Tag Archives: Jin-Xiong She

Type 1 diabetes patients have lower blood levels of four proteins that protect against immune attack

Patients with type 1 diabetes have significantly lower blood levels of four proteins that help protect their tissue from attack by their immune system, scientists report.

Conversely, their first-degree relatives, who share some of the high-risk genes but do not have the disease, have high levels of these proteins circulating in their blood, said Dr. Jin-Xiong She, director of the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia at Georgia Regents University.

Healthy individuals without the risky genes also have higher levels of the four proteins, IL8, IL-1Ra, MCP-1 and MIP-1β, according to the study in the Journal of Clinical Endocrinology & Metabolism.

The findings point toward a sort of protein cocktail that could help at-risk children avoid disease development as well as new biomarkers in the blood that could aid disease diagnosis, prognosis and management, said She, Georgia Research Alliance Eminent Scholar in Genomic Medicine and the study’s corresponding author.

The scientists looked at a total of 13 cytokines and chemokines, which are cell signaling molecules involved in regulating the immune response. They first looked at blood samples from 697 children with type 1 diabetes and from 681 individuals without antibodies to insulin-producing cells, a hallmark of this autoimmune disease. They then analyzed the blood of a second and larger set of individuals, which included 1,553 children with type 1 diabetes and 1,493 individuals without any sign of antibodies.

In this largest study of its kind, they consistently found a higher percentage of type 1 diabetes patients had significantly lower levels of the same four proteins.

“Their pancreatic cells are not secreting enough of these proteins,” said Dr. Sharad Purohit, MCG biochemist and the study’s first author. “Normally you are secreting enough of these cytokines so you prevent attack by the immune system.”

Individuals who have three of the known high-risk genes for type 1 diabetes but high serum levels of these four proteins are less likely to have disease, suggesting that these proteins may provide dominant levels of protection against type 1 diabetes even in a genetically high-risk group, Purohit said.

“If the individuals with high-risk genes weren’t making more of the proteins, they likely would have diabetes, said Dr. Ashok Sharma, an MCG bioinformatics expert and study co-first author.

One of the proteins found at low levels in patients, MIP-1β, has been shown in animal models to protect against type 1 diabetes development. A recombinant version of IL-1Ra, already used to combat rheumatoid arthritis, is also under study for both type 1 and 2 diabetes. And, human studies have shown that newly diagnosed patients with type 1 diabetes who go into remission have higher levels of IL-1Ra than those who don’t.

Cytokines and chemokines can promote or inhibit inflammation – cytokines such as MIP-1β can do both – and the proper mix helps keep inflammation in check. As an example, IL-1Ra, a cytokine secreted by several cell types, including immune cells, is a natural antagonist of the inflammation promoting cytokine IL-1β.

“We are providing evidence that clinical trials with any of these four molecules may work, and if we use them in combination, they may work even better,” She said. “One of the major research foci in our group is to identify biomarkers for various diseases, diabetes, cancer and others. We also want to identify new therapeutic strategies or targets through the discovery of biomarkers.”

Type 1 diabetes is an autoimmune disease, which primarily surfaces in childhood, where the immune system attacks the insulin-producing cells of the pancreas, leaving children facing a lifetime of daily insulin therapy to try to keep blood sugar levels under control.

Some of the 13 cytokines and chemokines originally screened for the study were known factors in type 1 diabetes, and the scientists were curious about the role of others.

Research funding was provided by the National Institutes of Health and the Juvenile Diabetes Research Foundation. Endocrine clinics based in Atlanta, including Atlanta Diabetes Associates, Pediatric Endocrine Associates and Southeastern Endocrine and Diabetes, contributed to the study.

TEDDY study yielding new approach to finding high-risk genes for type 1 diabetes

she1web[2]Massive samples emanating from a decade-old, international initiative to determine how genetics and environment cause type 1 diabetes are giving scientists a unique perspective on which molecular and environmental factors really contribute to the disease.

The TEDDY study, following nearly 9,000 at-risk children from birth to age 15, is enabling scientists to parse which genetic mutations correlate with progression or lack of progression to type 1 diabetes, said Dr. Jin-Xiong She, Director of the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia at Georgia Regents University.

She is principal investigator for The Environmental Determinants of Diabetes in the Young consortium in Georgia and Florida. He recently received $10 million in National Institutes of Health funding to continue his studies for another five years. TEDDY also has clinical centers in Colorado, Washington, Finland, Sweden and Germany.

Since 2003, 424,788 newborns have been screened by the centers for two genes believed to put them at high-risk for type 1 diabetes and nearly 9,000 children have been enrolled in TEDDY. The children’s blood is examined regularly for signs of an immune system attack on their insulin-producing cells. The blood also provides a window into the activity of genes as parents keep detailed records of what their children eat, when they exercise, get sick, stressed or vaccinated. Parents bring in water samples from where they live and collect fingernail clippings and stool samples as part of the effort to piece together the genetic and environmental causes of type 1 diabetes. It’s this close scrutiny through the peak ages of disease development that is enabling the unprecedented longitudinal genetic perspective.

“We are looking at the genes, genetic expression, the proteins, and the small molecules called metabolites, which are the products of our metabolism,” said She, Georgia Research Alliance Eminent Scholar in Genomic Medicine, running through the sequence of how genes produce both good and bad results in the body.

“We are using this information to correlate the progression or lack of progression of the disease with different molecular markers and environmental triggers to understand all the factors contributing to the development of type 1 diabetes as well as what factors can provide protection from disease progression,” She said.

They are identifying differences in gene expression between children showing signs of autoimmunity, children with diabetes and those who do not get the disease. “This is a whole new way of doing genetic studies. This is the beauty and the power of the TEDDY study and, ideally, how all diseases should be studied.”

It’s a big departure from traditional genome-wide association studies, which compare genetic variations in people with and without a disease that were used, for example, to identify the screening genes for the TEDDY study. “You are basically looking at the frequency of genes in patients versus controls,” She said of the approach that has been popular for about two decades. At least in type 1 diabetes, it appears the approach doesn’t work very well.

Massive data continually generated by TEDDY is enabling scientists to watch all the pertinent pieces play out: gene expression juxtaposed to environmental exposures and, ultimately to disease or lack thereof.

“We are watching it unfold at all levels. We are finding the real players. This is going to allow us to better predict which children will develop type 1 diabetes and, ultimately, what we can do to prevent or better manage this disease.”

She predicts the new approach will yield dozens of highly relevant genes and possibly more than 100 that have some impact on disease progression. He also predicts it will mean putting aside some of 40 genes considered players today.

The complexity and dynamics of disease development is playing out in Georgia where the scientists are finding progression rates to full-blown disease lag behind other parts of the world. Interestingly, a higher proportion of Georgia children are developing celiac disease, another autoimmune disease affecting intestinal cells that appears to share some risk genes with type 1 diabetes, She said.

Nearly 500 of TEDDY’s 9,000 enrollees, who are now an average age of about 5, have persistent evidence of antibodies to their own insulin-producing islet cells – evidence that their immune system is turning on their cells – and more than 100 of the children already have type 1 diabetes. Researchers estimate that both groups will essentially double in size in the coming years.

Jinfiniti Biosciences LLC, a biotech company led by She and housed in GRU’s Life Sciences Business Development Center, was selected as the genomics laboratory for TEDDY. At this stage of study, TEDDY also has added experts in other areas such as Metabolomics Fiehn Lab at the University of California, Davis.

The notes the ongoing necessity is the commitment of families to TEDDY. A party for Georgia/Florida participants this past summer had 400 attendees. “If the families weren’t excited and committed, they would not stay with this for 15 years.”

Type 1 diabetes is an autoimmune disease in which the body’s immune system attacks the insulin producing cells of the pancreas. Insulin enables the body to use glucose as energy.  Incidence of both type 1 and 2 diabetes, which is typically related to lifestyle, is increasing in young people in the United States, according to the American Diabetes Association.

For more information, visit www.teddystudy.org.

TEDDY study yielding new approach to finding high-risk genes for type 1 diabetes

she1web[2]Massive samples emanating from a decade-old, international initiative to determine how genetics and environment cause type 1 diabetes are giving scientists a unique perspective on which molecular and environmental factors really contribute to the disease.

The TEDDY study, following nearly 9,000 at-risk children from birth to age 15, is enabling scientists to parse which genetic mutations correlate with progression or lack of progression to type 1 diabetes, said Dr. Jin-Xiong She, Director of the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia at Georgia Regents University.

She is principal investigator for The Environmental Determinants of Diabetes in the Young consortium in Georgia and Florida. He recently received $10 million in National Institutes of Health funding to continue his studies for another five years. TEDDY also has clinical centers in Colorado, Washington, Finland, Sweden and Germany.

Since 2003, 424,788 newborns have been screened by the centers for two genes believed to put them at high-risk for type 1 diabetes and nearly 9,000 children have been enrolled in TEDDY. The children’s blood is examined regularly for signs of an immune system attack on their insulin-producing cells. The blood also provides a window into the activity of genes as parents keep detailed records of what their children eat, when they exercise, get sick, stressed or vaccinated. Parents bring in water samples from where they live and collect fingernail clippings and stool samples as part of the effort to piece together the genetic and environmental causes of type 1 diabetes. It’s this close scrutiny through the peak ages of disease development that is enabling the unprecedented longitudinal genetic perspective.

“We are looking at the genes, genetic expression, the proteins, and the small molecules called metabolites, which are the products of our metabolism,” said She, Georgia Research Alliance Eminent Scholar in Genomic Medicine, running through the sequence of how genes produce both good and bad results in the body.

“We are using this information to correlate the progression or lack of progression of the disease with different molecular markers and environmental triggers to understand all the factors contributing to the development of type 1 diabetes as well as what factors can provide protection from disease progression,” She said.

They are identifying differences in gene expression between children showing signs of autoimmunity, children with diabetes and those who do not get the disease. “This is a whole new way of doing genetic studies. This is the beauty and the power of the TEDDY study and, ideally, how all diseases should be studied.”

It’s a big departure from traditional genome-wide association studies, which compare genetic variations in people with and without a disease that were used, for example, to identify the screening genes for the TEDDY study. “You are basically looking at the frequency of genes in patients versus controls,” She said of the approach that has been popular for about two decades. At least in type 1 diabetes, it appears the approach doesn’t work very well.

Massive data continually generated by TEDDY is enabling scientists to watch all the pertinent pieces play out: gene expression juxtaposed to environmental exposures and, ultimately to disease or lack thereof.

“We are watching it unfold at all levels. We are finding the real players. This is going to allow us to better predict which children will develop type 1 diabetes and, ultimately, what we can do to prevent or better manage this disease.”

She predicts the new approach will yield dozens of highly relevant genes and possibly more than 100 that have some impact on disease progression. He also predicts it will mean putting aside some of 40 genes considered players today.

The complexity and dynamics of disease development is playing out in Georgia where the scientists are finding progression rates to full-blown disease lag behind other parts of the world. Interestingly, a higher proportion of Georgia children are developing celiac disease, another autoimmune disease affecting intestinal cells that appears to share some risk genes with type 1 diabetes, She said.

Nearly 500 of TEDDY’s 9,000 enrollees, who are now an average age of about 5, have persistent evidence of antibodies to their own insulin-producing islet cells – evidence that their immune system is turning on their cells – and more than 100 of the children already have type 1 diabetes. Researchers estimate that both groups will essentially double in size in the coming years.

Jinfiniti Biosciences LLC, a biotech company led by She and housed in GRU’s Life Sciences Business Development Center, was selected as the genomics laboratory for TEDDY. At this stage of study, TEDDY also has added experts in other areas such as Metabolomics Fiehn Lab at the University of California, Davis.

The notes the ongoing necessity is the commitment of families to TEDDY. A party for Georgia/Florida participants this past summer had 400 attendees. “If the families weren’t excited and committed, they would not stay with this for 15 years.”

Type 1 diabetes is an autoimmune disease in which the body’s immune system attacks the insulin producing cells of the pancreas. Insulin enables the body to use glucose as energy.  Incidence of both type 1 and 2 diabetes, which is typically related to lifestyle, is increasing in young people in the United States, according to the American Diabetes Association.

For more information, visit www.teddystudy.org.