Zinc's Beneficial Functions Help Prevent Diabetes Damage
Recent research at the University of Michigan (UM) provides new details about how zinc performs this protective "security guard" function. The findings appear in the July 8th issue of the Journal of Molecular Biology.
Amylin acts in two ways. In healthy people who have normal levels of zinc in the insulin-producing islet cells is allow cells of the pancreas, amylin contributes to help with blood sugar regulation, explains biophysics researchers from the College of Literature, Science, and the Arts (UM). An analog of amylin called Symlin is used in conjunction with insulin to manage blood sugar levels in diabetics.
Amylin's protective function results because zinc acts like a security guard, preventing it from becoming troublesome and destructive. In molecular terms, zinc prevents amylin, also known as Islet Amyloid Polypeptide (IAPP) from forming harmful clumps similar to those found in Alzheimer's, Parkinson's, Huntington's and other degenerative diseases.
But in a zinc-starved cellular environment of an person with type 2 diabetes, amylin has no watchful guard to bring it in. It's free to clump together with other amylin molecules in the molecular equivalent of a destructive gang.
The clumping ultimately leads to the formation of ribbon-like structures called fibrils; Fibril formation has been linked to a number of human diseases and it was long assumed that fibrils themselves were toxic. However, accumulating evidence now suggests that the actual culprits may be shorter snippets that assemble in the process of forming full-length fibrils. For this key reason, it's important to understand the entire aggregation
process, not just the structure of the final fibril.
The research team is now trying to understand exactly how zinc interacts with amylin with the objective of finding ways of treating or preventing type 2 diabetes and other diseases associated with aging. In earlier work, they showed that when zinc binds to amylin, at a point near the middle of the amylin molecule, the amylin molecule locks up, which blocks the formation of toxic clumps.
In their current research, they show that the binding of zinc in the middle makes one end of the amylin molecule, called the N-terminus, become more orderly. "This is significant, because the N-terminus is very important in clump formation and amylin toxicity," they explained.
The researchers also found that before amylin can begin forming fibrils, zinc must be moved from its nesting position. This eviction is costly in energetic terms, and the energy expenditure discourages fibril formation. A single zinc molecule can bind to several amylin molecules, so it ties up the amylin in assemblages that are not intermediates in the pathway that leads to fibril formation.
It's important to understand that zinc, like amylin, has a dual nature. At conditions similar to those outside islet cells, where even a tiny amount of amylin aggregates almost immediately, zinc inhibits fibril formation. But in conditions resembling the inside of the cell, the inhibitory effect begins to diminish and other factors, like insulin, take on zinc's security guard duties. The researches discovered this happens because amylin has not one, but two binding sites for zinc. Zinc prefers to bind at the first site (the one in the middle of the amylin molecule) where its binding discourages fibril formation. But when there's too much zinc around, all the binding sites in the middle positions are occupied and zinc must attach to amylin at the second site, which counteracts the effect of the first site. This may explain why decreased levels of insulin, the backup security guard, inside islet cells of diabetics result in islet cell death.
The experiments described in the Journal of Molecular Biology report were all done in a controlled laboratory environment, not a living organism where zinc levels constantly fluctuate. In future experiments, the team hopes to more closely approximate natural conditions in order to better understand how amylin
interacts with islet cells and what triggers its toxicity toward the cells. The results of these studies will facilitate the development of therapies for type 2 diabetes, similar to the promising metal-based drugs developed for Alzheimer's and other neuro-degenerative diseases.
The National Institutes of Health provided funding for the research.
Story Source: University of Michigan.
Journal Reference: Journal of Molecular Biology, 2011
This article is for informational and educational purposes only, and is not intended to provide medical advice, diagnosis or treatment. Consult with your doctor or healthcare professional for medical and nutrition advice.
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