Medical College Researchers Seek Genetic Keys to Diabetes

A Medical College of Wisconsin research team is collaborating with colleagues in Finland to study the genetics of Type 1 diabetes as part of an international effort to reveal what causes the disease and controls it when it strikes.

The project is fueled by a $6.25 million grant awarded to the Max McGee National Research Center for Juvenile Diabetes from the Juvenile Diabetes Research Foundation International. The Max McGee Center was co-founded by Children's Hospital of Wisconsin and the Medical College.

"Type 1 diabetes is absolute insulin deficiency," said Soumitra Ghosh, PhD, Medical College Associate Professor of Pediatrics and Max McGee Center director. "The body is not producing insulin, and in most cases it is the immune response that destroys the very cells in the pancreas that produce insulin - the beta cells. It can affect anyone, up to seventy and eighty years of age. There are more people who get it after the age of fifteen than before the age of fifteen."

The term "juvenile diabetes" has become a misnomer, Dr. Ghosh explained, as diabetes is now generally defined within two major variations, Type 1 and Type 2. Children can have either type. Although Type 1 is often diagnosed in children and young adults, its onset is sometimes delayed until later years.

According to the American Diabetes Association:
Type 1 Diabetes results from the body's failure to produce insulin, the hormone that "unlocks" the cells of the body, allowing glucose to enter and fuel them. It is estimated that 5% to 10% of Americans who are diagnosed with diabetes have Type 1.
Type 2 Diabetes results from insulin resistance (a condition in which the body fails to properly use insulin), combined with relative insulin deficiency. Approximately 90% to 95% of Americans (about 17 million) who are diagnosed with diabetes have Type 2.

Among other things, the research grant enabled the purchase of state-of-the-art equipment and the hiring of Project Director Victoria Magnuson, PhD, Medical College Assistant Professor of Pediatrics. Dr. Magnuson has overseen the building of an infrastructure to look at a large number of DNA samples that are being sent from Finland, the country with the highest incidence of Type 1 diabetes in the world.

Lab Work Tackles Many Samples
"There's a lot of laboratory infrastructure that you need to actually handle blood or DNA," said Dr. Magnuson. "First of all, you've got to come up with the protocols that you want to use and then you need to buy the equipment and train people on it. There have been a lot of technological changes in this field.

"We started with a lot of local samples, because we didn't have the samples from Finland yet, to work out the protocols and start the training. Now we're set up for what's called 'micro-satellite genotyping' and also 'snip' genotyping, which is single-nucleotide polymorphism genotyping."

'Single base' genetic mutations can actually be the cause of disease, Dr. Magnuson said, but there are a lot of polymorphic (different type) single base differences between people that are meaningless in terms of predisposition to diabetes but useful in research.

In simpler terms, the research team is producing a complex set of genetic maps for comparison and analysis. "We can use the 'meaningless' information because the differences occur fairly often along the DNA, so they're very useful for mapping and it also helps to study them because they could be one of the mutations you're looking for," Dr. Magnuson explains.

Samples now being received are DNA that has already been processed from blood, Dr. Magnuson said, but in the near future new equipment at the Medical College will allow researchers to process DNA from blood "in-house" for this and other projects. The machine can isolate DNA from 96 ten-milliliter blood samples in eight hours.

The study will last five years and use more than 13,000 Finnish samples including non-disease controls and samples from Finnish families affected by diabetes.

Mathematical Modeling and Gene Expression
"One of our colleagues, Dr. Wang, is writing a mathematical model to look at the differences between young and adult onset," said Dr. Ghosh. "The unique feature of this study is that we're looking at older onset Type 1 diabetics and what delays the disease. Through the mathematical modeling and some of the work that Dr. Magnuson is doing in terms of looking at the expression of the major genes and the things that control the expression of these genes, we think that along with prior evidence in this area that genes in this region are important in determining whether someone gets early onset or later onset.

"There's no grand hypothesis out there, and we're trying to build a new hypothesis that will target specific genes that we will go for immediately. I think we stand a very good chance of getting something that is very interesting, because we can use this and other capabilities to go into a specific pathway and try and understand the whole process of why diabetes is delayed in some people and early in some others."

While such projects are commonly described as trying to "find the one gene" that causes a disease, Drs. Magnuson and Ghosh agreed that when it comes to diabetes its not just about one gene. "It's complex, so there's going to be multiple genes," said Dr. Magnuson.

"I don't want to join the school that says it's all genes, because it's clearly not all genes," said Dr. Ghosh. "This study is part of the interface between immunology and genetics. It is a wonderful collaboration of colleagues, some of the best in the world."

A Better Overall Picture
Dr. Ghosh stressed what he called the "terrible morbidity and mortality" associated with diabetes. In addition to the day-to-day dietary and other lifestyle inhibitions it places on persons who must regularly inject insulin normally produced by the body, he noted that diabetes is the most common cause of blindness and the number one cause of amputations other than war.

The size of the sample and completeness of information related to it will have great value in putting together a better overall picture of diabetes and diabetics, Dr. Magnuson said.

"The same set of subjects is going to have a lot of epidemiological information collected, and they're also going to be collecting Type 1s and Type 2s at the same time, said Dr. Magnuson. "There's going to be a wealth of epidemiological and statistical comparisons that we'll have. By the time we have the genetics done, we'll be able to parse our population according to what else is known about them and their families.

"The more information you have, and the more you can 'sub-phenotype' - you're more likely to be collecting people who, when you analyze them together, have the same genetic problem. What you don't want to do is mix people who have too many different genes because it just confounds everything."

"What the team will do is really 'fingerprint' individuals," said Dr. Ghosh, "so that you divide up diabetics into three or four or maybe ten different types. Those types, depending in the environmental factors because it's not just the genes, may have a different form of disease. And then you tailor your gene therapy and immuno-modulation accordingly, so it's not just going to be one therapy for all."

Dan Ullrich
HealthLink Contributing Writer

This article includes information from the American Diabetes Association and the Juvenile Diabetes Research Foundation.

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.