Adenosine Kinase Inhibition Selectively Promotes Rodent and Porcine Islet β-cell Replication

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2012 Feb 21

PMID 22345561

Citations 75

Authors

Justin P Annes

Jennifer Hyoje Ryu

Kelvin Lam

Peter J Carolan

Katrina Utz

Jennifer Hollister-Lock

Anthony C Arvanites

Lee L Rubin

Gordon Weir

Douglas A Melton

Affiliations

Soon will be listed here.

Abstract

Diabetes is a pathological condition characterized by relative insulin deficiency, persistent hyperglycemia, and, consequently, diffuse micro- and macrovascular disease. One therapeutic strategy is to amplify insulin-secretion capacity by increasing the number of the insulin-producing β cells without triggering a generalized proliferative response. Here, we present the development of a small-molecule screening platform for the identification of molecules that increase β-cell replication. Using this platform, we identify a class of compounds [adenosine kinase inhibitors (ADK-Is)] that promote replication of primary β cells in three species (mouse, rat, and pig). Furthermore, the replication effect of ADK-Is is cell type-selective: treatment of islet cell cultures with ADK-Is increases replication of β cells but not that of α cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases β-cell replication but not exocrine cell or hepatocyte replication. Therefore, we propose ADK inhibition as a strategy for the treatment of diabetes.

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References

Mokdad A, Ford E, Bowman B, Dietz W, Vinicor F, Bales V . Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2002; 289(1):76-9. DOI: 10.1001/jama.289.1.76. View

Bernal-Mizrachi E, Wen W, Stahlhut S, Welling C, Permutt M . Islet beta cell expression of constitutively active Akt1/PKB alpha induces striking hypertrophy, hyperplasia, and hyperinsulinemia. J Clin Invest. 2001; 108(11):1631-8. PMC: 200992. DOI: 10.1172/JCI13785. View

Vasavada R, Gonzalez-Pertusa J, Fujinaka Y, Fiaschi-Taesch N, Cozar-Castellano I, Garcia-Ocana A . Growth factors and beta cell replication. Int J Biochem Cell Biol. 2005; 38(5-6):931-50. DOI: 10.1016/j.biocel.2005.08.003. View

Braun M, Ramracheya R, Amisten S, Bengtsson M, Moritoh Y, Zhang Q . Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells. Diabetologia. 2009; 52(8):1566-78. DOI: 10.1007/s00125-009-1382-z. View

Serup P, Petersen H, PEDERSEN E, Edlund H, Leonard J, Petersen J . The homeodomain protein IPF-1/STF-1 is expressed in a subset of islet cells and promotes rat insulin 1 gene expression dependent on an intact E1 helix-loop-helix factor binding site. Biochem J. 1995; 310 ( Pt 3):997-1003. PMC: 1135994. DOI: 10.1042/bj3100997. View

Xu X, DHoker J, Stange G, Bonne S, De Leu N, Xiao X . Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 2008; 132(2):197-207. DOI: 10.1016/j.cell.2007.12.015. View

Shapiro A, Ricordi C, Hering B, Auchincloss H, Lindblad R, Robertson R . International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006; 355(13):1318-30. DOI: 10.1056/NEJMoa061267. View

Park J, Gupta R . Adenosine kinase and ribokinase--the RK family of proteins. Cell Mol Life Sci. 2008; 65(18):2875-96. PMC: 11131688. DOI: 10.1007/s00018-008-8123-1. View

Tyrberg B, Eizirik D, HELLERSTROM C, Pipeleers D, Andersson A . Human pancreatic beta-cell deoxyribonucleic acid-synthesis in islet grafts decreases with increasing organ donor age but increases in response to glucose stimulation in vitro. Endocrinology. 1996; 137(12):5694-9. DOI: 10.1210/endo.137.12.8940401. View

10.

Dennis P, Jaeschke A, Saitoh M, Fowler B, Kozma S, Thomas G . Mammalian TOR: a homeostatic ATP sensor. Science. 2001; 294(5544):1102-5. DOI: 10.1126/science.1063518. View

11.

Porat S, Weinberg-Corem N, Tornovsky-Babaey S, Schyr-Ben-Haroush R, Hija A, Stolovich-Rain M . Control of pancreatic β cell regeneration by glucose metabolism. Cell Metab. 2011; 13(4):440-449. PMC: 11807376. DOI: 10.1016/j.cmet.2011.02.012. View

12.

Bonner-Weir S, Deery D, Leahy J, Weir G . Compensatory growth of pancreatic beta-cells in adult rats after short-term glucose infusion. Diabetes. 1989; 38(1):49-53. DOI: 10.2337/diab.38.1.49. View

13.

KREDICH N, Martin Jr D . Role of S-adenosylhomocysteine in adenosinemediated toxicity in cultured mouse T lymphoma cells. Cell. 1977; 12(4):931-8. DOI: 10.1016/0092-8674(77)90157-x. View

14.

Radek R, Decker M, Jarvis M . The adenosine kinase inhibitor ABT-702 augments EEG slow waves in rats. Brain Res. 2004; 1026(1):74-83. DOI: 10.1016/j.brainres.2004.08.011. View

15.

Van Assche F, Aerts L, De Prins F . A morphological study of the endocrine pancreas in human pregnancy. Br J Obstet Gynaecol. 1978; 85(11):818-20. DOI: 10.1111/j.1471-0528.1978.tb15835.x. View

16.

Thorel F, Nepote V, Avril I, Kohno K, Desgraz R, Chera S . Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature. 2010; 464(7292):1149-54. PMC: 2877635. DOI: 10.1038/nature08894. View

17.

Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R . Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci U S A. 2008; 105(50):19915-9. PMC: 2604974. DOI: 10.1073/pnas.0805803105. View

18.

Kowaluk E, Jarvis M . Therapeutic potential of adenosine kinase inhibitors. Expert Opin Investig Drugs. 2000; 9(3):551-64. DOI: 10.1517/13543784.9.3.551. View

19.

Wajchenberg B . beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007; 28(2):187-218. DOI: 10.1210/10.1210/er.2006-0038. View

20.

Xu G, Stoffers D, Habener J, Bonner-Weir S . Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999; 48(12):2270-6. DOI: 10.2337/diabetes.48.12.2270. View