College of Pharmacy and Health Sciences

Anjaneyulu Kowluru PhD

Professor, Pharmaceutical Sciences; Senior Research Career Scientist, John D. Dingell VA Medical Center
313 577-5490
313-576-4478
akowluru@med.wayne.edu
3146 Eugene Applebaum College of Pharmacy

Studies the way in which sugar promotes the release of insulin from normal beta cells as well as the identification of mechanisms responsible for the development of type 1 and type 2 diabetes.

Andhra University, India B.SC 1972 Biochemistry
Allahabad University, India M.Sc 1974 Biochemistry
Indian Institute of Technology, Delhi, India Ph.D 1978 Biochemistry
Lab. Exp. Med. Brussels Free University, Belgium [Prof. Willy Malaisse; Mentor] Post-Doc 79-81 Islet Biology
University of Wisconsin, Madison
[Prof. Michael MacDonald; Mentor] JDF-Fellow 81-84 Islet Biology

A. Positions:

07/84 - 08/91: Staff Member, Division of Life Sciences, Los Alamos National Laboratory, Los Alamos

09/91 - 08/98: Senior Scientist, Department of Medicine, University of Wisconsin-Madison

09/91- 08/98: Health Science Specialist, VA Medical Center-Madison

09/98 --- Associate Professor, Department of Pharmaceutical Sciences, Center for Molecular Medicine and Genetics, and Comprehensive Diabetes Center-Wayne State University,

09/98 --- Research Scientist, VA Medical Center-Detroit

03/00 --- Affiliate Professor, Institute of Gerontology, Wayne State University-Detroit

06/01-07/01: Visiting Professor [Burroughs Wellcome Trust], University of Keele, Staffordshire, UK

06/01-09/06: Research Career Scientist-VA Medical Center-Detroit

04/01-03/05: Coordinator, Diabetes Research Training Program, VA Medical Center, Detroit

05/02---- Member, Transplant Program, Department of Surgery, Wayne State University-Detroit

05/02---- Full Professor with tenure, Department of Pharmaceutical Sciences, Wayne State University-Detroit

03/03 Visiting Professor, National University of Singapore, Singapore

04/04--- Director of Program for Research, Pharmaceutical Sciences, Wayne State University.

10/06--- VA Senior Research Career Scientist

08/07--- Adjunct Professor of Internal Medicine, Division of Endocrinology, Wayne State University Medical School

Honors and Memberships: Fellow of the Council of Scientific and Industrial Research-India (1974-1978); Fellow of the Belgian Institute for Research in Scientific Industry and Agriculture (1979-1981); Fellow of the Juvenile Diabetes Foundation (1982-1984); Certificate of Exceptional Performance-Los Alamos National Laboratory [1988]; Certificates of Exceptional Performance VA Medical Center-Madison [1993-97]; Ph.D Study Commission-Wayne State University-Detroit [1998-1999]; Member- VA Medical Center R & D Committee [1993- ]; Board of Governors Charles H. Gershenson Distinguished Faculty Fellowship [2004]; and Elected member-WSU Academy of Scholars [2006].

Membership in Grant Review Panels: American Diabetes Association-National Affiliate [1999-2002]; Grant Review Panel, Endocrinology Subcommittee - Department of VA [2000-2003]; ad hoc Reviewer- Department of VA Career Development Grants; Special Emphasis Grant Review Panel-SSS-T, Nutrition and Metabolic Sciences IRG, NIH/NIDDK [1999--2001]; NIH/NIDDK Review Panel-Innovative Partnerships in type 1 Diabetes [2004]; Burroughs Wellcome Trust [current]. Grant Review Panel, Endocrinology Subcommittee - Department of VA [2005-]; Diabetes UK [2003-2005]; Review Panel, Innovative Grant Applications, Juvenile Diabetes Research Foundation [2005-2006]. Reviewer [ad hoc] for CADO-NIH/NIDDK [2007], and the National Science Foundation [2007].

Member-Editorial Boards: Member-Editorial Board-Endocrinology [2000-2004] ; Member-Editorial Board, American Journal of Physiology: Endocrinology and Metabolism [2000-current]; Member-Editorial Boad, Biochemical Pharmacology. Manuscript reviewer for over 30 biochemical and biomedical journals.

Select peer-reviewed publications [out of 115 peer-reviewed publications, reviews and book chapters, and 140 presentations in various national and international meetings]

Metz SA, Meredith M, Rabaglia ME, Kowluru A: Small elevations of glucose redirect and amplify the synthesis

of GTP involved in exocytotic insulin secretion. J. Clin. Invest. 92: 872-882,1993

Kowluru A, Metz SA: Stimulation by PGE2 of a high affinity GTPase in the secretory granules of normal rat and human pancreatic islets. Biochem J 297: 399-406, 1994.

Kowluru A, Metz SA: Characterization of nucleoside diphosphokinase activity in human and rodent pancreatic b cells: evidence for its role in the formation of guanosine triphosphate, a permissive factor for nutrient-induced insulin secretion. Biochemistry. 33: 12495-12503, 1994.

Kowluru A, Seavey SE, Rabaglia, ME, Metz SA: Non-specific stimulatory effects of mastoparan on pancreatic islet nucleoside diphosphokinase activity: dissociation from insulin secretion. Biochem. Pharmacol. 49: 263-266, 1995

Kowluru A, Metz SA: Subcellular distribution and post-translational modifications of GTP-binding proteins in insulin-secreting cells. Methods Neurosci. 29: 298-317, 1996.

Kowluru A, Seavey SE, Sorenson RL, Weinhaus AJ, Nesher R, Li G, Rabaglia ME, Vadakekalam J, Metz SA: GTP-dependent stimulation of the membrane association and the carboxyl methylation of Cdc42 in rodent and human pancreatic islets and pure b cells: evidence for an essential role in nutrient-induced insulin secretion. J. Clin. Invest. 98: 540-555, 1996

Kowluru A, Seavey SE, Rhodes CJ, Metz SA: A novel regulatory mechanism for trimeric GTP-binding proteins in the membrane and secretory granule fractions of human and rodent b cells. Biochem. J 313: 97-107, 1996.

Kowluru A, Seavey, SE, Rabaglia ME, Nesher R, Metz SA: carboxyl methylation of the catalytic subunit of protein phosphatase 2A in insulin-secreting cells. Endocrinology 137: 2315-2323, 1996.

Kowluru A, Li G, Metz SA: Glucose activates the carboxyl methylation of gamma subunits of trimeric GTP-binding proteins in pncreatic b cells. J. Clin. Invest. 100: 1596-1610, 1997

Kowluru A, Li G, Rabaglia ME, Segu VB, Hofmann F, Aktories K, Metz SA: evidence for differential roles of the Rho subfamily GTP-binding proteins in glucose-and calcium-induced insulin secretion from pancreatic b cells. Biochem. Pharmacol. 54: 1097-1108, 1997.

Kowluru A, Metz SA: Ceramide-activated protein phosphatase 2A activity in insulin-secreting cells. FEBS Lett. 418: 179-182, 1997

Li G, Rabaglia ME, Kowluru A, Metz SA: Prolonged depletion of GTP induces death of insulin-secreting cells by apoptosis. Endocrinology 139: 3752-3762,1998

Metz SA, Kowluru A: Inosine monophosphate dehydrogenase: A molecular switch integrating pleotropic GTP-dependent beta cell functions. Proc. Assoc. Amer. Physicians. 111: 335-346, 1999.

Metz, SA, Meredith M, Vadakekalam J, Rabaglia M, Kowluru A: An intrinsic defect in stimulus-secretion coupling impairs insulin secretion in GK rats. Diabetes 48:1754-1762, 1999.

Kowluru A: Evidence for the carboxyl methylation of nuclear lamin-B in the pancreatic b cell. Biochem. Biophys. Res. Commun 268: 249-254, 2000.

A Kowluru, RP Robertson and SA Metz. GTP-binding proteins in regulation of pancreatic β cell function. In Diabetes Mellitus; A Fundamental and Clinical Text. D LeRoith, JM Olefsky, and S Taylor (eds) JB Lippincott Company, Philadelphia, USA, pp 78-94, 2000

Kowluru A: Adenine and guanine nucleotide-specific succinyl-CoA synthetases in the pancreatic b cell mitochondria. Implications in b cell high-energy phosphate metabolism in relation to insulin secretion. Diabetologia. 44:89-94, 2001

M. Tannous, R.A. Amin, C. Fiorentini, M. Popoff, and A. Kowluru: Positive modulation by Ras of interleukin 1β-mediated nitric oxide generation in insulin

secreting clonal β [HIT-T15] cells. Biochem. Pharmacol. 62:1459-1468, 2001

A. Kowluru, H-Q. Chen, L.M. Modrick, and C. Stefanelli: Activation of acetyl-CoA carboxylase by a glutamate-and magnesium-sensitive protein phosphatase in the islet β cell. Diabetes 50: 1580-1587, 2001

A. Kowluru: Identification and characterization of a novel protein histidine kinase in the islet β cell: Evidence for its regulation by mastoparan, an activator of G-proteins and insulin secretion. Biochem. Pharmacol 63:2091-100, 2002.

A. Kowluru and NG Morgan: GTP-binding proteins in cell survival and demise: The emerging picture in the pancreatic β cell. Biochem. Pharmacol 63:1027-35, 2002.

A. Kowluru, M. Tannous and HQ Chen. Localization and characterization of the mitochondrial isoform of the nucleoside diphosphate kinase in the pancreatic β cell: Evidence for its complexation with mitochondrial succinyl-CoA synthetase. Arch. Biochem. Biophys 398:160-9, 2002.

Veluthakal R, Khan I, Tannous M, Kowluru A: Functional inactivation by interleukin-1beta of glyceraldehyde-3-phosphate dehydrogenase in insulin-secreting cells. Apoptosis 7:241-6, 2002.

Kowluru A and Amin R: Inhibitors of post-translational modifications of G-proteins as probes to study the pancreatic b cell function. Current Drug Targets-Immune, Endocrine & Metabolic Disorders, 2:129-139, 2002.

Amin R, Chen H-Q, Tannous M, Gibbs R, Kowluru A: Inhibition of glucose-and calcium-induced insulin secretion from bTC3 cells by novel inhibitors of protein prenylation. J. Pharmacol. Exp. Ther, 303:82-88, 2002.

Tannous M, Veluthakal R, Amin R, Kowluru A: IL-1b-induced nitric oxide release from insulin-secreting cells: Further evidence for the involvement of GTP-binding proteins. Diabetes and Metabolism 3S78-3S84, 2002.

Kowluru A: Defective protein histidine phosphorylation in islets from the GK diabetic rat. Amer. J. Physiol. Endocrinol. Metabol. 285: E498-E503, 2003.

Kowluru A: Regulatory roles for small G-Proteins in the pancreatic beta cell: Lessons from animal models of impaired insulin secretion. Amer. J. Physiol. Endocrinol. Metab. Invited Review E669-E684, 2003.

Kowluru A, Chen HQ,Tannous M: Novel regulation by Rho subfamily of GTP-binding proteins in insulin secretion elicited by mitochondrial fuels. Endocrine Res 29:363-376, 2003.

Chen H-Q, Tannous M, Veluthakal R, Amin R, Kowluru A: Palmitoylation of Ras is essential for interleukin-1 beta-induced NO release in insulin-secreting β cells. Biochem. Pharmacol 66: 1681-1694, 2003

Amin R, Chen H-Q, Veluthakal R, Silver R, Li J, Li G, Kowluru A: Mastoparan-induced insulin secretion from bTC3 cells: Evidence for its regulation via activation of Rac, a small molecular weight GTP-binding protein. Endocrinology 144: 4508-4518, 2003.

Chen HQ, Veluthakal R, Palanivel R, Kowluru A: GTP-binding protein-independent potentiation by mastoparan of IL1β-induced nitric oxide release from insulin-secreting HIT-T15 cells. Apoptosis 9:145-148, 2004.

Kowluru R, Kowluru A, Chakrabarty S, Khan Z; Potential contributory role of H-Ras, a small G-protein, in the development of retinopathy in diabetic rats.

Diabetes 53: 775-783, 2004.

Li J, Luo R, Kowluru A, Li G: Novel regulation by Rac1 of glucose and forskolin induced insulin secretion in (INS-1) β-cells. Am J Physiol Endocrinol Metab 286: E 818- E 827, 2004.

Palanivel R, Veluthakal R, Kowluru A: Regulation by glucose, its metabolites, and calcium of the carboxylmethylation of protein phosphatase 2A in INS-1 cells (2004).Am J Physiol Endocrinol Metab. 286: E1032- E1041, 2004.

Veluthakal R, Amin R, Kowluru A: IL-1β-induces post-translational carboxyl methylations and alterations in the subcellular distribution of lamin-B in insulin-secreting RINm5F cells. Am. J. Physiol. Cell. Physiol. C1152-C1162, 2004.

Kowluru A: Differential regulation by fatty acids of protein histidine phosphorylation in rat pancreatic islets. Mol Cell Biochem. 266:175-82, 2004.

Kowluru A: Novel regulatory roles for protein phosphatase-2A in the islet β cell. Biochem Pharmacol 69:1681-91, 2005.

Veluthakal R, Palanivel R, MacDonald P, Zhao Y, Gruber S, Kowluru A: Ceramide Induces Mitochondrial Abnormalities in Insulin-Secreting INS-1 Cells: Potential Mechanisms Underlying Ceramide-Mediated Metabolic Dysfunction of the β Cell. Apoptosis 10:841-50, 2005.

R. Veluthakal, I. Chvyrkova, M. Tannous, P. McDonald, R. Amin, T. Hadden, M. J. Quon^, A. Kowluru: Essential Role for Membrane Lipid Rafts in IL-1β-Induced Nitric Oxide Release from Insulin-Secreting Cells: Potential Regulation by Caveolin-1. Diabetes. 54:2576-85, 2005.

Kowluru A, Veluthakal R: Rho GDP-Dissociation Inhibitor [GDI] Plays a Negative Modulatory Role in Glucose-Stimulated Insulin Secretion. Diabetes 54:3523-9.2005.

Veluthakal R, Wadzinski B, Kowluru A: Selective Inhibition of Nuclear Protein Phosphatase 4 by IL-1beta in Insulin-Secreting INS-1 Cells. Apoptosis 11:1401-11, 2006.

Jangati GR, Veluthakal R, Kowluru A: siRNA-mediated depletion of endogenous PP2Acα markedly attenuates ceramide-activated protein phosphatase activity in insulin-secreting INS832/13 cells. Biochem. Biophys. Res. Commun 348:649-652, 2006.

Kowluru A, Veluthakal R, Kaetzel DM: Regulatory roles for nm23/nucleoside diphosphate kinase-like enzymes in insulin secretion from the pancreatic islet beta cell. J. Biomemb. Bioenerg. Invited Review 38: 227-232, 2006.

Veluthakal R, Kaur H, Goalstone M, Kowluru A: Dominant negative α-subunit of farnesyl- and geranyl-transferase inhibits glucose-stimulated insulin secretion from insulin-secreting INS-cells Diabetes 56:204-210, 2007.

McDonald P, Veluthakal R, Kaur H, Kowluru A: Biologically active lipids promote trafficking and membrane association of Rac1 in insulin-secreting INS-1 cells. Am J Physiol-cell Physiol 292:C1216-C1220, 2007.

Jangati GR, Veluthakal R, Susick L, Gruber SA, Kowluru A: Depletion of the catalytic subunit of protein phosphatase-2A [PP2Ac] markedly attenuates glucose-stimulated insulin secretion in pancreatic beta cells. Endocrine 31:248-253, 2007.

Kowluru A: Bridging the gap between protein carboxyl methylation and phospholipid methylation to understand glucose-stimulated insulin secretion from the pancreatic beta cell. Biochem Pharmacol [2007] in press.

Susick L, Veluthakal R, Kowluru A: Regulatory roles for histone deacetylation in IL-1β-induced nitric oxide release in pancreatic β cells. J Cell Mol Med [2007] in press

Kowluru A: Protein prenylation in glucose-stimulated insulin secretion from the pancreatic β cell: A perspective. J Cell Mol Med [2007] in press

Islet Biology - Insulin Secretion

Active Research Support

TITLE: Protein Prenyl transferases in Glucose-Stimulated Insulin Secretion