electron microscopy (TEM).
  • Cell viability assays (RIN-m5f beta-cells) assessed the protective effects of inhibitors against amylin aggregate toxicity.
  • Molecular docking simulations were employed to analyze the binding interactions between inhibitors and amylin.

Main Results:

  • Lipoic acid and ascorbic acid significantly reduced amylin fibril formation to 42.1% and 42.9% respectively.
  • Both inhibitors demonstrated protective effects on beta-cells, increasing cell viability from 42.8% to 70.3% (lipoic acid) and 63.3% (ascorbic acid).
  • Docking studies revealed hydrophobic interactions between the inhibitors and the amylin amyloidogenic region (Ser20-Ser29).

Conclusions:

  • Lipoic acid and ascorbic acid effectively inhibit amylin aggregation through hydrophobic interactions.
  • These compounds mitigate the cytotoxic effects of amylin aggregates on pancreatic beta-cells in vitro.
  • The findings suggest a potential therapeutic role for lipoic acid and ascorbic acid in managing T2DM by preventing amylin-related beta-cell dysfunction.
Keywords:
amylinamyloid inhibitionascorbic acidlipoic acidtype 2 diabetes

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