Genetic Research in Diabetes

Here is a look at some of the activities and accomplishments related to the genetics of diabetes at the University of Chicago Medical Center.

For more information: Diabetes and Genetics - By the Numbers

NEONATAL DIABETES

Genetic Finding Dramatically Improves Rare Type 1b Diabetes

Medication Replaces Insulin Pump & Injections

Drawing from a genetic discovery made in the United Kingdom, University of Chicago diabetes experts became among the first in the U.S. to use an innovative approach to treat a rare form of neonatal type 1 diabetes. In August 2006, six-year-old Lilly Jaffe put away the insulin pump that had been a lifeline since she was 1 month old. Instead of glucose checks 10 times a day, insulin injections up to five times a day, and constant scrutiny of what she eats, Lilly now takes pills twice a day and checks glucose a few times during the day. "It's like trading a severe case of type 1 diabetes for a mild case of type 2," said Louis Philipson, MD, PhD, Medical Director of the University of Chicago Kovler Diabetes Center and the physician who oversaw Lilly's care.

 

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The novel treatment has been effective for children with a rare form of neonatal diabetes that is caused by a mutation in a single gene ("monogenic"). The majority of cases of type 1 diabetes are associated with autoimmunity and are triggered by the interaction of several genes with the environment. The result is malfunctioning of the immune system and, consequently, destruction of insulin-secreting cells.

In Lilly's case, a sample of her DNA from saliva was tested by University of Chicago geneticist Graeme Bell, PhD, who had been involved in the first such U.S. case two years ago at Loma Linda Hospital in California. Bell, a professor of medicine and human genetics, has spent nearly 20 years researching the genetics of diabetes. Lilly's DNA tested positive for a genetic mutation in Kir6.2, so she was a candidate for treatment with sulfonylurea drugs. This mutation blocks a key molecular "gate" to prevent cells in the pancreas from releasing insulin. The cells are intact, but dormant.

Sulfonylurea drugs have been FDA-approved for years to enhance insulin treatment in people with type 2 diabetes. They also target the genes that are mutated and produce defective insulin secreting cells. For individuals with the Kir6.2 genetic mutation, the work of Prof. Hattersley, Penninsula Medical School, Exeter, U.K. showed that sulfonylurea pills in effect overcome the block so insulin can be released.

Weaning Lilly from the insulin pump required precise monitoring of her blood glucose levels and teamwork from physicians and nurses in the Clinical Research Center at the University of Chicago Medical Center over the course of a week. Lilly's pediatric endocrinologist also remained involved. By the end of the week, Lilly's body had begun producing its own insulin.

Publicity from the success of this case generated many inquiries from families around the U.S. whose children have neonatal diabetes. While this innovative therapy freed Lilly completely from supplementary insulin, it is currently only applicable for individuals with a specific form of monogenic diabetes diagnosed before the age of 6 months - an estimated one-tenth of 1% (1 in 1000) of all people with type 1 diabetes.
 

Team Expands Understanding of Genetic Mutation Related to Neonatal Diabetes

On September 10, 2007, investigators at the University of Chicago Medical Center and Peninsula University (U.K.) published new findings on 10 mutations in the insulin gene in patients with neonatal diabetes. Their findings are based on genetic testing and analysis performed on DNA samples from several hundred children, following publicity from the 2006 case of six-year-old Lilly Jaffe, the fourth patient in the U.S. to be treated with sulfonylurea drugs as an effective alternative to daily insulin injections.

The association of insulin mutations with neonatal diabetes has been confirmed in multiple studies around the world. This is the first time that an insulin gene mutation has been connected to severe diabetes with onset during infancy. The researchers suspect that the mutations alter the way insulin folds during synthesis. Improperly folded proteins may interfere with other cellular processes that eventually destroy the cells responsible for producing insulin.

"This is a novel and potentially treatable cause of diabetes in infants," said study author Louis Philipson, MD, PhD, Medical Director of the University of Chicago Kovler Diabetes Center. "It's exciting because each of these patients has one normal insulin gene as well as one mutated gene. If we could detect the disease early enough and somehow silence the abnormal gene, or just protect insulin-producing cells from the damage caused by misfolding, we might be able to preserve or restore the patient's own insulin production."

Insulin mutations may account for 20% of individuals with neonatal diabetes. These patients usually are diagnosed in the first year of life, and typically have a life-long dependency on insulin injections. In several families, individuals with both early and later onset have been found. The findings offer new hope for potential treatment.

Mutations in known genes can explain 50-60% of cases of neonatal diabetes. Research teams in the United States and Europe are trying to identify a genetic cause of diabetes in the remaining 40-50% of individuals with neonatal diabetes.

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The National Registry for Neonatal Diabetes

Funded by a grant from the Juvenile Diabetes Research Foundation, Dr. Philipson and his colleagues have established the first registry in the United States for neonatal diabetes. The goal of this registry is to help identify new and existing patients with neonatal diabetes; to provide a clearinghouse of information for individuals, their families and doctors about these syndromes; to keep track of patients with these mutations who are being treated with sulfonylureas; and to help identify new genes responsible for diabetes. To register or to find out more follow this link to the Neonatal Diabetes Mellitus Registry website:

http://www.kovlerdiabetescenter.org/registry

OTHER ADVANCES IN GENETIC RESEARCH

First Discovery of Genetic Mutations

The very first clue about the link between genetics and diabetes was discovered at the University of Chicago Medical Center. In 1979, Donald Steiner, MD, the A.N. Pritzker Professor in Biochemistry & Molecular Biology and a member of the Howard Hughes Medical Institute at the University of Chicago, was part of the team that discovered the first mutant insulin, known as "insulin Chicago." Discovery of this mutation was a major turning point that gave researchers important insight into the maturation of the insulin protein in humans. Graeme Bell, PhD's team was involved in showing that a key part of the insulin gene affected risk of type 1 diabetes.
 

Genetic Findings Offer Clues About Diabetes Causes and Potential Cures

Graeme Bell, PhD, and his team have been trailblazers in identifying errant genes related to diabetes, particularly maturity-onset diabetes of the young (MODY) and type 2 diabetes.

  • In 1990, Dr. Bell's team mapped MODY1 to a small region on chromosome 20.
  • In 1992 this team identified the MODY2 gene. This finding demonstrated that mutations of the gene for the enzyme glucokinase caused a different type of this genetic form of diabetes.
  • In 1997, Dr. Bell's lab found that patients from families with MODY3 had one of several different mutations in the gene for the transcripion factor hepatocyte nuclear factor-1alpha. Finding the MODY3 gene led to the rapid discovery of the exact gene for MODY1, a functionally related gene known as HNF-4alpha.
  • Importantly, these findings initiated a new way of looking at diabetes. No longer could diabetes be thought of exclusively as being caused by a defect in glucose metabolism; researchers began to consider that certain forms of diabetes result from a defect in gene expression.

 

Dr. Bell's research opened the door for a new way of looking at diabetes and for the development of more finely tuned ways to diagnose and treat diabetes based on a more complete understanding of the biological processes.

  • In 2000, Bell's team identified a major susceptibility gene for type 2 diabetes in Mexican Americans, a population that has higher-than-average incidence of diabetes. This discovery - the first time that a genome-wide approach successfully led to the identification of a susceptibility gene responsible for a common, genetically complex disorder - revealed an unexpected biochemical pathway leading to diabetes, suggesting novel approaches to prevention, diagnosis and treatment. University of Chicago researcher and head of the Section of Genetic Medicine Nancy J. Cox, PhD, was a partner in this research.

 

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GENETIC TESTING

Testing for mutations in Kir6.2 (KCNJ11), SUR1 (ABCC8) and various MODY genes is available through Athena Diagnostics, the University of Chicago Human Genetics Laboratory, the Exeter Diabetes Genetic Centre in the U.K., as well as other laboratories.

The Human Genetics Laboratory at the University of Chicago Medical Center is a CLIA-approved laboratory. This laboratory can test for the most common mutation in transient neonatal diabetes - uniparental disomy 6 (UPD6); and for mutations in the Kir6.2 (KCNJ11) and insulin genes.

 

GENETIC ANALYSIS

Nancy J. Cox, PhD, chief for the University of Chicago Section of Genetic Medicine, directs a research program focused on developing methods of analysis for identifying genetic variation affecting complex traits. The methods development has been primarily in linkage mapping of complex disorders and most recently in the analytic component to the positional cloning of genes for complex disorders. Although the primary research focus is on the development of methods that can be used for analyses of any complex trait, most of the methodology development has been driven by research conducted on type 2 diabetes. Thus, all of the initial applications for new methods in estimation of linkage likelihoods, accurate calculation of multipoint allele-sharing linkage likelihoods, framework for identifying and characterizing gene x gene interaction, and approaches for discriminating causal variants in positional cloning studies were in studies of type 2 diabetes. In addition to the research on type 2 diabetes, Dr. Cox's research interests include other complex disorders such as type 1 diabetes, asthma, stuttering, and psychiatric disorders.

Dr. Cox has identified many of the most important diabetes genes, in work with Dr. Bell.