title: Insulin secretion and insulin-producing tumors.
abstract: Insulinomas are rare neuroendocrine tumors of pancreatic islet cells that retain the ability to produce and secrete insulin. In contrast to normally differentiated β-cells, insulinoma cells continue to secrete insulin and proinsulin at low blood glucose. This deregulated insulin secretion manifests clinically as fasting hypoglycemia. The molecular pathways that characterize normal insulin secretion and β-cell growth are reviewed and contrasted to the biology of insulinomas. The second half of this review summarizes the clinical approach to the disorder. The diagnosis of insulinoma is established by demonstrating inappropriately high insulin levels with coincident hypoglycemia at the time of a supervised fast. Localization of insulinomas is challenging owing to their small size but should be attempted to maximize the chance for successful surgical resection and avoid risks associated with reoperation. In the majority of cases, successful surgical resection leads to lifelong cure.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Building 10-CRC, Room 6-5952, 10 Center Drive, Bethesda, MD 20892-1612, USA, Tel.: +1 301 496 1913, ,  guettierj@mail.nih.gov.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Guettier
authors.forename: Phillip
authors.initials: P
authors.lastname: Gorden
references.citation: Cell. 2002 May 3;109(3):321-34
references.pmid: 12015982
references.citation: Horm Metab Res. 1992 Apr;24(4):158-60
references.pmid: 1601389
references.citation: J Pathol. 2001 Aug;194(4):451-8
references.pmid: 11523053
references.citation: J Clin Invest. 2008 Nov;118(11):3629-38
references.pmid: 18846252
references.citation: Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8822-6
references.pmid: 1528899
references.citation: Expert Rev Anticancer Ther. 2009 May;9(5):557-66
references.pmid: 19445573
references.citation: J Clin Endocrinol Metab. 1994 May;78(5):1048-51
references.pmid: 8175958
references.citation: Diabetes. 1989 Jan;38(1):49-53
references.pmid: 2642434
references.citation: Diabetes. 1973 Sep;22(9):687-93
references.pmid: 4125576
references.citation: N Engl J Med. 1998 May 7;338(19):1352-7
references.pmid: 9571255
references.citation: J Biol Chem. 1999 Sep 3;274(36):25386-92
references.pmid: 10464266
references.citation: Nat Biotechnol. 2005 Jul;23(7):857-61
references.pmid: 16003374
references.citation: Br J Obstet Gynaecol. 1978 Nov;85(11):818-20
references.pmid: 363135
references.citation: Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):57-68
references.pmid: 17179930
references.citation: Nat Med. 2005 Feb;11(2):175-82
references.pmid: 15685168
references.citation: J Clin Invest. 1974 Oct;54(4):833-41
references.pmid: 4430717
references.citation: Pancreas. 1996 Jul;13(1):55-60
references.pmid: 8783334
references.citation: PLoS Biol. 2008 Feb;6(2):e37
references.pmid: 18288891
references.citation: Cell. 2004 Oct 1;119(1):61-74
references.pmid: 15454081
references.citation: Cell. 1988 Oct 21;55(2):281-90
references.pmid: 3048704
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19575-80
references.pmid: 17158802
references.citation: Mod Pathol. 1998 May;11(5):444-9
references.pmid: 9619597
references.citation: Nat Genet. 2006 May;38(5):583-8
references.pmid: 16642022
references.citation: Diabetes. 1990 Jun;39(6):647-52
references.pmid: 2189759
references.citation: J Biol Chem. 1994 Jul 8;269(27):17768-71
references.pmid: 8027029
references.citation: J Clin Invest. 2001 Dec;108(11):1631-8
references.pmid: 11733558
references.citation: J Biol Chem. 1989 Dec 25;264(36):21608-12
references.pmid: 2689441
references.citation: Endocr Rev. 2005 Aug;26(5):615-61
references.pmid: 15632315
references.citation: Endocrinology. 2000 Dec;141(12):4600-5
references.pmid: 11108273
references.citation: J Physiol. 1970 Sep;210(2):255-64
references.pmid: 5501259
references.citation: Diabetes. 2004 Jan;53(1):221-7
references.pmid: 14693719
references.citation: Lancet. 2004 Jan 31;363(9406):363-7
references.pmid: 15070567
references.citation: Diabetes. 2008 Jun;57(6):1584-94
references.pmid: 18334605
references.citation: J Clin Endocrinol Metab. 2007 Apr;92(4):1237-44
references.pmid: 17227804
references.citation: Gastrointest Endosc. 2000 May;51(5):552-5
references.pmid: 10805840
references.citation: J Clin Invest. 2007 Jan;117(1):246-57
references.pmid: 17200721
references.citation: Mayo Clin Proc. 1991 Jul;66(7):711-9
references.pmid: 1677058
references.citation: J Clin Invest. 2001 Aug;108(3):457-65
references.pmid: 11489939
references.citation: Am J Physiol Endocrinol Metab. 2005 Jan;288(1):E1-15
references.pmid: 15585595
references.citation: J Pediatr. 1971 Aug;79(2):226-31
references.pmid: 4104455
references.citation: Nature. 1988 May 5;333(6168):93-6
references.pmid: 3283564
references.citation: Am J Pathol. 1999 Dec;155(6):1787-94
references.pmid: 10595906
references.citation: Surgery. 1997 Dec;122(6):1189-93; discussion 1193-4
references.pmid: 9426437
references.citation: J Clin Endocrinol Metab. 1995 Oct;80(10):2884-7
references.pmid: 7559869
references.citation: N Engl J Med. 2005 Jul 21;353(3):249-54
references.pmid: 16034010
references.citation: Biochem J. 1994 Apr 1;299 ( Pt 1):1-18
references.pmid: 8166626
references.citation: Neuron. 1997 May;18(5):827-38
references.pmid: 9182806
references.citation: Nat Med. 2001 Oct;7(10):1133-7
references.pmid: 11590437
references.citation: J Clin Endocrinol Metab. 2009 Apr;94(4):1074-80
references.pmid: 19190102
references.citation: Nature. 1999 Dec 9;402(6762):685-9
references.pmid: 10604477
references.citation: Horm Metab Res. 1976;Suppl 6:7-18
references.pmid: 179934
references.citation: Gut. 1996 Oct;39(4):562-8
references.pmid: 8944566
references.citation: J Biol Chem. 2006 Oct 13;281(41):30593-602
references.pmid: 16912049
references.citation: N Engl J Med. 2008 Aug 14;359(7):766-8
references.pmid: 18703486
references.citation: J Clin Endocrinol Metab. 2009 Apr;94(4):1069-73
references.pmid: 19141587
references.citation: J Biol Chem. 2002 Dec 27;277(52):50805-11
references.pmid: 12393909
references.citation: J Biol Chem. 1994 Feb 18;269(7):4895-902
references.pmid: 8106462
references.citation: Diabetes. 2002 Feb;51 Suppl 1:S74-82
references.pmid: 11815462
references.citation: Biochem J. 2004 Jul 1;381(Pt 1):13-8
references.pmid: 15128287
references.citation: J Clin Invest. 2002 May;109(9):1193-201
references.pmid: 11994408
references.citation: Nature. 1998 Feb 26;391(6670):900-4
references.pmid: 9495343
references.citation: J Clin Endocrinol Metab. 1972 Aug;35(2):271-80
references.pmid: 4342038
references.citation: Endocr Relat Cancer. 2005 Jun;12(2):435-47
references.pmid: 15947114
references.citation: Nature. 1968 Jul 27;219(5152):389-90
references.pmid: 4873864
references.citation: Diabetes. 2000 Nov;49(11):1751-60
references.pmid: 11078440
references.citation: World J Surg. 1993 Jul-Aug;17(4):444-7
references.pmid: 8395748
references.citation: Endoscopy. 1996 Mar;28(3):273-6
references.pmid: 8781789
references.citation: J Biol Chem. 1995 Aug 25;270(34):20051-8
references.pmid: 7650022
references.citation: Biochem J. 1998 Jul 1;333 ( Pt 1):193-9
references.pmid: 9639579
references.citation: J Biol Chem. 1994 Jan 21;269(3):1756-62
references.pmid: 7507483
references.citation: Acta Oncol. 2004;43(7):617-25
references.pmid: 15545182
references.citation: Ann N Y Acad Sci. 1994 Sep 15;733:416-24
references.pmid: 7978890
references.citation: Int J Cancer. 2007 May 15;120(10):2157-64
references.pmid: 17278096
references.citation: J Biol Chem. 2006 Jun 9;281(23):15884-92
references.pmid: 16574657
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2708-13
references.pmid: 11880625
references.citation: Endocrinol Metab Clin North Am. 2006 Dec;35(4):753-66, viii-ix
references.pmid: 17127144
references.citation: J Pathol. 1998 Dec;186(4):363-71
references.pmid: 10209484
references.citation: Am J Surg Pathol. 2009 Mar;33(3):339-46
references.pmid: 19011561
references.citation: Endocrinology. 1992 Feb;130(2):748-54
references.pmid: 1733723
references.citation: J Clin Endocrinol Metab. 1970 Mar;30(3):273-81
references.pmid: 4312791
references.citation: Nature. 2000 Dec 21-28;408(6815):994-7
references.pmid: 11140689
references.citation: Diabetes Obes Metab. 2007 Nov;9 Suppl 2:118-32
references.pmid: 17919186
references.citation: Diabetologia. 1973 Apr;9(2):115-9
references.pmid: 4577291
references.citation: Genes Chromosomes Cancer. 2001 Dec;32(4):364-72
references.pmid: 11746977
references.citation: J Clin Endocrinol Metab. 1999 May;84(5):1582-9
references.pmid: 10323384
references.citation: Cancer Res. 1997 Nov 1;57(21):4682-6
references.pmid: 9354421
references.citation: J Biol Chem. 1992 Mar 25;267(9):5802-10
references.pmid: 1556096
references.citation: Ann Intern Med. 1998 Sep 15;129(6):484-94
references.pmid: 9735087
references.citation: Endocrinology. 1993 Feb;132(2):879-87
references.pmid: 8425500
references.citation: N Engl J Med. 1971 May 6;284(18):1003-8
references.pmid: 4324225
references.citation: Diabetes Care. 2006 Jul;29(7):1554-9
references.pmid: 16801578
references.citation: Am J Hum Genet. 2007 Sep;81(3):467-74
references.pmid: 17701893
references.citation: Genes Dev. 2003 Jul 1;17(13):1575-80
references.pmid: 12842910
references.citation: Nature. 1984 Nov 29-Dec 5;312(5993):446-8
references.pmid: 6095103
references.citation: Am J Pathol. 2001 Jun;158(6):1903-11
references.pmid: 11395364
references.citation: Cell. 1987 Jun 19;49(6):865-8
references.pmid: 3555846
references.citation: Diabetes Obes Metab. 2007 Nov;9 Suppl 2:147-57
references.pmid: 17919189
references.citation: Diabetes. 2006 Feb;55(2):441-51
references.pmid: 16443779
references.citation: Diabetes. 2003 Jan;52(1):199-204
references.pmid: 12502513
references.citation: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7432-6
references.pmid: 19372374
references.citation: Diabetes. 2007 Jul;56(7):1792-801
references.pmid: 17400928
references.citation: J Clin Invest. 1971 Oct;50(10):2113-22
references.pmid: 4330005
references.citation: Nature. 2004 May 6;429(6987):41-6
references.pmid: 15129273
references.citation: J Clin Invest. 2004 Oct;114(7):963-8
references.pmid: 15467835
references.citation: Proc Natl Acad Sci U S A. 1968 Sep;61(1):138-45
references.pmid: 4301586
references.citation: J Cell Sci. 2002 Nov 1;115(Pt 21):4177-89
references.pmid: 12356920
references.citation: Cancer. 2005 Jul 15;104(2):264-72
references.pmid: 15937909
references.citation: Scand J Gastroenterol. 2002 Jun;37(6):732-7
references.pmid: 12126255
references.citation: Proc Natl Acad Sci U S A. 1967 Feb;57(2):473-80
references.pmid: 16591494
references.citation: Am J Surg Pathol. 1989 Sep;13(9):766-75
references.pmid: 2669541
references.citation: N Engl J Med. 1998 Jan 22;338(4):226-30
references.pmid: 9435328
references.citation: Am J Surg Pathol. 2006 May;30(5):560-74
references.pmid: 16699310
references.citation: Nature. 1984 Sep 20-26;311(5983):271-3
references.pmid: 6090930
references.citation: J Clin Endocrinol Metab. 2000 Sep;85(9):3222-6
references.pmid: 10999812
references.citation: Diabetologia. 2005 Nov;48(11):2236-40
references.pmid: 16195867
references.citation: Biochem J. 1987 Jul 15;245(2):575-82
references.pmid: 2822027
references.citation: J Clin Invest. 2002 Dec;110(12):1839-47
references.pmid: 12488434
references.citation: Diabetes Care. 2006 Mar;29(3):717-8
references.pmid: 16505537
references.citation: Diabetes. 2003 Jan;52(1):102-10
references.pmid: 12502499