 |
|
Botched production of insulin molecule may lead to diabetes
October 02, 2007ANN 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.
That's 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 don't 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 can't 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 body's 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."
University of Michigan Health System
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 don't 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 can't 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 body's 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."
University of Michigan Health System
Diabetes Current Events and Diabetes News RSSPure insulin-producing cells produced in mouse
Singapore researchers have developed an unlimited number of pure insulin-producing cells from mouse embryonic stem cells (ESCs).
Researcher tricks immune system in diabetic mice
The body's immune system hates strangers. When its security patrol spots a foreign cell, it annihilates it.
Systems biology brings hope of speeding up drug development
Almost every day brings news of an apparent breakthrough against cancer, infectious diseases, or metabolic conditions like diabetes, but these rarely translate into effective therapies or drugs, and even if they do clinical development usually takes well over a decade.
Garlic chemical tablet treats diabetes I and II
A drug based on a chemical found in garlic can treat diabetes types I and II when taken as a tablet, a study in the new Royal Society of Chemistry journal Metallomics says.
Very low birth weight is a risk factor for 1 cause of CKD
Individuals who were underweight at birth are at increased risk of developing a condition called secondary focal segmental glomerulosclerosis, according to a study appearing in the January 2009 issue of the Clinical Journal of the American Society Nephrology (CJASN).
New insight into the controls on a go-to enzyme
Scientists at St. Jude Children's Research Hospital have gained new insights into regulation of one of the body's enzyme workhorses called calpains.
Survival of head and neck cancer patients is greatly affected by coexisting ailments
Current estimates for head and neck cancer survival are largely inaccurate because they widely disregard many of the most common diseases such patients have in addition to their primary cancer, says Jay Piccirillo, M.D., a head and neck specialist at Washington University School of Medicine in St. Louis, the Siteman Cancer Center and Barnes-Jewish Hospital.
JDRF funded research shows promise for prevention, reversal of type 1 diabetes
Researchers at the University of California, San Francisco have reported that two common cancer drugs have been used to block and reverse type 1 diabetes in mice.
New imaging technique tracks cancer-killing cells over prolonged period
Coaxing a patient's own cells to hunt down and tackle infected or diseased cells is a promising therapeutic approach for many disorders.
Vitamin C lowers levels of heart disease biomarker, finds study, adds to debate of health benefits
A new study led by researchers at the University of California, Berkeley, adds to the evidence that vitamin C supplements can lower concentrations of C-reactive protein (CRP), a central biomarker of inflammation that has been shown to be a powerful predictor of heart disease and diabetes.
More Diabetes Current Events and Diabetes News Articles
 | Diabetes For Dummies (For Dummies (Health & Fitness)) by Alan L., MD Rubin Covers the latest glucose meters and insulin treatments The straight facts on treating diabetes successfully and living a full life Want to know how to manage diabetes? Leading diabetes expert Dr. Alan Rubin gives you reassuring, authoritative guidance in putting together a state-of-the-art treatment program. You'll learn about all the advances in monitoring glucose, the latest... |
 | The First Year: Type 2 Diabetes: An Essential Guide for the Newly Diagnosed (First Year, The) by Gretchen Becker After Gretchen Becker was diagnosed with type 2 diabetes in 1996, she educated herself on every aspect of this chronic condition — by reading medical and scientific books and journals, talking with doctors and listening to her own body. In 2001, she marshaled everything she had learned as a "patient-expert" into the first edition of this book, which she has now completely updated and revised.... |
 | Dr. Bernstein's Diabetes Solution: The Complete Guide to Achieving Normal Blood Sugars by Richard K. Bernstein Since its first publication in 1997 Diabetes Solution has become the treatment of choice in the medical field in America. Dr Bernstein's ground-breaking approach to diabetes care enable patients to take control of their disease to live long and healthy lives by regulating their blood sugar without the usual swings. Dr Bernstein is living proof of the success of his method and in this revised and... |
 | The 30-Day Diabetes Miracle: Lifestyle Center of America's Complete Program to Stop Diabetes, Restore Health,and Build Natural Vitality by Franklin House, Stuart Seale, Ian Blake Newman A revolutionary program for combating and reversing diabetes. Over the past ten years, Lifestyle Center of America has emerged as the center in the country that offers a proven-successful program to combat diabetes-and even reverse its adverse effects on the body. Now available in book form for the first time, LCA's program enables individuals to actually get to the root of their problems by... |
 | The Official Pocket Guide to Diabetic Exchanges by American Diabetes Association Every day, every meal, millions and millions of people count on the world-famous "Exchange Lists for Meal Planning to make sure they're choosing the right kinds of foods and portion sizes from the various food groups. Now people with diabetes can take the "Exchange Lists with them to the grocery store or to restaurants with the "Official Pocket Guide to Diabetic Exchanges. Measuring just 3.5" x... |
 | The 4-Ingredient Diabetes Cookbook: Simple, Quick, and Delicious Recipes Using Just 4 Ingredients or Less by Nancy Hughes |
 | Reversing Diabetes: Reduce or Even Eliminate Your Dependence on Insulin or Oral Drugs by Julian Whitaker In a completely revised and updated edition of REVERSING DIABETES, Dr Julian Whitaker offers a comprehensive life-style programme that has helped more than 10,000 diabetic patients. The good news is that many diabetics can control their condition - naturally and effectively - with diet and exercise. Along with helping to reduce or even eliminate dependancy on medication, it can help diabetics... |
 | American Diabetes Association Complete Guide to Diabetes by American Diabetes Association The most complete self-care guide available from the leaders in diabetes informationThe most up-to-date information on:• New Diabetes Drugs and Insulin • Achieving Blood Sugar Control• Preventing Complications • Handling Emergencies • Testing • Using a Meter • Insulin Pumps• Nutrition • Exercise • Sexuality • Pregnancy • Insurance • And Much, Much MoreThe American... |
 | Diabetes & Heart Healthy Meals for Two by American Diabetes Association, American Heart Association Twice as tasty . . . but with half the ingredients! People with diabetes want heart-healthy recipes, since heart disease strikes people with diabetes twice as often as the rest of the population. But they also want recipes that taste great. In Diabetes & Heart Healthy Meals for Two, the two largest health associations in America team up to provide recipes that are simple, flavorful, and... |
 | The All-Natural Diabetes Cookbook by Jackie Newgent The All-Natural Diabetes Cookbook won the 2007 Gourmand Best in the World Award in the category of Best Health and Nutrition Cookbook The only whole food cookbook for people with diabetes—featuring 150 recipes Eating with diabetes means eating healthy. But many cookbooks for people with diabetes substitute artificial sweeteners and processed foods at the expense of great flavor. Now if... |
| © 2008 BrightSurf.com |