Maternal diabetes, programming of beta-cell disorders and intergenerational risk of type 2 diabetes

Diabetes and Metabolism

Volumn 40, Issue 5, 2014, Pages 323-330

  Chavey, A ^a   Ah Kioon, M D ^a   Bailbe D ^a   Movassat, J ^a   Portha, B ^a  

^a Groupe Hospitalier Pitié Salpêtrière   (France)

Author keywords

Beta cell mass; Diabetes risk; Epigenomics; Insulin secretion; Maternal diabetes; Type 2 diabetes

Indexed keywords

HISTONE DEACETYLASE; INSULIN RECEPTOR SUBSTRATE 2; SOMATOMEDIN B; SOMATOMEDIN C;

CALORIC RESTRICTION; EPIGENETICS; FEMALE; GLUCOSE TOLERANCE; HUMAN; INHERITANCE; MATERNAL DIABETES MELLITUS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET BETA CELL; PLACENTA INSUFFICIENCY; PROTEIN RESTRICTION; PUBLIC HEALTH; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; ANIMAL; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; DNA METHYLATION; EXPERIMENTAL DIABETES MELLITUS; FETUS DEVELOPMENT; GENETIC PREDISPOSITION; GENETICS; METABOLISM; MOUSE; OBESITY; PATHOPHYSIOLOGY; PREGNANCY; PREGNANCY DIABETES MELLITUS; PRENATAL EXPOSURE; RAT; RISK FACTOR;

ANIMALS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, EXPERIMENTAL; DIABETES MELLITUS, TYPE 2; DIABETES, GESTATIONAL; DNA METHYLATION; EPIGENOMICS; FEMALE; FETAL DEVELOPMENT; GENETIC PREDISPOSITION TO DISEASE; HUMANS; INSULIN-SECRETING CELLS; MICE; OBESITY; PREGNANCY; PREGNANCY IN DIABETICS; PRENATAL EXPOSURE DELAYED EFFECTS; RATS; RISK FACTORS;

EID: 84908507354     PISSN: 12623636     EISSN: 18781780     Source Type: Journal    
DOI: 10.1016/j.diabet.2014.02.003     Document Type: Review

References (101)

1. Harris M.I., Klein R., Welborn T.A., Knuiman M.W. Onset of NIDDM occurs at least 4-7yr before clinical diagnosis. Diabetes Care 1992, 15:815-819.
2. DeFronzo R.A., Banting, Lecture From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009, 58:773-795.
3. Butler A.E., Janson J., Bonner-Weir S., Ritzel R., Rizza R.A., Butler P.C. Beta-Cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003, 52:102-110.
4. Florez J.C. Newly identified loci highlight beta-cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes?. Diabetologia 2008, 51:1100-1110.
5. Saenger P., Czernichow P., Hughes I., Reiter E.O. Small for gestational age: short stature and beyond. Endocr Rev 2007, 28:219-251.
6. Martin A.O., Simpson J.L., Ober C., Freinkel N. Frequency of diabetes mellitus in probands with gestational diabetes: Possible maternal influence on the predisposition to gestational diabetes. Am J Obstet Gynecol 1985, 151:471-475.
7. Alcolado J.C., Laji K., Gill-Randall R. Maternal transmission of diabetes. Diabet Med 2002, 19:89-98.
8. Dabelea D., Hanson R.L., Lindsay R.S., Pettitt D.J., Imperatore G., Gabir M.M., et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000, 49:2208-2211.
9. Sobngwi E., Boudou P., Mauvais-Jarvis F., Leblanc H., Velho G., Vexiau P., et al. Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet 2003, 361:1861-1865.
10. Gautier J.F., Wilson C., Weyer C., Mott D., Knowler W.C., Cavaghan M., et al. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 2001, 50:1828-1833.
11. Hanson R.L., Elston R.C., Pettitt D.J., Bennett P.H., Knowler W.C. Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect. Am J Hum Genet 1995, 57:160-170.
12. Singh R., Pearson E., Avery P.J., Mc Carthy M.I., Levy J.C., Hitman G.A., et al. Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes. Diabetologia 2006, 49:1876-1880.
13. Barker D.J., Hales C.N., Fall C.H., Osmond C., Phipps K., Clark P.M. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced foetal growth. Diabetologia 1993, 36:62-67.
14. Barker D.J.P. The developmental origins of adult disease. J Am Coll Nutr 2004, 23:588S-595S.
15. Hales C.N., Barker D.D.J., Clark P.M., Cox L.J., Fall C., Osmond C., et al. Foetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991, 303:1019-1022.
16. Whincup P.H., Kaye S.J., Owen C.G., Huxley R., Cook D.G., et al. Birth weight and risk of type 2 diabetes: a systematic review. JAMA 2008, 300:2886-2897.
17. Jones R.H., Ozanne S.E. Intra-uterine origins of type 2 diabetes. Arch Physiol Biochem 2007, 113:25-29.
18. Phillips D.I., Barker D.J., Hales C.N., Hirst S., Osmond C. Thinness at birth and insulin resistance in adult life. Diabetologia 1994, 37:150-154.
19. Rahier J., Wallon J., Henquin J.C. Cell populations in the endocrine pancreas of human neonates and infants. Diabetologia 1981, 20:540-546.
20. Economides D.L., Nicolaides K.H., Gahl W.A., Bernardini I., Evans M.I. Plasma insulin in appropriate and small for gestational age fetuses. Am J Obstet Gynecol 1989, 160:1091-1094.
21. Brufani C., Grossi A., Fintini D., Tozzi A., Nocerino V., Patera P.I., et al. Obese children with low birth weight demonstrate impaired beta-cell function during oral glucose tolerance test. J Clin Endocrinol Metab 2009, 94:4448-4452.
22. Van Assche F.A., De Prins F., Aerts L., Verjans M. The endocrine pancreas in small-for dates infants. Br J Obstet Gynaecol 1977, 84:751-753.
23. Aerts L., Holemans K., Van Assche F.A. Maternal diabetes during pregnancy: consequences for the offspring. Diabetes Metab Rev 1990, 16:147-197.
24. Reusens-Billen B., Remacle C., Daniline J., Hoet J.J. Cell proliferation in pancreatic islets of rat fetus and neonates from normal and diabetic mothers. An in vitro and in vivo study. Horm Metab Res 1984, 16:565-571.
25. Reusens B., Remacle C. Intergenerational effects of adverse intrauterine environment on perturbation of glucose metabolism. Twin Res 2001, 4:406-411.
26. Kervran A., Guillaume M., Jost A. The endocrine pancreas of the foetus from diabetic pregnant rat. Diabetologia 1978, 15:387-393.
27. Aerts L., Vercruysse L., Van Assche A. The endocrtine pancreas in virgin and pregnant offspring of diabetic pregnant rats. Diabetes Res Clin Pract 1997, 38:1-19.
28. Verhaeghe J., Peeters T.L., Vandeputte M.M., Rombauts W., Bouillon R., Van Assche F.A. Maternal and foetal endocrine pancreas in the spontaneously diabetic BB rat. Biol Neonate 1989, 55:298-308.
29. Serradas P., Gangnerau M.N., Giroix M.H., Saulnier C., Portha B. Impaired pancreatic beta-cell function in the foetal GK rat. Impact of diabetic inheritance. J Clin Invest 1998, 101:899-904.
30. Miralles F., Portha B. Early development of beta-cells is impaired in the GK rat model of type 2 diabetes. Diabetes 2001, 50(Suppl. 1):S84-S88.
31. Aerts A., Van Assche F.A. Animal evidence for the transgenerational development of diabetes mellitus. Int J Biochem Cell Biol 2006, 38:894-903.
32. Han J., Xu J., Long Y.S., Epstein P.N., Liu Q.Y. Rat maternal diabetes impairs pancreatic beta-cell function in the offspring. Am J Physiol Endocrinol Metab 2007, 293:E228-E236.
33. Grill V., Johansson B., Jalkanen P., Eriksson U.J. Influence of severe diabetes mellitus early in pregnancy in the rat: effects on insulin sensitivity and insulin secretion in the offspring. Diabetologia 1991, 34:373-378.
34. Ktorza A., Gauguier D., Bihoreau M.T., Berthault M.F., Picon L. Adult offspring from mildly hyperglycaemic rats show impairment of glucose regulation and insulin secretion which is transmissible to the next generation. Frontiers in diabetic research. Lessons from animal diabetes 1990, 555-560. Smith-Gordon and Company Ltd, London. E. Shafrir (Ed.).
35. Oh W., Gelardi N.L., Cha C.J. Maternal hyperglycaemia in pregnant rats, its effect on growth and carbohydrate metabolism in the offspring. Metabolism 1988, 37:1146-1151.
36. Gauguier D., Bihoreau M.T., Picon L., Ktorza A. Insulin secretion in adult rats after intrauterine exposure to mild hyperglycaemia during late gestation. Diabetes 1991, 40(Suppl. 2):109-114.
37. Bihoreau M.T., Ktorza A., Kinebanyan M.F., Picon L. Impaired glucose homeostasis in adult rats from hyperglycaemic mothers. Diabetes 1986, 35:979-984.
38. Ryan E.A., Liu D., Bell R.C., Finegood D.T., Crawford J. Long-term consequences in offspring of diabetes in pregnancy: studies with syngeneic islet-transplanted streptozotocin-diabetic rats. Endocrinology 1995, 136:5587-5592.
39. Triadou N., Portha B., Picon L., Rosselin G.G. Experimental chemical diabetes and pregnancy in the rat. Evolution of glucose tolerance and insulin response. Diabetes 1982, 31:75-79.
40. Gill-Randall R., Adams D., Ollerton R.L., Lewis M., Alcolado J.C. Type 2 diabetes mellitus-genes or intrauterine environment? An embryo transfer paradigm in rats. Diabetologia 2004, 47:1354-1359.
41. Chavey A., Gangnerau M.N., Maulny L., Bailbé D., Movassat J., Renard J.P., et al. Intrauterine programming of beta-cell development and function by maternal diabetes. What does embryo-transfer experiments in GK/Par rats tell us?. Diabetologia 2008, 51(Suppl. 1):151A. [abstract].
42. Portha B., Chavey A., Maulny L., Gangnerau M.N., Bailbé D., Dolz M., et al. Des modèles animaux pour étudier l'origine développementale des maladies métaboliques de l'adulte: application à l'étude du risque de diabète. Cah Nutr Diet 2009, 44:77-84.
43. Ah-Kioon M.D., Bailbé D., Maulny L., Alawieh M., Ilias A., Portha B., et al. Impact de l'hyperglycémie maternelle sur l'homéostasie glucidique de la descendance à l'âge adulte. Cah Nutr Diet 2012, 47:S49. [abstract].
44. Chavey A., Bailbé D., Maulny L., Renard J.P., Movassat J., Portha B. A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model. Diabetologia 2013, 56:194-203.
45. Stanger B.Z., Tanaka A.J., Melton D.A. Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 2007, 445:886-891.
46. Garofano A., Czernichow P., Breant B. β-Cell mass and proliferation following late foetal and early postnatal malnutrition in the rat. Diabetologia 1998, 41:1114-1120.
47. Blondeau B., Avril I., Duchene B., Bréant B. Endocrine pancreas development is altered in foetuses from rats previously showing intra-uterine growth retardation in response to malnutrition. Diabetologia 2002, 45:394-401.
48. Seckl J.R. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 2004, 151(Suppl 3):U49-U62.
49. Blondeau B., Lesage J., Czernichow P., Dupouy J.P., Bréant B. Glucocorticoids impair foetal_beta-cell development in rats. Am J Physiol Endocrinol Metab 2001, 281:E592-E599.
50. Bréant B., Gesina E., Blondeau B. Glucocorticoids and pancreas development. Horm Res 2006, 65(Suppl. 3):98-104.
51. De Vries A., Holmes M.C., Heijnis A., Seier J.V., Heerden J., Louw J., et al. Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function. J Clin Invest 2007, 117:1058-1067.
52. Gesina E., Tronche F., Herrera P., Duchene B., Tales W., Czernichow P., et al. Dissecting the role of glucocorticoids on pancreas development. Diabetes 2004, 53:2322-2329.
53. Simmons R.A., Suponitsky-Kroyter I., Selak M.A. Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to β-cell failure. J Biol Chem 2005, 280:28785-28791.
54. Theys N., Bouckenooghe T., Ahn M.T., Remacle C., Reusens B. Maternal low-protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat. Am J Physiol Regul Integr Comp Physiol 2009, 97:R1516-R1525.
55. Peterside I.E., Selak M.A., Simmons R.A. Impaired oxidative phosphorylation in hepatic mitochondria in growth-retarded rats. Am J Physiol Endocrinol Metab 2003, 285:E1258-E1266.
56. Selak M.A., Storey B.T., Peterside I., Simmons R.A. Impaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats. Am J Physiol Endocrinol Metab 2003, 285:E130-E137.
57. Sen S., Simmons R.A. Maternal antioxidant supplementation prevents adiposity in the offspring of western diet-fed rats. Diabetes 2010, 59:3058-3065.
58. Chen J.H., Hales C.N., Ozanne S.E. DNA damage, cellular senescence and organismal ageing: causal or correlative?. Nucleic Acids Res 2007, 35:7417-7428.
59. Jennings B.J., Ozanne S.E., Dorling M.W., Hales C.N. Early growth determines longevity in male rats and may be related to telomere shortening in the kidney. FEBS Lett 1999, 448:4-8.
60. Tarry-Adkins J.L., Chen J.H., Smith N.S., Jones R.H., Cherif H., Ozanne S.E. Poor maternal nutrition followed by accelerated postnatal growth leads to telomere shortening and increased markers of cell senescence in rat islets. FASEB J 2009, 23:1521-1528.
61. Petrik J., Reusens B., Arany E., Remacle C., Coelho C., Hoet J.J., et al. A low protein diet alters the balance of islet cell replication and apoptosis in the fetus and is associated with a reduced pancreatic expression of insulin-like growth factor-II. Endocrinology 1999, 140:4861-4873.
62. Alvarez C., Martin M.A., Goya L., Bertin E., Portha B., Pascual-Leone A.M. Contrasted impact of maternal rat food restriction on the foetal endocrine pancreas. Endocrinology 1997, 138:2267-2273.
63. Martin M.A., Serradas P., Ramos S., Fernandez E., Goya L., Gangnerau M.N., et al. Protein-caloric food restriction affects insulin-like growth factor system in foetal Wistar rat. Endocrinology 2005, 146:1364-1371.
64. Fernandez E., Martin M.A., Fajardo S., Escriva F., Alvarez C. Increased IRS-2 content and activation of IGF-1 pathway contribute to enhance beta-cell mass in fetuses from undernourished pregnant rats. Am J Physiol Endocrinol Metab 2007, 292:E187-E195.
65. Calderari S., Gangnerau M.N., Thibault M., Meile M.J., Alvarez C., Kassis N., et al. Defective IGF-2 and IGF-1R protein expressions in embryonic pancreas precede beta-cell mass anomaly in GK rat. Diabetologia 2007, 50:1463-1471.
66. Serradas P., Goya L., Lacorne M., Gangnerau M.N., Ramos S., Alvarez C., et al. Foetal insulin-like growth factor-2 production is impaired in the GK rat model of type 2 diabetes. Diabetes 2002, 51:392-397.
67. Gauguier D., Froguel P., Parent V., Bernard C., Bihoreau M.T., Portha B., et al. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet 1996, 12:38-43.
68. Baylin S.B., Jones P.A.A. decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer 2011, 11:726-734.
69. Kirchner H., Osler M.E., Krook A., Zierath J.R. Epigenetic flexibility in metabolic regulation: disease cause and prevention?. Trends Cell Biol 2013, 5:203-209.
70. Bramswig N.C., Kaestner K.H. Epigenetics and diabetes treatment: an unrealized promise?. Trends Endocrinol Metab 2012, 6:286-291.
71. Volkmar M., Dedeurwaerder S., Cunha D.A., Ndlovu M.N., Defrance M., Deplus R., et al. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 2012, 31:1405-1426.
72. Dayeh T.A., Olsson A.H., Volkov P., Almgren P., Rönn T., Ling C. Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets. Diabetologia 2013, 5:1036-1046.
73. Haumaitre C., Lenoir O., Scharfmann R. Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol 2008, 20:6373-6383.
74. Simmons R. Epigenetics and maternal nutrition: nature v. nurture. Proc Nutr Soc 2011, 1:73-81.
75. Heijmans B.T., Tobi E.W., Stein A.D., Putter H., Blauw G.J., Susser E.S., et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 2008, 105:17046-17049.
76. Stoffers D.A., Desai B.M., DeLeon D.D., Simmons R.A. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes 2003, 3:734-740.
77. Park J.H., Stoffers D.A., Nicholls R.D., Simmons R.A. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 2008, 118:2316-2324.
78. Qian J., Kaytor E.N., Towle H.C., Olson L.K. Upstream stimulatory factor regulates Pdx-1 gene expression in differentiated pancreatic beta-cells. Biochem J 1999, 341(Pt 2):315-322.
79. Gupta R.K., Gao N., Gorski R.K., White P., Hardy O.T., Rafiq K., et al. Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes Dev 2007, 21:756-769.
80. Gupta R.K., Vatamaniuk M.Z., Lee C.S., Flaschen R.C., Fulmer J.T., Matschinsky F.M., et al. The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest 2005, 115:1006-1015.
81. Yamagata K., Furuta H., Oda N., Kaisaki P.J., Menzel S., Cox N.J., et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996, 384:458-460.
82. Sandovici I., Smith N.H., Nitert M.D., Ackers-Johnson M., Uribe-Lewis S., Ito Y., et al. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A 2011, 108:5449-5454.
83. Benyshek D.C., Johnston C.S., Martin J.F. Glucose metabolism is altered in the adequately-nourished grand-offspring (F3 generation) of rats malnourished during gestation and perinatal life. Diabetologia 2006, 49:1117-1119.
84. Zambrano E., Martinez-Samayoa P.M., Bautista C.J., Deas M., Guillen L., Rodriguez-Gonzalez G.L., et al. Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation. J Physiol 2005, 566:225-236.
85. Drake A.J., Walker B.R., Seckl J.R. Intergenerational consequences of foetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 2005, 288:R34-R38.
86. Ozanne S.E., Constancia M. Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. Nat Clin Pract Endocrinol Metab 2007, 3:539-546.
87. Pinney S.E., Simmons R.A. Epigenetic mechanisms in the development of type 2 diabetes. Trends Endocrinol Metab 2009, 21:223-229.
88. Drake A.J., Liu L. Intergenerational transmission of programmed effects: public health consequences. Trends Endocrinol Metab 2009, 21:206-212.
89. Waterland R.A., Michels K.B. Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 2007, 27:363-388.
90. Gluckman P.D., Hanson M.A., Beedle A.S. Non-genomic transgenerational inheritance of disease risk. Bio Essays 2007, 29:145-154.
91. Raychaudhuri N., Raychaudhuri S., Thamotharan M., Devaskar S.U. Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring. J Biol Chem 2008, 283:13611-13626.
92. Burdge G.C., Slater-Jefferies J., Torrens C., Phillips E.S., Hanson M.A., Lillycrop K.A. Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 2007, 97:435-439.
93. Hoile S.P., Lillycrop K.A., Thomas N.A., Hanson M.A., Burdge G.C. Dietary protein restriction during F0 pregnancy in rats induces transgenerational changes in the hepatic transcriptome in female offspring. PLoS One 2011, 6:e21668.
94. Skinner M.K. What is an epigenetic transgenerational phenotype? F3 or F2. Reprod Toxicol 2008, 1:2-6.
95. Kanagalingam M.G., Forouhi N.G., Greer I.A., Sattar N.N. Changes in booking body mass index over a decade: retrospective analysis from a Glasgow maternity hospital. Br J Obstet Gynaecol 2005, 112:1431-1433.
96. Catalano P.M. Obesity and pregnancy-the propagation of a viscous cycle?. J Clin Endocrinol Metab 2003, 88:3505-3506.
97. Lillycrop K.A., Phillips E.S., Jackson A.A., Hanson M.A., Burdge G.C. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 2005, 135:1382-1386.
98. Waterland R.A., Travisano M., Tahiliani K.G., Rached M.T., Mirza S. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes 2008, 32:1373-1379.
99. Vickers M.H., Gluckman P.D., Coveny A.H., Hofman P.L., Cutfield W.S., Gertler A., et al. Neonatal leptin treatment reverses developmental programming. Endocrinology 2005, 146:4211-4216.
100. Tourrel C., Bailbé D., Lacorne M., Meile M.J., Kergoat M., Portha B. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with Glucagon-like peptide-1 or Exendin-4. Diabetes 2002, 51:1443-1452.
101. Kim S.J., Nian C., McIntosh C.H. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 modulate b-cell chromatin structure. J Biol Chem 2009, 284:12896-12904.