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Molecular Genetics of Diabetes Mellitus
Summary: Graeme Bell is interested in identifying the causes of diabetes mellitus.
Diabetes mellitus is a heterogeneous group of metabolic diseases, all of which are characterized by high blood glucose levels. If untreated, diabetes can lead to blindness, kidney and heart disease, stroke, loss of limbs, and reduced life expectancy. Diabetes is a major public health problem, affecting 150 million people worldwide, and it has an enormous personal and economic impact on society, with direct medical and indirect expenditures of about $100 billion attributable to diabetes in the United States alone.
Genetic factors play an important role in the development of diabetes; some forms result from mutations in a single gene, whereas others are multifactorial in origin (i.e., both genetic and nongenetic factors contribute). Our goal is to identify the genes that contribute to the development of diabetes and to determine the molecular and physiological mechanisms by which they control blood glucose levels.
We have taken an approach that combines genetic studies, clinical investigation, and studies in animal models and cultured cells. Our genetic studies of patients with single-gene disorders that result in diabetes have led to the identification of mutations in the genes encoding the glycolytic enzyme glucokinase and the transcription factors hepatocyte nuclear factor (HNF)-1α, HNF-4α, and HNF-1β as causes of diabetes. Mutations in these genes (in the heterozygous state) cause diabetes by impairing insulin secretion and normal pancreatic β-cell function; i.e., they are genetic disorders of the β cell. Mutations in HNF-1β can also result in renal and genital abnormalities.
We have also determined the cause of one form of permanent neonatal diabetes mellitus, a rare condition (1/400,000 live births) in which diabetes is present at birth. We found that this form of diabetes can result from complete deficiency of the glycolytic enzyme glucokinase (i.e., affected infants have mutations in both glucokinase alleles). Thus, mutations in glucokinase can cause two different forms of diabetes. Partial deficiency of glucokinase activity resulting from a mutation in only one allele results in a mild elevation of blood glucose levels, termed impaired fasting glucose, which only progresses to overt diabetes in a small fraction of subjects. Complete deficiency resulting from mutations in both alleles leads to severe life-threatening hyperglycemia requiring insulin treatment.
We are also interested in identifying the genes whose variation increases susceptibility to type 2 diabetes, the most common form of diabetes worldwide, affecting about 2 percent of the world's population, including 16 million people in the United States. Our studies of type 2 diabetes have focused on the Mexican American population of Starr County, Texas. Starr County is the 53rd largest of the 254 counties in Texas and is one of 14 counties sharing a border with Mexico. According to 2000 census figures, Starr County has a population of 53,597. About 2,500 individuals in this community are being treated for diabetes. The combination of high frequency of diabetes, large and stable families, and local cooperation enabled assembly of a primary data resource consisting of members of 252 families. Our genetic studies indicate that type 2 diabetes in this population results from the action of a gene on chromosome 2, designated
NIDDM1
, and other genes including a locus on chromosome 15. We recently showed that
NIDDM1
encodes the cysteine protease calpain-10 and that some variants in the calpain-10 gene are associated with increased risk of type 2 diabetes and others with decreased risk. This unexpected finding identified a novel pathway leading to type 2 diabetes. Clinical studies in nondiabetic subjects suggest that calpain-10 is one of the factors affecting the action of insulin on muscle tissue and the secretion of insulin from the pancreatic β cell. Studies in mice lacking calpain-10 suggest that calpain-10 mediates fatty acid–induced apoptosis in insulin-secreting pancreatic β cells, providing a possible link between diet and the development of type 2 diabetes. The genetic studies of type 2 diabetes are a collaboration with Nancy Cox (University of Chicago) and Craig Hanis and Eric Boerwinkle (University of Texas at Houston). (A grant from the United States Public Health Service provided partial support for these studies.)
Preventing or slowing the epidemic of type 2 diabetes depends on understanding how underlying genetic susceptibility interacts with changing environmental conditions. Our studies are providing a foundation that may lead to new approaches for diagnosing, preventing, and treating diabetes mellitus.
Last updated May 20, 2004
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