Navigation Links
Botched production of insulin molecule may lead to diabetes
Date:10/1/2007

ANN ARBOR, Mich. Picture a pretzel factory production line, with conveyer belts carrying the dough, formed into unbaked pretzels, down to the oven to be cooked.

Now imagine what would happen if pretzel dough started to overflow the mixer and oozed as a blob onto the conveyor, misshapen, and sticking fast to the dough of the other fully formed, unbaked pretzels. The result: a mess. And if that mess could no longer be conveyed into the oven, the backup of messy dough in the system would get worse and worse, and might eventually shut down the whole factory.

Thats essentially what might be happening in a much smaller kind of factory: the cells that make insulin in the body of people with diabetes.

According to new findings by a team from the University of Michigan Medical School, those tiny factories may shut down because of glitches in the production of a molecule called proinsulin the precursor, or dough, out of which insulin is made.

The insulin factories are called beta cells, and they normally churn out large quantities of insulin within the pancreas. This insulin supply can be released into the bloodstream as needed, to help the body turn sugars from food into energy for cells.

But in people with diabetes, the beta cell factories dont keep up with the demand for insulin, and sugar builds up in the blood, wreaking havoc on nerves, blood vessel walls and kidneys. And just like a factory that cant fill a growing number of orders for a hot product, the situation just keeps getting worse and the diabetes progresses.

Scientists have been working to understand why insulin production falters in people with diabetes, and the U-M team has focused on the production and folding of the proinsulin molecule deep within the beta cell. Using a tag that can make proinsulin glow green, they have now found a way to watch proinsulin being made within animal cells, and folded into a shape that can then be turned into insulin. Of course, this also allows them to study what happens when that process goes awry.

In the new paper, published online before print publication in the Proceedings of the National Academy of Sciences, the team details its findings and proposes that proinsulin 'blobs' might lead to beta cell dysfunction and death, which in turn can lead to the start, or progression, of diabetes.

Senior author Peter Arvan, M.D., Ph.D., says, "We believe that in the insulin production factory, misfolded copies of newly-made proinsulin can gum up the works in several ways. This paper shows that one of the first things that can happen is that misfolded proinsulin can stick to other proinsulin in the very first stages of production within the endoplasmic reticulum, the area of the cell where proteins are made.

Arvan, who is chief of Metabolism, Endocrinology and Diabetes at the U-M Medical School and director of the Michigan Comprehensive Diabetes Center, explains that this chain reaction can start with just a few misfolded proinsulin molecules. It can then lead to beta cell shutdown and an insulin shortage. The misfolded proinsulin does not get exported from the factory, and neither does the normally folded proinsulin made after it, he says. Pretty soon, pancreatic beta cells are running out of insulin to secrete in response to the customer's demand for the product that is, an increase in blood glucose. And that is a key hallmark of diabetes.

Arvan, who is the William and Delores Brehm Professor of Type 1 Diabetes Research, and first author Ming Liu, M.D., Ph.D., led the research team in developing the techniques needed to visualize proinsulin production and then study problems with the process by following misfolded molecules through the production pathway.

First, the team engineered the gene for human proinsulin to insert a tag that makes the protein fluorescent, but does not interfere with the production, function or secretion of insulin. They inserted the human gene into rat pancreas cells, which allows them to see the human proinsulin being made in live rat cells under the microscope.

Next, the team introduced a mutation into the tagged human insulin gene that causes the proinsulin molecule to fold incorrectly. This allowed them to see what happened when the misfolded human proinsulin and the normal rat proinsulin were produced together inside the same cell.

What they saw was misfolded fluorescent proinsulin getting stuck in the endoplasmic reticulum, so it could not move along normal conveyor belt to make insulin. Simultaneously, this blocked the traffic of the normal proinsulin in the same cells. This protein mess in the endoplasmic reticulum directly inhibits insulin production in the beta cells, even including insulin production that comes from the otherwise normal rat proinsulin. The beta cells begin to suffer from this, and they ultimately die.

The Arvan lab is also collaborating with other groups to identify new mutations in the proinsulin gene of people with congenital diabetes, and to understand how these mutations may cause a similar protein mess.

These mutations are apparently the second most common genetic cause of congenital diabetes, which is a relatively rare genetic illness. Congenital diabetes differs from Type 1 diabetes because congenital diabetes is not caused by an attack by the immune system on the bodys own beta cells, and because it is passed down from parent to child. Arvan and his team suspect that congenital diabetes in babies mirrors the proinsulin misfolding seen in their new study, and in a strain of mice known as Akita mice, which develop diabetes spontaneously after birth.

The big question -- still to be determined -- is how much of the more common forms of diabetes also involve proinsulin misfolding in beta cells that are stressed to the max to make all the insulin they can, Arvan notes. This is a question that we are actively pursuing.


'/>"/>

Contact: Kara Gavin
kegavin@umich.edu
734-764-2220
University of Michigan Health System
Source:Eurekalert

Related biology news :

1. Researchers discover key gene involved in bark beetle pheromone production
2. First production of human monoclonal antibodies in chicken eggs published in Nature Biotechnology
3. Mass production of human papillomavirus could lead to gains against cervical cancer
4. UW scientists report a new method to speed bird flu vaccine production
5. New cell transplantation technique restores insulin production in diabetics
6. New molecule may aid in production of biofuels and fungi-resistant plants
7. Getting an evolutionary handle on life after reproduction
8. Olfactory system detects pheromones that control reproduction
9. The brain is broadly wired for reproduction
10. Sexual reproduction delays aging in a mammalian species
11. Sustainable farm practices improve Third World food production
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/2/2016)... Technology Enhancements Accelerate Growth of X-ray Imaging ... and computed radiography markets in Thailand ... Indonesia (TIM). It provides an in-depth analysis ... as regional market drivers and restraints. The study offers ... market attractiveness, both for digital and computed radiography. Market ...
(Date:2/1/2016)... Feb. 1, 2016  Today, the first day of ... plans to develop a first of its kind workplace ... IBM Watson. In the first application of ... IBM ), and Welltok will create a new ... with cognitive analytics, delivered on Welltok,s health optimization platform. ...
(Date:1/25/2016)... Unisys Corporation (NYSE: UIS ) today announced the implementation ... New York City , to help U.S. ... the United States using passports that are ... of the system at Dulles last year. The system will ... 2016. --> pilot testing of the system at ...
Breaking Biology News(10 mins):
(Date:2/11/2016)... Inc. (NASDAQ: NBIX ) today announced its financial results for ... --> --> For the fourth quarter of ... $0.34 loss per share, compared to a net loss of $19.4 ... 2014. For the year ended December 31, 2015, the Company reported ... as compared to a net loss of $60.5 million, or $0.81 ...
(Date:2/11/2016)... , Feb. 11, 2016  Wellcentive today announced ... Portland, Oregon -based community care organization ... population health analytics, quality reporting and care management ... strengthen its team of quality managers, analysts and ... the provider groups serving FamilyCare members. ...
(Date:2/11/2016)... ... February 11, 2016 , ... ... 150 years, continues today to pursue the highest level of accuracy and quality ... the AR9 Refractometer and the AR5 Refractometer. Accurate, reliable and tough enough ...
(Date:2/10/2016)... Md. , Feb. 10, 2016  The Maryland ... Busch , has announced that University of Maryland School ... PhD, MBA and University of Maryland Medical System President ... of the "Speaker,s Medallion," the highest honor given to ... of Delegates. Dean Reece and Mr. ...
Breaking Biology Technology: