Featured Research

from universities, journals, and other organizations

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

Date:
July 1, 2011
Source:
University of Michigan
Summary:
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.

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.


Story Source:

The above story is based on materials provided by University of Michigan. Note: Materials may be edited for content and length.


Journal Reference:

  1. Samer Salamekh, Jeffrey R. Brender, Suk-Joon Hyung, Ravi Prakash Reddy Nanga, Subramanian Vivekanandan, Brandon T. Ruotolo, Ayyalusamy Ramamoorthy. A Two-Site Mechanism for the Inhibition of IAPP Amyloidogenesis by Zinc. Journal of Molecular Biology, 2011; 410 (2): 294 DOI: 10.1016/j.jmb.2011.05.015

Cite This Page:

University of Michigan. "Preventing diabetes damage: Zinc's effects on a kinky, two-faced cohort." ScienceDaily. ScienceDaily, 1 July 2011. <www.sciencedaily.com/releases/2011/06/110630171742.htm>.
University of Michigan. (2011, July 1). Preventing diabetes damage: Zinc's effects on a kinky, two-faced cohort. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2011/06/110630171742.htm
University of Michigan. "Preventing diabetes damage: Zinc's effects on a kinky, two-faced cohort." ScienceDaily. www.sciencedaily.com/releases/2011/06/110630171742.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Generics Eat Into Pfizer's Sales

Generics Eat Into Pfizer's Sales

Reuters - Business Video Online (July 29, 2014) Pfizer, the world's largest drug maker, cut full-year revenue forecasts because generics could cut into sales of its anti-arthritis drug, Celebrex. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins