Zinc safety net missing in diabetes

U. MICHIGAN (US) — A protein that normally pitches in to help with blood sugar regulation shows its dark side in people with type 2 diabetes, forming dense clumps that shut down insulin-producing cells.

New research, published in the Journal of the American Chemical Society, finds the difference is in the company the protein, called amylin, keeps. In the presence of zinc, amylin is mild-mannered; without zinc, it runs amok.

“We found that one of the likely factors stopping amylin from attacking the insulin-producing islet cells of the pancreas is zinc, which normally is found in high amounts in these cells, but is deficient in people with type 2 diabetes,” says Ayyalusamy Ramamoorthy, professor of chemistry and of biophysics at the University of Michigan.

“By understanding what stops amylin from attacking islet cells in normal people, we hope we’ll be able to understand how it is attacking them in people with diabetes.”

In healthy cells, 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 various other degenerative diseases.

But in the zinc-starved cellular environment of someone with type 2 diabetes, amylin has no watchful guard to rein it in. It’s free to band together other amylin molecules in the molecular equivalent of a gang.

Ramamoorthy and colleagues investigated zinc’s role in amylin aggregation using several methods, including nuclear magnetic resonance (NMR) spectroscopy.

“We wanted to see how zinc was affecting the structure of amylin,” says Ramamoorthy, “and NMR is the technique we use to do this.”

Images of amylin with and without zinc present showed that zinc binds to a particular side chain, disrupting the structure of amylin in the process. Other experiments showed that—at zinc concentrations typical of those found in the environment in which aggregation occurs—the binding significantly slows aggregation.

Ramamoorthy’s laboratory is now examining interactions between zinc and insulin and between insulin and amylin. “Ultimately, we want to understand how the whole scenario leads to type 2 diabetes,” he says.

The research was funded by the National Institutes of Health and the Michigan Diabetes Research Training Center.

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