Pancreatic islet cell therapy for type I diabetes: understanding the effects of glucose stimulation on islets in order to produce better islets for transplantation

Journal of Translational Medicine

David F Stroncek¹  Xin Li¹  David M Harlan²  Eric Liu²  Ena Wang¹  Ping Jin¹  Jiaqiang Ren¹ 

[1] Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA;National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD, 20892, USA

Others  :  1208416
DOI  :  10.1186/1479-5876-5-1

 received in 2006-10-05, accepted in 2007-01-03,  发布年份 2007

【 摘 要 】

While insulin replacement remains the cornerstone treatment for type I diabetes mellitus (T1DM), the transplantation of pancreatic islets of Langerhans has the potential to become an important alternative. And yet, islet transplant therapy is limited by several factors, including far too few donor pancreases. Attempts to expand mature islets or to produce islets from stem cells are far from clinical application. The production and expansion of the insulin-producing cells within the islet (so called β cells), or even creating cells that secrete insulin under appropriate physiological control, has proven difficult. The difficulty is explained, in part, because insulin synthesis and release is complex, unique, and not entirely characterized. Understanding β-cell function at the molecular level will likely facilitate the development of techniques to manufacture β-cells from stem cells. We will review islet transplantation, as well as the mechanisms underlying insulin transcription, translation and glucose stimulated insulin release.

【 授权许可】

   
2007 Ren et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Steffes MW, Sibley S, Jackson M, Thomas W: Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 2003, 26(3):832-836.
• [2]Gruessner AC, Sutherland DE: Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005, 19(4):433-455.
• [3]Coppelli A, Giannarelli R, Vistoli F, Del Prato S, Rizzo G, Mosca F, Boggi U, Marchetti P: The beneficial effects of pancreas transplant alone on diabetic nephropathy. Diabetes Care 2005, 28(6):1366-1370.
• [4]Venstrom JM, McBride MA, Rother KI, Hirshberg B, Orchard TJ, Harlan DM: Survival after pancreas transplantation in patients with diabetes and preserved kidney function. Jama 2003, 290(21):2817-2823.
• [5]Gruessner RW, Sutherland DE, Gruessner AC: Mortality assessment for pancreas transplants. Am J Transplant 2004, 4(12):2018-2026.
• [6]Ballinger WF, Lacy PE: Transplantation of intact pancreatic islets in rats. Surgery 1972, 72(2):175-186.
• [7]Najarian JS, Sutherland DE, Matas AJ, Steffes MW, Simmons RL, Goetz FC: Human islet transplantation: a preliminary report. Transplant Proc 1977, 9(1):233-236.
• [8]Largiader F, Kolb E, Binswanger U: A long-term functioning human pancreatic islet allotransplant. Transplantation 1980, 29(1):76-77.
• [9]Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Falqui L, Marchetti P, Gingerich RL, Jaffe AS, Cryer PE, et al.: Insulin independence after islet transplantation into type I diabetic patient. Diabetes 1990, 39(4):515-518.
• [10]Matsumoto S, Okitsu T, Iwanaga Y, Noguchi H, Nagata H, Yonekawa Y, Yamada Y, Fukuda K, Tsukiyama K, Suzuki H, Kawasaki Y, Shimodaira M, Matsuoka K, Shibata T, Kasai Y, Maekawa T, Shapiro J, Tanaka K: Insulin independence after living-donor distal pancreatectomy and islet allotransplantation. Lancet 2005, 365(9471):1642-1644.
• [11]Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW: Automated method for isolation of human pancreatic islets. Diabetes 1988, 37(4):413-420.
• [12]Bromberg JS, LeRoith D: Diabetes cure--is the glass half full? N Engl J Med 2006, 355(13):1372-1374.
• [13]Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000, 343(4):230-238.
• [14]Rother KI, Harlan DM: Challenges facing islet transplantation for the treatment of type 1 diabetes mellitus. J Clin Invest 2004, 114(7):877-883.
• [15]Naftanel MA, Harlan DM: Pancreatic islet transplantation. PLoS Med 2004, 1(3):e58; quiz e75.
• [16]Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert-Margolis V, Bluestone J, Lakey JR: International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006, 355(13):1318-1330.
• [17]Hirshberg B, Rother KI, Digon BJ 3rd, Lee J, Gaglia JL, Hines K, Read EJ, Chang R, Wood BJ, Harlan DM: Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience. Diabetes Care 2003, 26(12):3288-3295.
• [18]Hussain MA, Theise ND: Stem-cell therapy for diabetes mellitus. Lancet 2004, 364(9429):203-205.
• [19]Trucco M: Regeneration of the pancreatic beta cell. J Clin Invest 2005, 115(1):5-12.
• [20]Choi Y, Ta M, Atouf F, Lumelsky N: Adult pancreas generates multipotent stem cells and pancreatic and nonpancreatic progeny. Stem Cells 2004, 22(6):1070-1084.
• [21]Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M: Insulin production by human embryonic stem cells. Diabetes 2001, 50(8):1691-1697.
• [22]Shiroi A, Yoshikawa M, Yokota H, Fukui H, Ishizaka S, Tatsumi K, Takahashi Y: Identification of insulin-producing cells derived from embryonic stem cells by zinc-chelating dithizone. Stem Cells 2002, 20(4):284-292.
• [23]Kahan BW, Jacobson LM, Hullett DA, Ochoada JM, Oberley TD, Lang KM, Odorico JS: Pancreatic precursors and differentiated islet cell types from murine embryonic stem cells: an in vitro model to study islet differentiation. Diabetes 2003, 52(8):2016-2024.
• [24]Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R: Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 2001, 292(5520):1389-1394.
• [25]Hori Y, Rulifson IC, Tsai BC, Heit JJ, Cahoy JD, Kim SK: Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc Natl Acad Sci U S A 2002, 99(25):16105-16110.
• [26]Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L, Wobus AM: Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci U S A 2003, 100(3):998-1003.
• [27]Rajagopal J, Anderson WJ, Kume S, Martinez OI, Melton DA: Insulin staining of ES cell progeny from insulin uptake. Science 2003, 299(5605):363.
• [28]D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE: Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 2006, 24(11):1392-1401.
• [29]Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, Atkinson MA, Yang LJ: In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes 2004, 53(7):1721-1732.
• [30]Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, Barshack I, Seijffers R, Kopolovic J, Kaiser N, Karasik A: Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 2000, 6(5):568-572.
• [31]Koizumi M, Doi R, Toyoda E, Tulachan SS, Kami K, Mori T, Ito D, Kawaguchi Y, Fujimoto K, Gittes GK, Imamura M: Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver. Surgery 2004, 136(2):449-457.
• [32]Yamada S, Yamamoto Y, Nagasawa M, Hara A, Kodera T, Kojima I: In Vitro Transdifferentiation of Mature Hepatocytes into Insulin-Producing Cells. Endocr J 2006.
• [33]Cardona K, Korbutt GS, Milas Z, Lyon J, Cano J, Jiang W, Bello-Laborn H, Hacquoil B, Strobert E, Gangappa S, Weber CJ, Pearson TC, Rajotte RV, Larsen CP: Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med 2006, 12(3):304-306.
• [34]Hering BJ, Wijkstrom M, Graham ML, Hardstedt M, Aasheim TC, Jie T, Ansite JD, Nakano M, Cheng J, Li W, Moran K, Christians U, Finnegan C, Mills CD, Sutherland DE, Bansal-Pakala P, Murtaugh MP, Kirchhof N, Schuurman HJ: Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006, 12(3):301-303.
• [35]Ohneda K, Ee H, German M: Regulation of insulin gene transcription. Semin Cell Dev Biol 2000, 11(4):227-233.
• [36]Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS: Regulation of the insulin gene by glucose and fatty acids. J Nutr 2006, 136(4):873-876.
• [37]Ohneda K, Mirmira RG, Wang J, Johnson JD, German MS: The homeodomain of PDX-1 mediates multiple protein-protein interactions in the formation of a transcriptional activation complex on the insulin promoter. Mol Cell Biol 2000, 20(3):900-911.
• [38]Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, Oishi H, Hamada M, Morito N, Hasegawa K, Kudo T, Engel JD, Yamamoto M, Takahashi S: MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol 2005, 25(12):4969-4976.
• [39]Kataoka K, Han SI, Shioda S, Hirai M, Nishizawa M, Handa H: MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene. J Biol Chem 2002, 277(51):49903-49910.
• [40]Kataoka K, Shioda S, Ando K, Sakagami K, Handa H, Yasuda K: Differentially expressed Maf family transcription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet alpha- and beta-cells. J Mol Endocrinol 2004, 32(1):9-20.
• [41]Matsuoka TA, Artner I, Henderson E, Means A, Sander M, Stein R: The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc Natl Acad Sci U S A 2004, 101(9):2930-2933.
• [42]Orci L, Ravazzola M, Storch MJ, Anderson RG, Vassalli JD, Perrelet A: Proteolytic maturation of insulin is a post-Golgi event which occurs in acidifying clathrin-coated secretory vesicles. Cell 1987, 49(6):865-868.
• [43]Orci L, Ravazzola M, Amherdt M, Yanaihara C, Yanaihara N, Halban P, Renold AE, Perrelet A: Insulin, not C-peptide (proinsulin), is present in crinophagic bodies of the pancreatic B-cell. J Cell Biol 1984, 98(1):222-228.
• [44]Wek RC, Jiang HY, Anthony TG: Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 2006, 34(Pt 1):7-11.
• [45]Harding HP, Ron D: Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 2002, 51 Suppl 3:S455-61.
• [46]Haghighat A, Mader S, Pause A, Sonenberg N: Repression of cap-dependent translation by 4E-binding protein 1: competition with p220 for binding to eukaryotic initiation factor-4E. Embo J 1995, 14(22):5701-5709.
• [47]Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC Jr., Sonenberg N: Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature 1994, 371(6500):762-767.
• [48]Curry DL, Bennett LL, Grodsky GM: Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 1968, 83(3):572-584.
• [49]Henquin JC, Nenquin M, Stiernet P, Ahren B: In Vivo and In Vitro Glucose-Induced Biphasic Insulin Secretion in the Mouse: Pattern and Role of Cytoplasmic Ca2+ and Amplification Signals in {beta}-Cells. Diabetes 2006, 55(2):441-451.
• [50]Fehse F, Trautmann M, Holst JJ, Halseth AE, Nanayakkara N, Nielsen LL, Fineman MS, Kim DD, Nauck MA: Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2005, 90(11):5991-5997.
• [51]Kwan EP, Gaisano HY: Glucagon-like peptide 1 regulates sequential and compound exocytosis in pancreatic islet beta-cells. Diabetes 2005, 54(9):2734-2743.
• [52]Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J, Schermerhorn T, Straub SG, Yajima H, Sharp GW: Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion. Diabetes 2002, 51 Suppl 1:S83-90.
• [53]Rorsman P, Renstrom E: Insulin granule dynamics in pancreatic beta cells. Diabetologia 2003, 46(8):1029-1045.
• [54]Daniel S, Noda M, Straub SG, Sharp GW: Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. Diabetes 1999, 48(9):1686-1690.
• [55]Itoh N, Okamoto H: Translational control of proinsulin synthesis by glucose. Nature 1980, 283(5742):100-102.
• [56]Welsh M, Scherberg N, Gilmore R, Steiner DF: Translational control of insulin biosynthesis. Evidence for regulation of elongation, initiation and signal-recognition-particle-mediated translational arrest by glucose. Biochem J 1986, 235(2):459-467.
• [57]Maechler P, Carobbio S, Rubi B: In beta-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion. Int J Biochem Cell Biol 2006.
• [58]MacDonald PE, Wheeler MB: Voltage-dependent K(+) channels in pancreatic beta cells: role, regulation and potential as therapeutic targets. Diabetologia 2003, 46(8):1046-1062.
• [59]Fukui K, Yang Q, Cao Y, Takahashi N, Hatakeyama H, Wang H, Wada J, Zhang Y, Marselli L, Nammo T, Yoneda K, Onishi M, Higashiyama S, Matsuzawa Y, Gonzalez FJ, Weir GC, Kasai H, Shimomura I, Miyagawa J, Wollheim CB, Yamagata K: The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. Cell Metab 2005, 2(6):373-384.
• [60]Bruns D, Jahn R: Molecular determinants of exocytosis. Pflugers Arch 2002, 443(3):333-338.
• [61]Easom RA: Beta-granule transport and exocytosis. Semin Cell Dev Biol 2000, 11(4):253-266.
• [62]Barg S, Ma X, Eliasson L, Galvanovskis J, Gopel SO, Obermuller S, Platzer J, Renstrom E, Trus M, Atlas D, Striessnig J, Rorsman P: Fast exocytosis with few Ca(2+) channels in insulin-secreting mouse pancreatic B cells. Biophys J 2001, 81(6):3308-3323.
• [63]Barg S, Eliasson L, Renstrom E, Rorsman P: A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells. Diabetes 2002, 51 Suppl 1:S74-82.
• [64]Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M, Yamada Y, Mikoshiba K, Seino Y, Matsui H, Tomizawa K: Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nat Med 2005, 11(10):1104-1108.
• [65]Detimary P, Dejonghe S, Ling Z, Pipeleers D, Schuit F, Henquin JC: The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in beta cells but not in alpha cells and are also observed in human islets. J Biol Chem 1998, 273(51):33905-33908.
• [66]Maechler P, Wollheim CB: Mitochondrial function in normal and diabetic beta-cells. Nature 2001, 414(6865):807-812.
• [67]Barg S, Huang P, Eliasson L, Nelson DJ, Obermuller S, Rorsman P, Thevenod F, Renstrom E: Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification. J Cell Sci 2001, 114(Pt 11):2145-2154.
• [68]Thevenod F: Ion channels in secretory granules of the pancreas and their role in exocytosis and release of secretory proteins. Am J Physiol Cell Physiol 2002, 283(3):C651-72.
• [69]Goodge KA, Hutton JC: Translational regulation of proinsulin biosynthesis and proinsulin conversion in the pancreatic beta-cell. Semin Cell Dev Biol 2000, 11(4):235-242.
• [70]Efrat S, Surana M, Fleischer N: Glucose induces insulin gene transcription in a murine pancreatic beta-cell line. J Biol Chem 1991, 266(17):11141-11143.
• [71]Welsh M, Nielsen DA, MacKrell AJ, Steiner DF: Control of insulin gene expression in pancreatic beta-cells and in an insulin-producing cell line, RIN-5F cells. II. Regulation of insulin mRNA stability. J Biol Chem 1985, 260(25):13590-13594.
• [72]Philippe J, Pacheco I, Meda P: Insulin gene transcription is decreased rapidly by lowering glucose concentrations in rat islet cells. Diabetes 1994, 43(4):523-528.
• [73]Brunstedt J, Chan SJ: Direct effect of glucose on the preproinsulin mRNA level in isolated pancreatic islets. Biochem Biophys Res Commun 1982, 106(4):1383-1389.
• [74]Wicksteed B, Herbert TP, Alarcon C, Lingohr MK, Moss LG, Rhodes CJ: Cooperativity between the preproinsulin mRNA untranslated regions is necessary for glucose-stimulated translation. J Biol Chem 2001, 276(25):22553-22558.
• [75]Shalev A, Blair PJ, Hoffmann SC, Hirshberg B, Peculis BA, Harlan DM: A proinsulin gene splice variant with increased translation efficiency is expressed in human pancreatic islets. Endocrinology 2002, 143(7):2541-2547.
• [76]Leibowitz G, Oprescu AI, Uckaya G, Gross DJ, Cerasi E, Kaiser N: Insulin does not mediate glucose stimulation of proinsulin biosynthesis. Diabetes 2003, 52(4):998-1003.
• [77]Wicksteed B, Alarcon C, Briaud I, Lingohr MK, Rhodes CJ: Glucose-induced translational control of proinsulin biosynthesis is proportional to preproinsulin mRNA levels in islet beta-cells but not regulated via a positive feedback of secreted insulin. J Biol Chem 2003, 278(43):42080-42090.
• [78]Leibiger B, Moede T, Schwarz T, Brown GR, Kohler M, Leibiger IB, Berggren PO: Short-term regulation of insulin gene transcription by glucose. Proc Natl Acad Sci U S A 1998, 95(16):9307-9312.
• [79]Marshak S, Totary H, Cerasi E, Melloul D: Purification of the beta-cell glucose-sensitive factor that transactivates the insulin gene differentially in normal and transformed islet cells. Proc Natl Acad Sci U S A 1996, 93(26):15057-15062.
• [80]Olbrot M, Rud J, Moss LG, Sharma A: Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci U S A 2002, 99(10):6737-6742.
• [81]Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R: Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol Cell Biol 2003, 23(17):6049-6062.
• [82]Qiu Y, Sharma A, Stein R: p300 mediates transcriptional stimulation by the basic helix-loop-helix activators of the insulin gene. Mol Cell Biol 1998, 18(5):2957-2964.
• [83]Kaneto H, Sharma A, Suzuma K, Laybutt DR, Xu G, Bonner-Weir S, Weir GC: Induction of c-Myc expression suppresses insulin gene transcription by inhibiting NeuroD/BETA2-mediated transcriptional activation. J Biol Chem 2002, 277(15):12998-13006.
• [84]Melloul D, Ben-Neriah Y, Cerasi E: Glucose modulates the binding of an islet-specific factor to a conserved sequence within the rat I and the human insulin promoters. Proc Natl Acad Sci U S A 1993, 90(9):3865-3869.
• [85]Sharma A, Fusco-DeMane D, Henderson E, Efrat S, Stein R: The role of the insulin control element and RIPE3b1 activators in glucose-stimulated transcription of the insulin gene. Mol Endocrinol 1995, 9(11):1468-1476.
• [86]Aramata S, Han SI, Yasuda K, Kataoka K: Synergistic activation of the insulin gene promoter by the beta-cell enriched transcription factors MafA, Beta2, and Pdx1. Biochim Biophys Acta 2005, 1730(1):41-46.
• [87]Glick E, Leshkowitz D, Walker MD: Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter. J Biol Chem 2000, 275(3):2199-2204.
• [88]Zhao L, Guo M, Matsuoka TA, Hagman DK, Parazzoli SD, Poitout V, Stein R: The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription. J Biol Chem 2005, 280(12):11887-11894.
• [89]Hagman DK, Hays LB, Parazzoli SD, Poitout V: Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans. J Biol Chem 2005, 280(37):32413-32418.
• [90]Mosley AL, Corbett JA, Ozcan S: Glucose regulation of insulin gene expression requires the recruitment of p300 by the beta-cell-specific transcription factor Pdx-1. Mol Endocrinol 2004, 18(9):2279-2290.
• [91]Pedersen AA, Petersen HV, Videbaek N, Skak K, Michelsen BK: PDX-1 mediates glucose responsiveness of GAD(67), but not GAD(65), gene transcription in islets of Langerhans. Biochem Biophys Res Commun 2002, 295(2):243-248.
• [92]Melloul D, Marshak S, Cerasi E: Regulation of insulin gene transcription. Diabetologia 2002, 45(3):309-326.
• [93]Peshavaria M, Cissell MA, Henderson E, Petersen HV, Stein R: The PDX-1 activation domain provides specific functions necessary for transcriptional stimulation in pancreatic beta-cells. Mol Endocrinol 2000, 14(12):1907-1917.
• [94]Shushan EB, Cerasi E, Melloul D: Regulation of the insulin gene by glucose: stimulation of trans-activation potency of human PDX-1 N-terminal domain. DNA Cell Biol 1999, 18(6):471-479.
• [95]Elrick LJ, Docherty K: Phosphorylation-dependent nucleocytoplasmic shuttling of pancreatic duodenal homeobox-1. Diabetes 2001, 50(10):2244-2252.
• [96]Rafiq I, da Silva Xavier G, Hooper S, Rutter GA: Glucose-stimulated preproinsulin gene expression and nuclear trans-location of pancreatic duodenum homeobox-1 require activation of phosphatidylinositol 3-kinase but not p38 MAPK/SAPK2. J Biol Chem 2000, 275(21):15977-15984.
• [97]Leibiger IB, Leibiger B, Moede T, Berggren PO: Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol Cell 1998, 1(6):933-938.
• [98]Xu GG, Gao ZY, Borge PD Jr., Jegier PA, Young RA, Wolf BA: Insulin regulation of beta-cell function involves a feedback loop on SERCA gene expression, Ca(2+) homeostasis, and insulin expression and secretion. Biochemistry 2000, 39(48):14912-14919.
• [99]Leibiger B, Wahlander K, Berggren PO, Leibiger IB: Glucose-stimulated insulin biosynthesis depends on insulin-stimulated insulin gene transcription. J Biol Chem 2000, 275(39):30153-30156.
• [100]Mosley AL, Ozcan S: The pancreatic duodenal homeobox-1 protein (Pdx-1) interacts with histone deacetylases Hdac-1 and Hdac-2 on low levels of glucose. J Biol Chem 2004, 279(52):54241-54247.
• [101]Naya FJ, Stellrecht CM, Tsai MJ: Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dev 1995, 9(8):1009-1019.
• [102]Odagiri H, Wang J, German MS: Function of the human insulin promoter in primary cultured islet cells. J Biol Chem 1996, 271(4):1909-1915.
• [103]Amemiya-Kudo M, Oka J, Ide T, Matsuzaka T, Sone H, Yoshikawa T, Yahagi N, Ishibashi S, Osuga J, Yamada N, Murase T, Shimano H: Sterol regulatory element-binding proteins activate insulin gene promoter directly and indirectly through synergy with BETA2/E47. J Biol Chem 2005, 280(41):34577-34589.
• [104]Khoo S, Griffen SC, Xia Y, Baer RJ, German MS, Cobb MH: Regulation of insulin gene transcription by ERK1 and ERK2 in pancreatic beta cells. J Biol Chem 2003, 278(35):32969-32977.
• [105]Lawrence MC, McGlynn K, Park BH, Cobb MH: ERK1/2-dependent activation of transcription factors required for acute and chronic effects of glucose on the insulin gene promoter. J Biol Chem 2005, 280(29):26751-26759.
• [106]Susini S, Roche E, Prentki M, Schlegel W: Glucose and glucoincretin peptides synergize to induce c-fos, c-jun, junB, zif-268, and nur-77 gene expression in pancreatic beta(INS-1) cells. Faseb J 1998, 12(12):1173-1182.
• [107]Josefsen K, Sorensen LR, Buschard K, Birkenbach M: Glucose induces early growth response gene (Egr-1) expression in pancreatic beta cells. Diabetologia 1999, 42(2):195-203.
• [108]Leibowitz G, Uckaya G, Oprescu AI, Cerasi E, Gross DJ, Kaiser N: Glucose-regulated proinsulin gene expression is required for adequate insulin production during chronic glucose exposure. Endocrinology 2002, 143(9):3214-3220.
• [109]Leibiger B, Moede T, Uhles S, Berggren PO, Leibiger IB: Short-term regulation of insulin gene transcription. Biochem Soc Trans 2002, 30(2):312-317.
• [110]Schuit FC, In't Veld PA, Pipeleers DG: Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells. Proc Natl Acad Sci U S A 1988, 85(11):3865-3869.
• [111]Gilligan M, Welsh GI, Flynn A, Bujalska I, Diggle TA, Denton RM, Proud CG, Docherty K: Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. J Biol Chem 1996, 271(4):2121-2125.
• [112]Yan L, Nairn AC, Palfrey HC, Brady MJ: Glucose regulates EF-2 phosphorylation and protein translation by a protein phosphatase-2A-dependent mechanism in INS-1-derived 832/13 cells. J Biol Chem 2003, 278(20):18177-18183.
• [113]Xu G, Marshall CA, Lin TA, Kwon G, Munivenkatappa RB, Hill JR, Lawrence JC Jr., McDaniel ML: Insulin mediates glucose-stimulated phosphorylation of PHAS-I by pancreatic beta cells. An insulin-receptor mechanism for autoregulation of protein synthesis by translation. J Biol Chem 1998, 273(8):4485-4491.
• [114]Gomez E, Powell ML, Greenman IC, Herbert TP: Glucose-stimulated protein synthesis in pancreatic beta-cells parallels an increase in the availability of the translational ternary complex (eIF2-GTP.Met-tRNAi) and the dephosphorylation of eIF2 alpha. J Biol Chem 2004, 279(52):53937-53946.
• [115]Nielsen DA, Welsh M, Casadaban MJ, Steiner DF: Control of insulin gene expression in pancreatic beta-cells and in an insulin-producing cell line, RIN-5F cells. I. Effects of glucose and cyclic AMP on the transcription of insulin mRNA. J Biol Chem 1985, 260(25):13585-13589.
• [116]Yasuda K, Yamada Y, Inagaki N, Yano H, Okamoto Y, Tsuji K, Fukumoto H, Imura H, Seino S, Seino Y: Expression of GLUT1 and GLUT2 glucose transporter isoforms in rat islets of Langerhans and their regulation by glucose. Diabetes 1992, 41(1):76-81.
• [117]Brun T, Roche E, Kim KH, Prentki M: Glucose regulates acetyl-CoA carboxylase gene expression in a pancreatic beta-cell line (INS-1). J Biol Chem 1993, 268(25):18905-18911.
• [118]Marie S, Diaz-Guerra MJ, Miquerol L, Kahn A, Iynedjian PB: The pyruvate kinase gene as a model for studies of glucose-dependent regulation of gene expression in the endocrine pancreatic beta-cell type. J Biol Chem 1993, 268(32):23881-23890.
• [119]Choi Y, Ta M, Atouf F, Lumelsky N: Adult pancreas generates multipotent stem cells and pancreatic and nonpancreatic progeny. Stem Cells 2004, 22:1070-1084.