Professor
B.S., University of Wisconsin-Madison;
Ph.D., University of California-San Diego

attie@biochem.wisc.edu
543A Biochemistry Addition, (608) 262-1372

Attie Curriculum Vita

Molecular Genetics of Type 2 Diabetes

The diabetes epidemic. We are in the midst of a worldwide diabetes epidemic. About 171 million people have diabetes and this figure is expected to double in the next 20 years. In the United States, 21 million people (7% of the population) have diabetes and this number is also rapidly growing. Diabetes is the leading cause of blindness, kidney failure, limb amputations, and a major risk factor for premature cardiovascular disease.
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. Virtually everyone who is obese is 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.

Research
Genetics of diabetes. Our laboratory uses mouse genetics to identify genes and pathways involved in obesity-induced type 2 diabetes. We have reproduced the obesity/diabetes dichotomy in mice by studying two strains that when made obese, differ in diabetes susceptibility. Using this model system, we have mapped several diabetes gene loci. We recently identified one of the genes underlying these loci, the SorCS1 gene.
Gene 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.
Genetical metabolomics. Taking eQTL one step further, we are also determining the abundance of small molecule metabolic intermediates in tissues from experimental crosses. Like mRNA abundance, metabolite abundance is a heritable trait and thus amenable to genetic mapping. We have mapped several metabolomic QTL and are studying their relationships with eQTL to build network models for metabolic regulation.

Recent publications
Lan, H. Chen, M., Byers, J.E., Yandell, B.S., Stapelton, D.S., Mata, C.M., Mui, E.T., Flowers, M.T., Scheuler, K.L., Manly, K.F., Williams, R.W., Kendziorski, C.M., Attie, A.D. (2006) Combined expression trait correlations and expression quantative trait locus mapping. PLoS Genetics 2:52-61. 
Clee, S.M., Yandell, B.S., Schueler, K.M., Rabaglia, M.E., Richards, O.C., Raines, S.M., Kabara, E.A., Klass, D.M., Stapleton, D.S., Gray-Keller, M.P., Boronenkov, I., Raess, P.W., Flowers, M.T., and Attie, A.D. (2006) Positional cloning of a type 2 diabetes quanitative trait locus. Nature Genetics 38,688-693. 
Clee, S.M. and Attie, A.D. The genetic landscape of type 2 diabetes in mice. Endocrine Reviews (in press)