Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Preventing diabetes damage: Zinc's effects on a kinky, two-faced cohort

01.07.2011
In type 2 diabetes, a protein called amylin forms dense clumps that shut down insulin-producing cells, wreaking havoc on the control of blood sugar. But zinc has a knack for preventing amylin from misbehaving.

Recent research at the University of Michigan offers new details about how zinc performs this "security guard" function. The findings appear in the July 8 issue of the Journal of Molecular Biology.

Amylin is something of a two-faced character. In healthy people who have normal levels of zinc in the insulin-producing islet cells of the pancreas, amylin actually pitches in to help with blood sugar regulation, says Ayyalusamy Ramamoorthy, a U-M professor of chemistry and of biophysics in the College of Literature, Science, and the Arts. In fact, an analog of amylin called Symlin is used in conjunction with insulin to manage blood sugar levels in diabetics.

This good behavior on amylin's part comes about because zinc acts like a security guard at a rock concert, whose job is keeping fans from turning 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 various other degenerative diseases.

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

The clumping ultimately leads to the formation of ribbon-like structures called fibrils, and because fibril formation has been linked to a number of human diseases, it was long assumed that fibrils themselves were toxic. But accumulating evidence now suggests that the actual culprits may be shorter snippets that assemble in the process of forming full-length fibrils. For this reason, it's important to understand the whole aggregation process, not just the structure of the final fibril.

Ramamoorthy and colleagues are trying to better understand exactly how zinc interacts with amylin, in hopes 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 kinks, which interferes with the formation of toxic clumps. In the current work, 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," Ramamoorthy said.

In addition, the researchers found that before amylin can begin forming fibrils, zinc must be rousted from its nesting place. This eviction is costly in energetic terms, and the sheer expense of it discourages fibril formation. And because a single zinc molecule can bind to several amylin molecules, it ties up the amylin in assemblages that, unlike certain other aggregations, are not intermediates in the pathway that leads to fibril formation.

However zinc, like amylin, has a dual nature. At conditions similar to those outside islet cells, where even a tiny amount of amylin aggregates in the blink of an eye, zinc inhibits fibril formation. But in conditions resembling the inside of the cell, the inhibitory effect begins to wane and other factors, like insulin, take on zinc's security guard duties. Ramamoorthy's group found that 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 paper were all done in an artificial environment, not a living organism where zinc levels constantly fluctuate. In future experiments, Ramamoorthy 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 metal-based therapies for type 2 diabetes, similar to the promising metal-based drugs developed for Alzheimer's and other neurodegenerative diseases, Ramamoorthy said.

Ramamoorthy's coauthors in the paper are undergraduate student Samer Salamekh, postdoctoral fellows Jeffrey Brender and Suk-Joon Hyung, former graduate student Ravi Prakash Reddy Nanga, NMR specialist Subramanian Vivekanandan and assistant professor of chemistry Brandon Ruotolo

The National Institutes of Health provided funding for the research.

Contact: Nancy Ross-Flanigan
Phone: (734) 647-1853

Nancy Ross-Flanigan | EurekAlert!
Further information:
http://www.umich.edu

More articles from Health and Medicine:

nachricht The end of pneumonia? New vaccine offers hope
23.10.2017 | University at Buffalo

nachricht Scientists track ovarian cancers to site of origin: Fallopian tubes
23.10.2017 | Johns Hopkins Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Salmonella as a tumour medication

HZI researchers developed a bacterial strain that can be used in cancer therapy

Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

3rd Symposium on Driving Simulation

23.10.2017 | Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

 
Latest News

Microfluidics probe 'cholesterol' of the oil industry

23.10.2017 | Life Sciences

Gamma rays will reach beyond the limits of light

23.10.2017 | Physics and Astronomy

The end of pneumonia? New vaccine offers hope

23.10.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>