Alan D. Attie, PhD

543a Biochemistry Addition
433 Babcock Dr
Madison, WI 53706
(608) 262-1372
Focus Groups: 
Signal Transduction
PhD, University of California-San Diego
Research Summary: 
Genetics of type 2 diabetes and lipid metabolism
Research Detail: 

Genetics of type 2 diabetes and lipid metabolism

Our laboratory studies genetic and biochemical processes underlying metabolic diseases, especially obesity and diabetes, and disorders in cholesterol and lipoprotein metabolism.

Genetic pipeline.

We use mouse genetics to discover new genes and pathways that lead to metabolic disease. Our main focus has been obesity-induced type 2 diabetes. Obesity increases the demand for insulin (insulin resistance), thus placing a demand on pancreatic b-cells to secrete more insulin. The capacity of b-cells to meet this demand is largely affected by genetic variation. We have identified several genes that affect b-cell replication and insulin secretion.

Newly discovered genes.

We recently completed a screen for genes that affect insulin secretion. We identified 30 genetic regions harboring causal genes. We selected three regions and generated knockout mouse models that validate these genes. The genes encode a protein kinase, a protein phosphatase, and a transcription factor. These genes are the gateway into novel pathways that regulate 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. We are applying our genetic and bioinformatic data to identify key drivers of gene expression

Selected Publications: 
Morgan, A.P., Fu, C.P., Kao, C.Y., Welsh, C.E., Didion, J.P., Yadgary, L., Hyacinth, L., Ferris, M.T., Bell, T.A., Miller, D.R., et al. 2015. The Mouse Universal Genotyping Array: From Substrains to Subspecies. G3 (Bethesda).
Gu, T., Gatti, D.M., Srivastava, A., Snyder, E.M., Raghupathy, N., Simecek, P., Svenson, K.L., Dotu, I., Chuang, J.H., Keller, M.P., et al. 2015. Genetic Architectures of Quantitative Variation in RNA Editing Pathways. Genetics.
Shortreed, M.R., Wenger, C.D., Frey, B.L., Sheynkman, G.M., Scalf, M., Keller, M.P., Attie, A.D., and Smith, L.M. 2015. Global Identification of Protein Post-translational Modifications in a Single-Pass Database Search. J Proteome Res 14:4714-4720.
Attie, A.D. 2015. How do reducing equivalents increase insulin secretion? J Clin Invest 125:3754-3756.
Tian, J., Keller, M.P., Oler, A.T., Rabaglia, M.E., Schueler, K.L., Stapleton, D.S., Broman, A.T., Zhao, W., Kendziorski, C., Yandell, B.S., et al. 2015. Identification of the Bile Acid Transporter Slco1a6 as a Candidate Gene That Broadly Affects Gene Expression in Mouse Pancreatic Islets. Genetics 201:1253-1262.
Savas, J.N., Ribeiro, L.F., Wierda, K.D., Wright, R., DeNardo-Wilke, L.A., Rice, H.C., Chamma, I., Wang, Y.Z., Zemla, R., Lavallee-Adam, M., et al. 2015. The Sorting Receptor SorCS1 Regulates Trafficking of Neurexin and AMPA Receptors.Neuron 87:764-780.
Broman, K.W., Keller, M.P., Broman, A.T., Kendziorski, C., Yandell, B.S., Sen, S., and Attie, A.D. 2015. Identification and Correction of Sample Mix-Ups in Expression Genetic Data: A Case Study. G3 (Bethesda) 5:2177-2186.
Shang, J., Li, J., Keller, M.P., Hohmeier, H.E., Wang, Y., Feng, Y., Zhou, H.H., Shen, X., Rabaglia, M., Soni, M., et al. 2015. Induction of miR-132 and miR-212 Expression by Glucagon-Like Peptide 1 (GLP-1) in Rodent and Human Pancreatic beta-Cells. Mol Endocrinol 29:1243-1253.
Lai L, Leone TC, Keller MP, Martin OJ, Broman AT, Nigro J, Kapoor K, Koves TR, Stevens R, Ilkayeva OR, Vega RB, Attie AD, Muoio DM, Kelly DP. (2014) Energy Metabolic Re-Programming in the Hypertrophied and Early Stage Failing Heart: A Multi-systems Approach. Circ Heart Fail. PMID 25236884.
Munger SC, Raghupathy N, Choi K, Simons AK, Gatti DM, Hinerfeld DA, Svenson KL, Keller MP, Attie AD, Hibbs MA, Graber JH, Chesler EJ, Churchill GA. (2014) RNA-Seq Alignment to Individualized Genomes Improves Transcript Abundance Estimates in Multiparent Populations. Genetics. 198(1):59-73. PMID 25236449.
Johnson LM, Barrick S, Hager MV, McFedries A, Homan EA, Rabaglia ME, Keller MP, Attie AD, Saghatelian A, Bisello A, Gellman SH. (2014) A Potent α/β-Peptide Analogue of GLP-1 with Prolonged Action in Vivo. J Am Chem Soc. 2014 136(37):12848-51. PMID 25191938.
Kebede MA, Oler AT, Gregg T, Balloon AJ, Johnson A, Mitok K, Rabaglia M, Schueler K, Stapleton D, Thorstenson C, Wrighton L, Floyd BJ, Richards O, Raines S, Eliceiri K, Seidah NG, Rhodes C, Keller MP, Coon JL, Audhya A, Attie AD. (2014) SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells. J Clin Invest. 124(10):4240-56. PMID 25157818.
Kebede MA, Attie AD. (2014) Insights into obesity and diabetes at the intersection of mouse and human genetics. Trends Endocrinol Metab. 25(10):493-501. PMID 25034129.
Bhatnagar S, Soni MS, Wrighton LS, Hebert AS, Zhou AS, Paul PK, Gregg T, Rabaglia ME, Keller MP, Coon JJ, Attie AD. (2014) Phosphorylation and Degradation of Tomosyn-2 De-represses Insulin Secretion. J Biol Chem. 289(36):25276-86. PMID 25002582.
Soni MS, Rabaglia ME, Bhatnagar S, Shang J, Ilkayeva O, Mynatt R, Zhou YP, Schadt EE, Thornberry NA, Muoio DM, Keller MP, Attie AD. (2014)Downregulation of Carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion. Diabetes. DB_131677. PMID 24969106.
Raines, S.M., Richards, O.C., Schneider, L.R., Schueler, K.L., Rabaglia, M.E., Oler, A.T., Stapleton, D.S., Genové, G., Dawson, C., and Attie, A.D. (2011) Loss of PDGF-B activity increases hepatic vascular delivery of insulin and enhances insulin sensitivity. Am. J. Physiol. (in press).
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., Beinfeld, M.C., Davis, D.B., Hellerstein, M.K., Keller, M.P., And Attie A.D. (2010) Cholecystokinin is Up-regulated in obese islets and expands β-cell mass by increasing β-cell survival. Endocrinol 151,3577-3588. PMID: 20534724
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., Schadt, E.E., and Attie, A.D. (2010) FoxM1 is up-regulated by obesity and stimulates β-cell proliferation. Mol. Endocrinol. 24,1822-1834 PMID: 20660304
Zhao E, Keller MP, Rabaglia ME, Oler AT, Stapleton DS, Schueler KL, Neto EC, Moon JY, Wang P, Wang IM, Lum PY, Ivanovska I, Cleary M, Greenawalt D, Tsang J, Choi YJ, Kleinhanz R, Shang J, Zhou YP, Howard AD, Zhang BB, Kendziorski C, Thornberry NA, Yandell BS, Schadt EE, Attie AD. (2009) Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice. Mamm. Genome 20,476-485. PMC2879069
Flowers M.T., Choi, M.P., Lan, H., Kendziorski, C., Ntambi, J.M., and Attie, A.D. (2008) Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet. Physiol. Genomics 13,361-372.
Keller, M.P., Choi, Y., Wang, P., Rabaglia, M.E., Oler, A.T., Stapleton, D.S., Argmann, C., Schuler, K.L., Davis, D.B., Edwards, S., Steinberg, H.A., Neto, E.C., Klienhanz, R., Sutner, S., Hellerstein, M., Schadt, E.E., Yandell, B.S., Kendziorksi, C.M., Attie, A.D. (2008) A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility. Genome Res.18,706-716 PMC2336811.
Ferrara, C.T., Wang, P., Stevens, R.D., Neto, E.C., Bain, J.R., Keller, M.P., Wenner, B.R., Ilkayeva, O.R., Kendziorski, C.M., Yandell, B.S., Newgard, C.B., and Attie, A.D. (2008) Genetic networks of liver metabolism revealed by integration of metabolic and transcriptome profiling. PLoS Genetics 4,e1000034 PMC2265422.
Flowers, J.B., Rabaglia, M.E., Schueler, K.L., Flowers, M.T., Lan, H., Keller, M.P., Ntambi, J.M., and Attie, A.D. (2007) Loss of stearoyl-CoA desaturase-1 improves insulin sensitivity in lean mice but worsens diabetes in leptin-deficient obese mice. Diabetes 56,1228-1239.
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. Positional cloning of a type 2 diabetes quanitative trait locus. Nature Genetics 38,688-693.