Ph.D., University of California-San Diego, 1980
Postdoctoral Research: University of California-San Deigo, Department of Medicine
Address: 534A Biochemistry Addn
Research InterestsGenetics of type 2 diabetes and related metabolic diseases.
Research FieldsDisease Biology
Computational, Systems & Synthetic Biology
Genomics & Proteomics
Human, mouse & rat
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 two genes underlying
these loci. One of the genes affects insulin action and the other affects
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.
Genetics of hepatic steatosis. Hepatic steatosis (fatty liver) is the pathological accumulation of excess lipid (usually triglyceride) in hepatocytes. We have mapped a locus that affects this trait and identified two novel candidate genes.
Kimple, M.E., Keller, M.P., Rabaglia, M.R., Pasker, R.L., Truchan,
N.A., Neuman, J.C., Brar, H.K., and Attie, A.D. 2013. The prostaglandin
E2 receptor, EP3, is induced in diabetic islets and negatively regulates
glucose- and hormone-stimulated insulin secretion. Diabetes.
Tu, Z., Keller, M.P., Zhang, C., Rabaglia, M.E., Greenawalt, D.M., Yang, X., Wang, I.M., Dai, H., Bruss, M.D., Lum, P.Y., et al. 2012. Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets. PLoS Genet 8:e1003107.
Wang, C.Y., Stapleton, D.S., Schueler, K.L., Rabaglia, M.E., Oler, A.T., Keller, M.P., Kendziorski, C.M., Broman, K.W., Yandell, B.S., Schadt, E.E., et al. 2012. Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis. J Lipid Res 53:1493-1501.
Bhatnagar, S., Oler, A.T., Rabaglia, M.E., Stapleton, D.S., Schueler, K.L., Truchan, N.A., Worzella, S.L., Stoehr, J.P., Clee, S.M., Yandell, B.S., et al. 2011. Positional cloning of a type 2 diabetes quantitative trait locus; tomosyn-2, a negative regulator of insulin secretion. PLoS Genet 7:e1002323.
Raines, S.M., Richards, O.C., Schneider, L.R., Schueler, K.L., Rabaglia, M.E., Oler, A.T., Stapleton, D.S., Genove, G., Dawson, J.A., Betsholtz, C., et al. 2011. Loss of PDGF-B activity increases hepatic vascular permeability and enhances insulin sensitivity. Am J Physiol Endocrinol Metab 301:E517-526.
Lavine, J.A., and Attie, A.D. 2010. Gastrointestinal hormones and the regulation of beta-cell mass. Ann N Y Acad Sci 1212:41-58.
Lane, R.F., Raines, S.M., Steele, J.W., Ehrlich, M.E., Lah, J.A., Small, S.A., Tanzi, R.E., Attie, A.D., and Gandy, S. 2010. Diabetes-associated SorCS1 regulates Alzheimer's amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex. J Neurosci 30:13110-13115.
Babak, T., Garrett-Engele, P., Armour, C.D., Raymond, C.K., Keller, M.P., Chen, R., Rohl, C.A., Johnson, J.M., Attie, A.D., Fraser, H.B., et al. 2010. Genetic validation of whole-transcriptome sequencing for mapping expression affected by cis-regulatory variation. BMC Genomics 11:473.
Davis, D.B., Lavine, J.A., Suhonen, J.I., Krautkramer, K.A., Rabaglia, M.E., Sperger, J.M., Fernandez, L.A., Yandell, B.S., Keller, M.P., Wang, I.M., et al. 2010. FoxM1 is up-regulated by obesity and stimulates beta-cell proliferation. Mol Endocrinol 24:1822-1834.
Lavine, J.A., Raess, P.W., Stapleton, D.S., Rabaglia, M.E., Suhonen, J.I., Schueler, K.L., Koltes, J.E., Dawson, J.A., Yandell, B.S., Samuelson, L.C., et al. 2010. Cholecystokinin is up-regulated in obese mouse islets and expands beta-cell mass by increasing beta-cell survival. Endocrinology 151:3577-3588.
Keller, M.P., and Attie, A.D. 2010. Physiological insights gained from gene expression analysis in obesity and diabetes. Annu Rev Nutr 30:341-364.
Newgard, C.B., and Attie, A.D. 2010. Getting biological about the genetics of diabetes. Nat Med 16:388-391.