Genetics of Diabetes, beta-cell biology
Our laboratory studies genetic and biochemical processes underlying metabolic diseases, especially obesity and diabetes.
Electron micrograph of a pancreatic beta-cell showing theabundance of dense core vesicles containing insulin.
Fluorescence micrograph of a pancreatic islet showing insulin-containing beta-cells (red) and glucagon-containing alpha-cells (green)
The obesity and diabetes epidemics
The obesity epidemic is evoking a parallel epidemic in metabolic diseases, including diabetes, cardiovascular disease, hypertension, fatty liver, neurological diseases, and kidney failure. 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 β-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 β-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. We study the mechanisms by which β-cells sense glucose and trigger insulin secretion.
A novel gene responsible for biogenesis of insulin containing vesicles. We have identified a novel gene that is critical for the normal formation of the dense core vesicles that transport insulin to the plasma membrane for regulated exocytosis.
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.
Gene causal networks and diabetes. By combining global gene expression profiling and genetics, we are able to construct causal networks linking specific genes with diabetes phenotypes. One of those genes is the transcription factor NFATc2. We are studying its regulation in relation to β-cell function and diabetes.
Molecular biology of ß-cell proliferation. We have identified several factors involved in stimulating β-cell proliferation. We aim to discover the receptors and the signaling pathways involved in this critically important process.
Our working model for the way in which Tomosyn-2 regulates insulin secretion and is inactivated by glucose