Type 2 diabetes is an increasing global epidemic, accelerated by chronic obesity in the aging population. Although 80% of those with type 2 diabetes are obese, most obese individuals are not diabetic. Dr. Alan Attie, Jack Gorski Professor of Biochemistry at University of Wisconsin-Madison (UW Madison), seeks to understand this dichotomy by exploring the genetic factors that affect the diabtes susceptibility of obese individuals. He is applying a novel genetics platform for discovering genes in complex metabolic diseases, integrating exquisite physiological studies with state-of-the art genomics and proteomics, to discover pathways leading to disease.

Typically, type 2 diabetes occurs when beta-cells, which produce insulin in the pancreas, are unable to meet the increased demand for insulin caused by obesity. Non-diabetics are able to effectively adjust their insulin secretion to meet this increased demand, but in diabetic individuals, the beta-cells fall short. Dr. Attie and his team of experienced technicians, postdoctoral fellows, graduate students, and a senior scientist collaborate extensively with statisticians and researchers at UW-Madison and Jackson Laboratory. Their genetic pipeline uses a mouse outbred stock that represents as much genetic diversity as the human population. Essentially all of the gene loci he is finding have counterparts in the human genome.

Current research includes:

• The Genetics Pipeline Screen - Dr. Attie and his team collaborate with researchers from Jackson Laboratory to screen an outbred population of mice derived from eight inbred strains. This novel platform enables them to interrogate the entire genome and identify the gene loci that directly affect the function of pancreatic beta-cells. Dr. Attie and his team have been working on this screen for five years. They have already genetically mapped many new and important gene loci that affect beta cell responses.
• Novel Genes for Insulin Secretion - Genetics studied at the basic science level can have important implications for disease, as it opens a door to new pathways and mechanisms. Using genetics, Dr. Attie and his team identified an important gene involved in insulin secretion. They deleted this gene from mice. Upon becoming obese the modified mice developed type 2 diabetes. This enables Dr. Attie and his team to perform detailed studies characterizing the gene's involvement in secretory granule production during insulin secretion.
• Identification of Master Controllers - Using their genetics pipeline, Dr. Attie and his team closely studied genes that contribute to the development of type 2 diabetes in humans, in order to identify a “master controller” of human genes. They found a gene that acted as a master controller for about 40% of the identified gene loci. Now, Dr. Attie and his team want to understand how that controller—a transcription factor—fundamentally works. They’re performing experiments to discover what the direct targets of that transcription factor are and define its biological function.
• Role of Microbiome in Beta-Cell Function and Insulin Secretion - Dr. Attie and his team are collaborating with an expert in microbiome research to look at the effect of the microbiome on insulin secretion. They found that the microbiome regulates insulin secretion. This is an extremely complex problem to unravel, due to the many organisms in the microbiome. Dr. Attie and his team are aiming to identify which of those organisms and their products are responsible for the effect on insulin secretion. Of the many possible outcomes, a potential result will be the development of a probiotic that supports the health of the insulin-producing cells.