Molecular Biology of Metabolic Disease
The obesity epidemic is evoking a parallel epidemic in metabolic diseases, including diabetes, cardiovascular disease, hypertension, fatty liver, and neurological diseases. Genetic factors contribute to these diseases and obesity acts as a stressor that elicits phenotypes that might otherwise be silent. Our laboratory uses genetics to identify novel causal and responsive genes leading to metabolic diseases.
Diabetes results from an absolute or a relative insulin deficiency. Pancreatic ß-cells sense blood glucose and respond by secreting insulin. Insulin lowers blood glucose by promoting its clearance from the circulation and by inhibiting gluconeogenesis. In type 1 diabetes, there is an absolute insulin deficiency due to autoimmune destruction of the cells that produce insulin, the pancreatic ß-cells. However, in type 2 diabetes, there is an increased requirement for insulin, caused by a dampened response to the hormone, coupled with a failure to meet this increased requirement.
Obesity and diabetes
Most obese people are insulin resistant. But, although >80% of people with type 2 diabetes are obese, most obese people do not develop diabetes. In order to avoid developing diabetes, an insulin resistant person must compensate for insulin resistance by producing more insulin. This can occur through an expansion in ß-cell mass or through increased ß-cell insulin secretion.
Tomosyn-2, a protein involved in insulin exocytosis. We recently identified Tomosyn-2 as a gene involved in type 2 diabetes. It places a brake insulin exocytosis. We are studying the signaling pathway that releases this brake, leading to insulin secretion.
Sorcs1, a protein involved in insulin action. We identified Sorcs1 in a screen for diabetes genes. We have clues to its involvement in several distinct metabolic disorders.
Gene causal networks and diabetes. Using microarray technology, we have identified genes whose expression changes before, during, and after the onset of diabetes. Many of these patterns are highly correlated, indicating coordinate regulation of networks of gene expression. These networks have control points, e.g. signaling molecules or transcription factors. We are identifying these points and testing their function in biological systems.
Molecular biology of ß-cell proliferation. We have identified several factors involved in stimulating ß-cell proliferation. We wish to discover the receptors and the signaling pathways involved in this critically important process.
The genetics of gene expression. Traditional genetics correlates genotype with phenotype in a complex outbred population or in an experimental cross. This identifies areas of the genome controlling the phenotype of interest. We expand our definition of phenotype to include mRNA abundance on the large scale available through microarray technology. By mapping mRNA abundance, we map gene loci controlling the expression of many thousands of mRNA transcripts. These loci are termed expression quantitative trait loci (eQTL). With this approach, we are uncovering gene regulatory networks that are dysregulated in obesity and diabetes.
Micro-RNA regulation of insulin secretion. We have identified two miRNAs that stimulate insulin secretion. We are working to identify the targets of these miRNAs the mechanisms underlying their effect on insulin secretion.