Insulin secretion and insulin-producing tumors.
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.
Guettier
Jean-Marc
JM
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.
Gorden
Phillip
P
Cell. 2002 May 3;109(3):321-34
12015982
Horm Metab Res. 1992 Apr;24(4):158-60
1601389
J Pathol. 2001 Aug;194(4):451-8
11523053
J Clin Invest. 2008 Nov;118(11):3629-38
18846252
Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8822-6
1528899
Expert Rev Anticancer Ther. 2009 May;9(5):557-66
19445573
J Clin Endocrinol Metab. 1994 May;78(5):1048-51
8175958
Diabetes. 1989 Jan;38(1):49-53
2642434
Diabetes. 1973 Sep;22(9):687-93
4125576
N Engl J Med. 1998 May 7;338(19):1352-7
9571255
J Biol Chem. 1999 Sep 3;274(36):25386-92
10464266
Nat Biotechnol. 2005 Jul;23(7):857-61
16003374
Br J Obstet Gynaecol. 1978 Nov;85(11):818-20
363135
Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):57-68
17179930
Nat Med. 2005 Feb;11(2):175-82
15685168
J Clin Invest. 1974 Oct;54(4):833-41
4430717
Pancreas. 1996 Jul;13(1):55-60
8783334
PLoS Biol. 2008 Feb;6(2):e37
18288891
Cell. 2004 Oct 1;119(1):61-74
15454081
Cell. 1988 Oct 21;55(2):281-90
3048704
Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19575-80
17158802
Mod Pathol. 1998 May;11(5):444-9
9619597
Nat Genet. 2006 May;38(5):583-8
16642022
Diabetes. 1990 Jun;39(6):647-52
2189759
J Biol Chem. 1994 Jul 8;269(27):17768-71
8027029
J Clin Invest. 2001 Dec;108(11):1631-8
11733558
J Biol Chem. 1989 Dec 25;264(36):21608-12
2689441
Endocr Rev. 2005 Aug;26(5):615-61
15632315
Endocrinology. 2000 Dec;141(12):4600-5
11108273
J Physiol. 1970 Sep;210(2):255-64
5501259
Diabetes. 2004 Jan;53(1):221-7
14693719
Lancet. 2004 Jan 31;363(9406):363-7
15070567
Diabetes. 2008 Jun;57(6):1584-94
18334605
J Clin Endocrinol Metab. 2007 Apr;92(4):1237-44
17227804
Gastrointest Endosc. 2000 May;51(5):552-5
10805840
J Clin Invest. 2007 Jan;117(1):246-57
17200721
Mayo Clin Proc. 1991 Jul;66(7):711-9
1677058
J Clin Invest. 2001 Aug;108(3):457-65
11489939
Am J Physiol Endocrinol Metab. 2005 Jan;288(1):E1-15
15585595
J Pediatr. 1971 Aug;79(2):226-31
4104455
Nature. 1988 May 5;333(6168):93-6
3283564
Am J Pathol. 1999 Dec;155(6):1787-94
10595906
Surgery. 1997 Dec;122(6):1189-93; discussion 1193-4
9426437
J Clin Endocrinol Metab. 1995 Oct;80(10):2884-7
7559869
N Engl J Med. 2005 Jul 21;353(3):249-54
16034010
Biochem J. 1994 Apr 1;299 ( Pt 1):1-18
8166626
Neuron. 1997 May;18(5):827-38
9182806
Nat Med. 2001 Oct;7(10):1133-7
11590437
J Clin Endocrinol Metab. 2009 Apr;94(4):1074-80
19190102
Nature. 1999 Dec 9;402(6762):685-9
10604477
Horm Metab Res. 1976;Suppl 6:7-18
179934
Gut. 1996 Oct;39(4):562-8
8944566
J Biol Chem. 2006 Oct 13;281(41):30593-602
16912049
N Engl J Med. 2008 Aug 14;359(7):766-8
18703486
J Clin Endocrinol Metab. 2009 Apr;94(4):1069-73
19141587
J Biol Chem. 2002 Dec 27;277(52):50805-11
12393909
J Biol Chem. 1994 Feb 18;269(7):4895-902
8106462
Diabetes. 2002 Feb;51 Suppl 1:S74-82
11815462
Biochem J. 2004 Jul 1;381(Pt 1):13-8
15128287
J Clin Invest. 2002 May;109(9):1193-201
11994408
Nature. 1998 Feb 26;391(6670):900-4
9495343
J Clin Endocrinol Metab. 1972 Aug;35(2):271-80
4342038
Endocr Relat Cancer. 2005 Jun;12(2):435-47
15947114
Nature. 1968 Jul 27;219(5152):389-90
4873864
Diabetes. 2000 Nov;49(11):1751-60
11078440
World J Surg. 1993 Jul-Aug;17(4):444-7
8395748
Endoscopy. 1996 Mar;28(3):273-6
8781789
J Biol Chem. 1995 Aug 25;270(34):20051-8
7650022
Biochem J. 1998 Jul 1;333 ( Pt 1):193-9
9639579
J Biol Chem. 1994 Jan 21;269(3):1756-62
7507483
Acta Oncol. 2004;43(7):617-25
15545182
Ann N Y Acad Sci. 1994 Sep 15;733:416-24
7978890
Int J Cancer. 2007 May 15;120(10):2157-64
17278096
J Biol Chem. 2006 Jun 9;281(23):15884-92
16574657
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2708-13
11880625
Endocrinol Metab Clin North Am. 2006 Dec;35(4):753-66, viii-ix
17127144
J Pathol. 1998 Dec;186(4):363-71
10209484
Am J Surg Pathol. 2009 Mar;33(3):339-46
19011561
Endocrinology. 1992 Feb;130(2):748-54
1733723
J Clin Endocrinol Metab. 1970 Mar;30(3):273-81
4312791
Nature. 2000 Dec 21-28;408(6815):994-7
11140689
Diabetes Obes Metab. 2007 Nov;9 Suppl 2:118-32
17919186
Diabetologia. 1973 Apr;9(2):115-9
4577291
Genes Chromosomes Cancer. 2001 Dec;32(4):364-72
11746977
J Clin Endocrinol Metab. 1999 May;84(5):1582-9
10323384
Cancer Res. 1997 Nov 1;57(21):4682-6
9354421
J Biol Chem. 1992 Mar 25;267(9):5802-10
1556096
Ann Intern Med. 1998 Sep 15;129(6):484-94
9735087
Endocrinology. 1993 Feb;132(2):879-87
8425500
N Engl J Med. 1971 May 6;284(18):1003-8
4324225
Diabetes Care. 2006 Jul;29(7):1554-9
16801578
Am J Hum Genet. 2007 Sep;81(3):467-74
17701893
Genes Dev. 2003 Jul 1;17(13):1575-80
12842910
Nature. 1984 Nov 29-Dec 5;312(5993):446-8
6095103
Am J Pathol. 2001 Jun;158(6):1903-11
11395364
Cell. 1987 Jun 19;49(6):865-8
3555846
Diabetes Obes Metab. 2007 Nov;9 Suppl 2:147-57
17919189
Diabetes. 2006 Feb;55(2):441-51
16443779
Diabetes. 2003 Jan;52(1):199-204
12502513
Proc Natl Acad Sci U S A. 2009 May 5;106(18):7432-6
19372374
Diabetes. 2007 Jul;56(7):1792-801
17400928
J Clin Invest. 1971 Oct;50(10):2113-22
4330005
Nature. 2004 May 6;429(6987):41-6
15129273
J Clin Invest. 2004 Oct;114(7):963-8
15467835
Proc Natl Acad Sci U S A. 1968 Sep;61(1):138-45
4301586
J Cell Sci. 2002 Nov 1;115(Pt 21):4177-89
12356920
Cancer. 2005 Jul 15;104(2):264-72
15937909
Scand J Gastroenterol. 2002 Jun;37(6):732-7
12126255
Proc Natl Acad Sci U S A. 1967 Feb;57(2):473-80
16591494
Am J Surg Pathol. 1989 Sep;13(9):766-75
2669541
N Engl J Med. 1998 Jan 22;338(4):226-30
9435328
Am J Surg Pathol. 2006 May;30(5):560-74
16699310
Nature. 1984 Sep 20-26;311(5983):271-3
6090930
J Clin Endocrinol Metab. 2000 Sep;85(9):3222-6
10999812
Diabetologia. 2005 Nov;48(11):2236-40
16195867
Biochem J. 1987 Jul 15;245(2):575-82
2822027
J Clin Invest. 2002 Dec;110(12):1839-47
12488434
Diabetes Care. 2006 Mar;29(3):717-8
16505537
Diabetes. 2003 Jan;52(1):102-10
12502499