Terapia per il diabete gestazionale

Tutte le nuove terapie antidiabetiche sono da considerarsi in presenza del diabete mellito di tipo 1 e 2. Il diabete gestazionale è una condizione clinica diversa.

La cura per le donne in stato interessante viene decisa dal diabetologo e dal ginecologo. In un primo momento viene consigliata una dieta povera di glucidi e grassi, ma ricca di proteine, accompagnata da attività fisica ( una donna in gravidanza dovrebbe camminare dai 30 ai 60 minuti 2-3 volte alla settimana per evitare appunto iperglicemie e aumento eccessivo di peso).

Ovviamente l'attività fisica deve tenere conto dello stato di salute della donna. Nel caso in cui dieta ed esercizio fisico non bastino a controllare la glicemia, viene consigliata la terapia insulinica, essendo l'unica a non interferire con il bambino.

6- Conclusione:

La variabilità nella risposta al trattamento farmacologico tra paziente e paziente costituisce da sempre uno dei problemi più rilevanti nella pratica clinica. Le risposte individuali ai farmaci, infatti, variano molto: si possono osservare in alcuni pazienti rispetto ad altri, effetti terapeutici ridotti o addirittura assenti, reazioni avverse o effetti collaterali, nonostante sia stato somministrato lo stesso farmaco con la stessa posologia. Questa variabilità inter-individuale veniva, nel passato, attribuita principalmente all’influenza di fattori non genetici come ad esempio l’età, il sesso, lo stato nutrizionale, quello di funzionalità renale ed epatica, le abitudini di vita con particolare riferimento alla dieta e all’abuso di alcool e fumo, concomitante all’assunzione di altri farmaci.

Attualmente si ritiene che, oltre ai fattori sopra menzionati, giochino un ruolo importante nella risposta individuale ai farmaci anche quelli ereditari.

Il titolo “Pochi farmaci, per Infiniti genotipi” potrebbe andar bene per qualsiasi tipo di malattia che colpisce il genere umano.

Il genotipo è il corredo genetico di un individuo, cioè l’insieme dei geni (unità funzionali) contenuti nel DNA e custoditi nel nucleo delle cellule. Ogni organismo eredita dai genitori il corredo genetico e possiede una specifica combinazione di geni, che in parte sono alla base della sua unicità.

Il fenotipo, invece, è l’insieme dei caratteri che l’individuo manifesta e che

dall’apparenza si possono osservare in maniera più o meno evidente. Il fenotipo dipende dal genotipo, ma anche dalle interazioni fra geni ed ambiente.

Il fatto di avere tutti un genotipo diverso dall’altro ( a parte i gemelli monozigoti), crea ovviamente differenze nelle risposte alle varie terapie. Farmaci che possono rivelarsi ottimali per un individuo, potrebbero dimostrarsi inutili o addirittura dannosi per altri.

BIBLIOGRAFIA 1. Inx.endocrinologiaoggi.it/2011/06/diabete-mellito-definizione/ 2. www.albanesi.it/salute/diabete/htm 3. http://en.wikipedia.org/wiki/biguanide 4. www.my-personaltrainer.it/farmaci/biguanid i-metformina.html 5. http://it.wikipedia.org/wiki/sulfaniluree 6. http://commons.wikimedia.org/wiki/File:Glucagen.jpg 7. http://it.wikipedia.or g/wiki/tiazolidinedioni 8. http://commons.wikimedia.org/wiki/File:troglitazone_structure.png 9. http://commons.wikimedia.org/wiki/File:rosiglitazone.svg 10. http://it.wikipedia.org/wiki/pioglitazone 11. http://it.wikipedia.org/wiki/bromocriptina 12. http://en.wikipedia.org/wik i/colesevelam 13. http://www.minerva.unito.it/storia/insulina/insulinastruttura.htm 14. http://it.123rf.com/photo_4678678_monouso-insulina-su-sfondo-bianco.html 15. http://www.pillole.org/public/aspnuke/article.asp?id=106&page=4 16. medmedicine.it/articoli/73-endocrinologia-e-metabolismo/farmaci-antidiabetici 17. http://it-wikipedia.org 18. http://en.wikipedia.org/wiki/sitagliptin 19. http://hu.wikipedia.org/w iki/linagliptin 20. http://commons.wikimedia.org/wiki/File:Saxagliptin.svg 21. http://es.wikipedia.org/wiki/vidagliptin 22. http://en.wikip edia.org/wiki/alogliptin

23. Esposito K, Cazzolino D, Bellastella G, et Al. Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7%in type 2 diabetes:meta –analysis of randomized controlled trials. Diabetes Obes Metab 201;13(7):594-603

24. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 008 Group. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63(1):46–55.

25. Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo- controlled study. Curr Med Res Opin. 2009;25(10):2361–2371.

26. Pratley RE, KipnesMS, Fleck PR, Wilson C, Mekki Q; Alogliptin Study 007 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009;11(2):167–176.

27. Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009;11(12):1145–1152. 28. Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q. Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies. J Am Geriatr Soc. 2009;57(11):2011–2019.

29. http://www.lookchem.com/cas-141/141732-76-5.html

30. http://savenaturesavehuman.blogspot.it/20127057gila-monster.html 31. http://chemblink.com/products/204656-20-2.html

32. Sethi BK, Viswanathan V, Kumar A, Chatterjee S, Chandalia HB. Liraglutide in Clinical Practice: Insights from LEAD Programme. Supplement to JAPI. 2010;58(June 2010):18–22.

33. Scott DA, Boye KS, Timlin L, Clark JF, Best JH. A network meta-analysis to compare glycaemic control in patients with type 2 diabetes treated with exenatide once weekly or liraglutide once daily in comparison with insulin glargine, exenatide twice daily or placebo. Diabetes Obes Metab. 2012.

34. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met + TZD). Diabetes Care. 2009;32(7):1224–30.

35. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372(9645):1240–50.

36. Russell-Jones D, Cuddihy RM, Hanefeld M, Kumar A, Gonzalez JG, Chan M, et al. Efficacy and Safety of Exenatide Once Weekly Versus Metformin, Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 Diabetes (DURATION-4) A 26-week double-blind study. Diabetes Care. 2012;35(2):252–8.

37. Diamant M, Van Gaal L, Stranks S, Northrup J, Cao D, Taylor K, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375(9733):2234– 43.

38. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in

type 2 diabetes mellitus (LEAD-5 met + SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046–55.

39. Buse JB, Nauck MA, Forst T, Sheu WHH, Hoogwerf BJ, Shenouda SK, et al. Efficacy and safety of exenatide once weekly versus liraglutide in subjects with type 2 diabetes (DURATION-6): a randomised, open-label study. Diabetologia. 2012;55[suppl1]. 40. http://www.lookchem.com/lixisenatide

41. Ratner RE, Rosenstock J, Boka G, Investigators DS. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. Diabetic Med. 2010;27(9):1024–32

42. Aronson R, Riddle M, Home P, Marre M, Niemoeller E, Ping J, et al. Efficacy and safety of once-daily lixisenatide in type 2 diabetes insufficiently controlled with basal insulin ± metformin: GetGoal-L study [EASD OP-3]. Diabetologia. 2012;55[suppl1].

43. http://img1.guidechem.com/chem/e/dict/33/114495-97-5.jpg

44. Pratley RE, Barnett AH, Feinglos MN, Harman-Boehm I, Nauck MA, Ovalle F, et al. Efficacy and safety of Once-Weekly (QW) albiglutide vs Once-Daily (QD) liraglutide in Type 2 Diabetes (T2D) inadequately controlled on oral agents: harmony 7 trial [ADA 945- P]. Diabetes. 2012;61[suppl1].

45. Rosenstock J, Ahren B, Chow F, Fonseca V, Gross J, Ratner R, et al. Once- Weekly GLP-1 receptor agonist albiglutide vs titrated prandial lispro added on to titrated basal insulin glargine in Type 2 Diabetes (T2D) uncontrolled on glargine plus oral agents: similar glycemic control with weight loss and less hypoglycemia [ADA 55-OR]. Diabetes. 2012;61[suppl1].

46. GSK announces positive data from Harmony 8 and completion of clinical registration package for albiglutide in type 2 diabetes. 2012. http://us.gsk.com/html/media- news/pressreleases/2012/2012-pressrelease-1178461.htm. Accessed 23 October 2012. 47. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label-non-inferiority study. Lancet. 2008;372:1240–1250.

48. Bergenstal RM, Wysham C, MacConell L, et al. efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010; 376:431–439.

49. Diamant M, Gaal LV, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated in patients with type 2 diabetes (DURATION-3): an open label randomized trial. Lancet. 2012;375:2234–2243.

50. Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug- naïve patients with type 2 diabetes (DURATION-4). Diabetes Care. 2012;35:252–258. 51. Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:1301–1310.

52. http://www.medscape.org/viewarticle/57876

53. http://commons.wikimedia.org/wiki/File:dapaglifozin_structure.svg

54. Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin.

Diabetes Care. 2011;34:2015–2022.

55. Bailey CG, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycemic control with metformin:a randomized, doubleblind,

placebo-controlled trial. Lancet. 2010;375:2223– 2233.

56. Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in patients with type 2 diaebetes who have inadequate glycaemic control with glimepiride:a randomized, 24- week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011;13:928–938. 57. Rosenstock J, Vico M, Wei L, et al. Effects of dapagliflozin, an SGLT 2 inhibitor, on A1c, weight and hypoglycemia risk in patients with type 2 diabetes inadequately controlled

with pioglitazone monotherapy. Diabetes Care. 2012;35: 1473–1478.

58. Wilding JP, Woo V, Soler NG, et al. Long term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156:405–415.

59. http://pharmafeed.blogspot.it/2013/10/SGLT2-inhibitors-in.crowded-space-of.html 60. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on therapy to metformin in subjects with

type 2 diabetes. Diabetes Care. 2012;35:1232–1238.

61. http://commons.wikimedia.org/wiki/File:empaglifozin.png 62. http://www.erboristeriarcobaleno.com/glicemia.html

63. http://www.my-personaltrainer.it/fisiologia/metabolismo-glucidi.html

64. Kevin J Filipski, Jianwei Bian, David C. Ebner, Esther C.Y Lee, Jian-Cheng Li,Matthew F.Sammons, Stephen W.Wright, Benjamin D. Stevens, Mary T. Didiuk, Meihua Tu, Christian Perreault, Janice Brown, Karen Atkinson, Beijing Tan, Christopher T. Salatto,

John Lichtfield, Jeffrey A. Pfefferkorn, Angel Guzman-Perez A novel series of glucagon receptor antagonists with reduced molecular weight and lipophilicity.

65. Kevin J Filipski, Jianwei Bian, David C. Ebner, Esther C.Y Lee, Jian-Cheng Li,Matthew F.Sammons, Stephen W.Wright, Benjamin D. Stevens, Mary T. Didiuk, Meihua Tu, Christian Perreault, Janice Brown, Karen Atkinson, Beijing Tan, Christopher T. Salatto, John Lichtfield, Jeffrey A. Pfefferkorn, Angel Guzman-Perez A novel series of glucagon receptor antagonists with reduced molecular weight and lipophilicity.

66. Kodra J. T, Jorgensen A.S, Andersen B, Behrens C, Brand C. L, Christensen I. T, Guldbrandt M, Jeppersen C.B, Knudsen L.B, Madsen P, Nishimura E, Sams C, Sidelmann U. G, Pedersen R. A, Linn F. C, Lau J.J, . Med chem 2008. 51, 5387-

67. http://w ww.abstractsonline.com Authors: David J Kazierard, Jeffrey A Pfefferkorn,

Arthur Bergman, Xin Wang, Timothy P.Rolph, James M. Rusnak, Cambridge, MA. 68. British journal of pharmacology (2013) 168 339-353

69. http://www.globusmagazine.it/tumori-il-corpo-umano-killer-programmato-dal- giappone-la-sveglia-delle-staminali

70. http://www.bioinst.com/?p=cosa_sono

71. http://www.smartbank.it/cellule-staminali/staminali-cosa-sono/

72. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S et Al. Pancreatic endoderm derivedfrom human embryonicstem cells generates glucose-responsive insulin- secreting cells in vivo. Nat Biotech2008;26:443-52

73. Zhang D, Jiang W, Shi Y, Deng H. Generation of pancreatic islet cells from human embryonic stem cells. Sci China C life Sci 2009;52:615-21

74. Li H, Lam A, Xu AM, Lam KS, Chung SK. High dosage of exendin-4 increased early insulin secretion in differentiated beta cells from mouse embryonicstem cells. Acta pharmacol Sin 2010;31:570-7

75. http://www.donna.nanopress.it/mamma/cellule-staminali-del-cordone-ombelicale- ecco-perchè-servono/P205341

76. Broxmeyer HE, Douglas GW, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U.S.A. 1989;86:3828-32

77. Pessina A, Eletti B, Croera C, Savalli N, Diodovich C, Gribaldo L. Pancreas developing markers expressed on human mononucleated umbilical cord blood cells. Biochem Biophys Res

Commun 2004;323:315-22.

78. Yoshida S, Ishikawa F, Kawano N, Shimoda K, Nagafuchi S, Shimoda S et al. Human cord blood-derived cells generate insulin-producing cells in vivo. Stem Cells 2005;23:1409-16.

79. Seaberg RM, Smukler SR, Kieffer TJ, Enikolopov G, Asghar Z, Wheeler MB et al. Clonal identification of multipotent precur sors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol 2004;22:1115-24.

80a. Bonner-Weir S, Baxter L A, Schuppin G T, et al. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes, 1993, 42: 1715– 1720

80b. Dor Y, Brown J, Martinez OI et al. Adult pancreatic beta-cells are formed by self- duplication rather than stem-cell differentiation. Nature 2004;429:41–6.

81. Bonner-Weir S, Taneja M, Weir GC et al. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000;97:7999–8004.

82. Xuh et Al β cells can be generated from endogenous progenitorsin injured adult mouse pancreas cell 2008;132:197-207.

83. Zhou Q, Brown J,Kanarek A et Al, In vivo reprogramming of adult pancreatic exocrinecells to beta-cells. Nature 2008; 455:627-32.

84. Ferber S, Halkin A, Cohen H et Al. Pancreatic and duodenal homebox gene 1 induces expression of insulin genes in liver and ameliorates streptozocin-induced hyperglycemia. Nat Med 200; 568-72.

85. Yechoor V, Liu V, Espiritu C et Al. Neurogenin3 is sufficient for transdetermination of hepatic progenitor cells into neo-islet in vivo but but not transdifferentiation of hepatocytes. Dev cell 2009;16:358-73.

86. Sapir T, Shternhall K, Meivar-Levy I, Blumenfeld T, Cohen H, Skutelsky E et al. Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult

human liver cells. Proc Natl Acad Sci USA 2005;102:7964-9.

87. Oh S.H., Muzzonigro T.M., Bae S.H. et al., Adult bone marrow-derived cells trans differentiating into insulinproducing cells for treatment of type I diabetes Lab

Invest 2004; 84:607–17.

88. Chen L.B., Jiang X.B.,Yang L., Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells World J Gastroenterol 2004; 10:3016–20.

89. Wu X.H., Liu C.P., Xu K.F., Mao X.D. , Zhu J., Jiang J.J., Cui D., Zhang M., Xu Y., Liu C., Reversal of hyperglycaemia in diabetic rats by portal vein transplantation of islet- like cells generated from bone marrow mesenchymal stem cells World J Gastroenterol 2007; 13: 3342–9.

90. Karnieli O., I.-P. Y., Bulvik S., Efrat S., “Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation.” Stem Cells 11(25): 2007 2837–2844.

91. Izumida Y, Aoki T, Koizumi T, Suganuma C, Saito K et Al. Hepatocyte growth factor is constitutively produced by donor-derived bone marrow cells and promotes regeneration of pancreatic beta -cells.Biochem Biophys res commun 2005;333:273-282

92. Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD et al. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci USA 2006; 103:17438-43. 93. Chao CK, Chao FK, Fu YS, Liu SH. Islet-like clusters derived from mesenchymal stem cells in Wharton’s jellyof the human umbilical cord for transplantation to control type 1 of diabetes. PLoS ONE 2008;3:e1451.

94. Gao F, Wu DQ, Hu YH, Jin GX, Li GD, Sun TW et al. In vitro cultivation of islet-like cell clusters from human umbilical cord

blood-derived mesenchymal stem cells. Transl Res 2008;151: 293-302.

95. Timper K., Seboek D., Eberhardt M., Linscheid P., Christ-Crain M., Keller U., Müller B., Zulewski H., Human adipose tissue-derived mesenchymal stem cells

differentiate into insulin, somatostatin, and glucagon expressing cellsBiochem Biophys Res Commun. 2006 Mar 24; 341(4): 2006 1135–40.

96. Eberhardt M, Salmon P, Von mach MA, Hengstler JG, Brulport M, Linscheid P, et Al. Multipotential nestin and Isl 1 positive mesenchymalstem cells isolated from human pancreatic islets. Biochem Biophys Res Commun 2006; 345:1167-76.

97. S.D Dave, A.V. Vanirar, H.L. Trivedi, U.G. Thakkar, S.C.Gopal, T. Chandra, Novel therapy for insulin-dependentdiabetes mellitus: infusion of in vitro-generated insulin- secreting cells.

98. Kroon E, Martinson L A, Kadoya K, et al. Pancreatic endoderm derived

from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol, 2008, 26: 443–452

99. Tang D Q, Wang Q, Burkhardt B R, et al. In vitro generation of functional

insulin-producing cells from human bone marrow-derived stem cells, but long-term culture running risk of malignant transformation. Am J Stem Cells, 2012, 1: 114–127

100. Vajdic C M, van Leeuwen M T. Cancer incidence and risk factors after solid organ transplantation. Int J Cancer, 2009, 125: 1747–1754

101. Halban P A, German M S, Kahn S E, et al. Current status of islet cell

replacement and regeneration therapy. J Clin Endocrinol Metab, 2010, 95: 1034–1043 102. Colombo GL, Rossi E, De Rosa M, Benedetto D, Gaddi AV. Antidiabetic therapy in real practice: indicators for adherence and treatment cost.

Patient Preference and Adherence 2012; 6: 653-61. 103. http://it.wikipedia.org/wiki/Repaglinide

104. http://it.wikipedia.org/wiki/Acarbosio

105. http://it.wikipedia.org/wiki/File:Pramlintide_sequence.svg

106. V. Sordi, L. Piemonti Le cellule staminali nella terapia del diabete G It Diabetol Metab 2008:28:71-89

107. Katsuma S, Hirasawa A, Tsujimoto G Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun 329: 386–390, 2005

108. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, Macchiarulo A,Yamamoto H, Mataki C, Pruzanski M, Pellicciari R, Auwerx J, Schoonjans K

TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10: 167– 177, 2009.

109. Advances in Pharmacologic Therapies for Type 2 Diabetes Linde M. Morsink1_{, Mark M. Smits}1 _{and Michaela Diamant}1

Diabetes Center, Department of Internal Medicine, VU University Medical Center (VUMC), De Boelelaan 1117 (room 4A58), PO BOX 7057, 1007, MB, Amsterdam, The Netherlands 110. http://commons.wikimedia.org/wiki/File:Phenformin.svg

111. Adeghate E. An update on the biology and physiology of resistin. Cell Mol Life Sci. 2004 Oct;61(19-20):2485-96.

112. 11. Shang Q, Saumoy M, Holst JJ, Salen G, Xu G. Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing

the release of GLP-1. Am J Physiol Gastrointest Liver Physiol 2010;298: G419–G424

113. Chen L, McNulty J, Anderson D, et al. Cholestyramine reverses hyperglycemia and enhances glucose-stimulated glucagon-like peptide 1 release in Zucker diabetic fatty rats. J Pharmacol Exp Ther 2010;334:164–170

114. Beysen C, Murphy EJ, Deines K, et al. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia 2012;55:432–442

115. Marina AL, Utzschneider KM, Wright LA, Montgomery BK, Marcovina SM, Kahn SE. Colesevelam improves oral but not intravenous glucose tolerance by a mechanism independent of insulin sensitivity and b-cell function. Diabetes Care 2012;35:1119–1125 116. Hirasawa A, Tsumaya K, Awaji T, et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 2005;11: 90–94

117. Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line

118. Van Dijk TH, Grefhorst A, Oosterveer MH, et al. An increased flux through the glucose 6-phosphate pool in enterocytes delays glucose absorption in Fxr-/- mice. J Biol Chem 2009;284:10315–10323

119. Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. 2010;33(2):428–433.

120. Schmid S, Buuck D, Knopff A, Bonifacio E, Ziegler AG. BABYDIET, a feasibility study to prevent the appearance of islet autoantibodies in relatives of patients with type 1 diabetes by delaying exposure to gluten. Diabetologia 2004;47:1130-1.

121. Lorini R, Minicucci L, Napoli F, Padovani P, Bazzigaluppi E, Tortoioli C et al. Screening for type 1 diabetes genetic risk in newborns of continental Italy. Primary prevention (Prevefin Italy) – preliminary data. Acta Biomed Ateneo Parmense 2005;76(suppl 3):31-5.

122. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin- 1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989;320:265-71.

123. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin- 1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989;320:265-71.

124. Diabetes Prevention Trial Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346:1685-91. 125. Diabetes Prevention Trial - Type 1 Study Group. Effects of oral insulin in relatives of patients with type 1 diabetes. Diabetes Care 2005;28:1068-76

126. The Canadian-European randomized control trial group. Cyclosporin- induced remission of IDDM after early intervention: association of 1 year of cyclosporin treatment with enhanced insulin secretion. Diabetes 1988;37:1574-82.

127. Clinical optimization of antigen specific modulation of type 1 diabetes with the