Faster Amylin Aggregation on Fibrillar Collagen I Hastens Diabetic Progression through β-Cell Death and Loss of Function
Amyloid deposition of the neuroendocrine peptide amylin in islet tissues is a hallmark of type 2 diabetes (T2DM), leading to β-cell toxicity through nutrient deprivation, membrane rupture, and apoptosis. Though accumulation of toxic amylin aggregates in islet matrices is well documented, the role of the islet extracellular matrix in mediating amylin aggregation and its pathological consequences remains elusive. Here, we address this question by probing amylin interaction with collagen I (Col)─whose expression in the islet tissue increases during diabetes progression. By combining multiple biophysical techniques, we show that hydrophobic, hydrophilic, and cation-π interactions regulate amylin binding to Col, with fibrillar Col driving faster amylin aggregation. Amylin-entangled Col matrices containing high amounts of amylin induce death and loss of function in INS1E β-cells. Together, our results illustrate how amylin incorporation in islet matrices through amylin-Col interactions drives T2DM progression by impacting β-cell viability and insulin secretion.
Authors
- Md Asrafuddoza Hazari
- Hamim Zafar (ORCID: https://orcid.org/0000-0002-1617-2806)
- Sai P. Pydi (ORCID: https://orcid.org/0000-0001-7170-6519)
- Sankhadeep Dutta (ORCID: https://orcid.org/0000-0002-8144-4345)
- Akash Kumar Jha (ORCID: https://orcid.org/0000-0002-4580-1480)
- Farhin Sultana (ORCID: https://orcid.org/0000-0002-3285-6407)
- Subrata Dasgupta (ORCID: https://orcid.org/0009-0001-1131-5986)
- Prasenjit Bhaumik (ORCID: https://orcid.org/0000-0003-1257-9809)
- Ashutosh Kumar (ORCID: https://orcid.org/0000-0002-5061-8162)
- Shamik Sen (ORCID: https://orcid.org/0000-0002-8639-8659)
- Sarbajeet Dutta (ORCID: https://orcid.org/0009-0002-6391-9535)
- Musale Krushna Pavan (ORCID: https://orcid.org/0000-0002-7856-8224)
- Soumya Ranjan Pujahari (ORCID: https://orcid.org/0000-0002-0739-1732)
- Simran Singh
- Gautam Kannan
Institutions
- Indian Institute of Technology Bombay (IN)
- Centre for Family Medicine (CA)
- Indian Institute of Technology Kanpur (IN)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1021/jacs.4c15698
- Citations
- 3
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 6.02
Funders
- Department of Biotechnology, Ministry of Science and Technology, India
- Council of Scientific and Industrial Research, India
- University Grants Commission