IIT Bombay Study Finds Collagen May Aggravate Type 2 Diabetes
Type 2 diabetes affects more than 500 million people worldwide, a number expected to grow significantly in the coming decades, posing a major public health crisis. This growing health problem is caused by a mix of lifestyle, genetics, and complex biological mechanisms that drive the disease progression. At the cellular level, the disease is marked by the progressive dysfunction of pancreatic β-cells, which are responsible for producing insulin—a hormone essential for regulating blood sugar levels. In type 2 diabetes, either not enough insulin is produced, or the body’s cells become less responsive to it, resulting in high blood sugar levels.
Along with insulin, another hormone called amylin helps control blood sugar after meals. The same β-cells in the pancreas release both insulin and amylin. In diabetes, when the body tries to release more insulin, it also ends up making more amylin. However, unlike insulin, amylin molecules tend to misfold (form a structure that differs from the one required for normal functioning), especially at high concentrations.
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Misfolded amylin tends to stick together, forming clumps that are toxic to cells. Previous research has shown that these clumps can damage the outer layer of cells, block the movement of nutrients, and even cause cell death. However, it is unclear what factors in the tissues of people with diabetes promote this clumping.
In a recent study published in the Journal of the American Chemical Society, researchers from the Indian Institute of Technology Bombay (IIT Bombay), and collaborators from the Indian Institute of Technology Kanpur (IIT Kanpur), and the Chittaranjan National Cancer Institute (CNCI), Kolkata have identified an important missing link: fibrillar collagen I, a major component of the extracellular matrix. “Every tissue is composed of cells and an acellular component, the extracellular matrix. It is the matrix that holds together all cells and gives shape to organs,” explains Prof. Shamik Sen from the Department of Biosciences and Bioengineering at IIT Bombay, who led and oversaw the project.
In diabetic pancreatic tissue, the protein collagen I, that is found abundantly in connective tissues like skin and bones, becomes more abundant. And now, from the study, it is found to serve as a platform that accelerates amylin aggregation, which damages the insulin-producing β-cells and makes amylin more toxic. This damage reduces the body’s ability to control blood sugar, pushing individuals closer to full-blown diabetes.
To explore how collagen I influences amylin aggregation, the team used a range of biophysical techniques. Led by Prof. Ashutosh Kumar from the Department of Biosciences and Bioengineering, IIT Bombay, the team synthesised the human amylin. They monitored its behaviour in the presence of fibrillar collagen I using suitable tools. They used surface plasmon resonance to see how strongly the proteins stick to each other, atomic force microscopy to look at the adhesion strength between amylin and collagen I, thioflavin T fluorescence to track how quickly the clumps form and NMR spectroscopy to find out which parts of the proteins are interacting.
The experiments showed that amylin binds directly to collagen I fibrils, with aggregation occurring significantly faster in its presence. “It almost seems that the amylin completely physically coats the collagen surface forming stable aggregates that are more difficult for cells to clear. That was a very striking finding for us,” says Prof. Sen. “Rather than aggregating in isolation, amylin appears to use the collagen fibres like train tracks, accelerating its accumulation and increasing toxicity to nearby cells,” adds Prof. Sen. Molecular dynamics computer simulations, performed by Prof. Prasenjit Bhaumik’s group from the Department of Biosciences & Bioengineering at IIT Bombay, supported the finding that fibrillar collagen I accelerates amylin aggregation.
To understand how this interaction plays out in actual biological tissues, Prof. Sen collaborated with Prof. Hamim Zafar and Prof. Sai Prasad Pydi from IIT Kanpur, and Dr. Sankhadeep Dutta from CNCI. They examined the pancreatic tissue from diabetic mice and also analysed single-cell data from human pancreatic tissue. They found that as diabetes progressed, both collagen and amylin levels increased simultaneously, indicating that they were closely linked. At the same time, there is disruption in the structure of the pancreatic islets, which are groups of cells where the insulin-making β-cells live.
To test how amylin and collagen together affect cells, Prof. Sen’s lab conducted experiments using lab-grown insulin-making β-cells. They grew these cells on a gel made of collagen that contained amylin and checked how healthy the cells were. Compared to cells grown on substrates without collagen and amylin, cells grown with amylin and collagen showed increased cell death, higher stress from harmful molecules (oxidative stress), made less insulin, and activated various cell death pathways. These findings highlight the importance of the extracellular matrix environment (like the collagen) in enhancing toxicity.
This study also helps explain why some diabetes treatments, that mainly focus on processes inside the cells may not be very effective in halting disease progression. “Unless we disrupt this interaction between amylin and collagen, we may not be able to fully eliminate the toxic microenvironment in the pancreas,” Prof. Sen adds.
The research team is now working to develop cryo-electron microscopy (cryo-EM) models of how amylin and collagen interact, aiming to guide the development of new drugs. They are also exploring ways to repair the pancreas, such as transplanting islets with support from 3D structures that mimic the natural environment, to restore β-cell function before significant damage occurs.
