Alan D. Attie, PhD

Professor
Biochemistry
Address: 
543a Biochemistry Addition
433 Babcock Dr
Madison, WI 53706
Telephone: 
(608) 262-1372
Focus Groups: 
Signal Transduction
Education: 
PhD, University of California-San Diego
Research Summary: 
Molecular genetics of type 2 diabetes
Research Detail: 

Genetics of Diabetes, beta-cell biology

Our laboratory studies genetic and biochemical processes underlying metabolic diseases, especially obesity and diabetes.

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

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.

Research

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 ofSorcs1 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.

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.