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.
Genetic Pipeline. Our projects come from genes we identify in our genetic screens. Our past screens were conducted on F2 populations derived from 2-way crosses of inbred mouse strains. At present, we are conducting a screen of an outbred population derived from an 8-way cross. This population has as much genetic diversity as the entire human population.
Sorcs1 and insulin trafficking. We identified the Sorcs1 gene as causal for a serum insulin phenotype. We knocked out the gene and discovered that deficiency of Sorcs1 in obese mice results in a loss of the insulin containing vesicles in pancreatic β-cells. We are investigating the function of this and related proteins in β-cell lines.
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.
grow magazine article, Spring 2015, about Attie's Diabetes research click here