Persistent hyperinsulinemic hypoglycemia of infancy: Constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications

International Journal of Clinical and Experimental Pathology

Volumn 3, Issue 7, 2010, Pages 691-705

  Alexandrescu, Sanda ^a   Tatevian, Nina ^a   Olutoye, Oluyinka ^b   Brown, Robert E ^a  

^a UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^b BAYLOR COLLEGE OF MEDICINE   (United States)

Author keywords

MTOR; PHHI; Rapamycin; Transdifferentiation

Indexed keywords

INSULIN; MAMMALIAN TARGET OF RAPAMYCIN; MTOR PROTEIN, HUMAN;

ARTICLE; BIOSYNTHESIS; CASE REPORT; CELL TRANSDIFFERENTIATION; HUMAN; IMMUNOHISTOCHEMISTRY; MALE; METABOLISM; NEWBORN; PANCREAS; PANCREAS ISLET; PATHOLOGY; PERSISTENT HYPERINSULINEMIC HYPOGLYCEMIA OF INFANCY; PHYSIOLOGY; SIGNAL TRANSDUCTION; TRANSMISSION ELECTRON MICROSCOPY;

CELL TRANSDIFFERENTIATION; HUMANS; IMMUNOHISTOCHEMISTRY; INFANT, NEWBORN; INSULIN; ISLETS OF LANGERHANS; MALE; MICROSCOPY, ELECTRON, TRANSMISSION; PANCREAS; PERSISTENT HYPERINSULINEMIA HYPOGLYCEMIA OF INFANCY; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 77956075102     PISSN: None     EISSN: 19362625     Source Type: Journal    
DOI: None     Document Type: Article

References (36)

1. Suchi M, MacMullen C, Thornton PS, Ganguly A, Stanley CA, Ruchelli ED. Histopathology of Congenital Hyperinsulinism: Retrospective Study with Genotype Correlations. Pediatr Dev Pathol 2003;6:322-333
2. Rahier J, Sempoux C, Fournet JC, Poggi F, et al. Partial or near total pancreatectomy for persistent neonatal hyperinsulinaemic hypoglycaemia: the pathologist's role. Histopathology, 1998;32:15-19
3. Sempoux C, Guiot Y, Lefevre A, et al. Neonatal hyperinsulinemic hypoglycemia: Heterogeneity of the syndrome and keys for differential diagnosis. Journal of Clinical Endocrinology and Metabolism, 1998;83:1455-1461
4. Brunetti-Pierri N, Olutoye O, Heptulla R, Tatevian N. Pathological features of aberrant pancreatic development in congenital hyperinsulinism due to ABCC8 mutations. Annals of Clinical and Laboratory Science, 2008; vol. 38(4):386-389
5. Thornton PS, MacMullen C, Ganguly A et al. Clinical and molecular characterization of a dominant form of congenital hyperinsulinism caused by a mutation in the high-affinity sulfonylurea receptor. Diabetes, September 2003;52:2403-2410
6. Sempoux C, Guiot Y, Dahan K, et al. The focal form of persistent hyperinsulinemic hypoglycemia of infancy. Morphological and Molecular studies show structural and functional differences with insulinoma. Diabetes, March 2003; vol. 52:784-794
7. Brown RE. Morphogenomics and morphoproteomics. A role for Anatomic pathology in personalized medicine. Arch Pathol Lab Med, 2009;vol. 133:568-579
8. Estrada JC, Selim MA, Miller SE. TEM of paraffinembedded H&E-stained sections for viral diagnosis (an unusual papovavirus case). Microsc Microanal 11(Suppl 2), 2005:964-965
9. Mori H, Inoki K, Opland D, et al. Critical roles for the TSC-mTOR pathway in {beta}-cell function. Am. J. Physiol. Endocrinol. Metab., 2009; 8:18
10. Bani D, Bani Sacchi T, Biliotti G. Nesidioblastosis and intermediate cells in the pancreas of patients with hyperinsulinemic hypoglycemia. Virchows Arch [Cell Pathol] 1995;48:19-32
11. Chiarle R, Fan Y, Piva R, et al. S-Phase kinaseassociated protein 2 expression in non-Hodgkin's lymphoma inversely correlated with p27 expression and defines cells in S phase. Am J Pathol. 2002 Apr;160(4):1457-66
12. Chiarle R, Pagano M, Inghirami G. The cyclin dependent kinase inhibitor p27 and its prognostic role in breast cancer. Breast Cancer Res. 2001; 3(2):91-94
13. Sempoux C. Pancreatic beta-cell proliferation in persistent hyperinsulinemic hypoglycemia of infancy: an immunohistochemical study of 18 cases. Mod. Pathol. 1998 May;11(5):444-449
14. Lovisolo SM, Mendonca BB, Pinto EM, Della Manna T, Saldiva PH, Zerbini MC. Congenital hyperinsulinism in Brazillian neonates: A study of histology, K ATP channel genes and proliferation of beta-cells. Pediatr. Dev. Pathol. 2010 May19 [Epub ahead of print].
15. Kushner JA. B-cell growth. An unusual paradigm of organogenesis that is cyclin D2/Cdk4 dependent. Cell Cycle, February 2006; 5:3, 234-237
16. Song KH, Ko SH, Ahn YB, et al. In vitro transifferentiation of adult pancreatic acinar cells into insulin-expressing cells. Biochemical and Biophysical Research Communications 2004;316:1094-1100
17. Bouwens L. Transdifferentiation versus stem cell hypothesis for the regeneration of islet beta-cells in the pancreas. Microscopy Research and Technique 1998;43:332-336
18. Thorel F, Nepote V, Avril I, et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 2010, Apr 4.
19. Kane C, Shepherd RM, Squires PE, et al. Loss of functional KATP channels in pancreatic betacells causes persistent hyperinsulinemic hypoglycemia of infancy. Nat Med. 1996 Dec;2 (12):1344-1347
20. Adebiyi A, McNally EM, Jagar JH. Sulfonylurea receptor-dependent and independent pathways mediate vasodilation induced by ATP-sensitive K+channel openers. Mol Pharmacol. 2008 Sep;74(3):736-743
21. Gulati P, Gaspers LD, Dann SG, et al. Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab. 2008 May;7 (5):456-465
22. Avruch J, Long X, Ortiz-Vega S, et al. Amino acid regulation of TOR complex1. Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E592-602
23. Masia R, Caputa G, Nichols CG. Regulation of KATP channel expression and activity by the SUR1 nucleotide binding fold 1. Channels (Austin) 2007 Jul-Aug;1(4):315-323
24. Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion. Diabetes 2002 Dec;51 Suppl 3:S368-376
25. Sanchez D, Gmyr V, Kerr-Conte J, et al. Implication of Reg I in human pancreatic duct-like cells in vivo in the pathological pancreas and in vitro during exocrine dedifferentiation. Pancreas 2004 July; 29(1):14-21
26. Tezel E, Nagasaka T, Tezel G, et al. Reg I as a marker for human pancreatic acinoductular cells. Hepatogastroenterology 2004 Jan-Feb; 51 (55):91-96
27. Weernink PAO, Lopez de Jesus M, Schmidt M. Phospholipase D signaling: orchestration by PIP2 and small GTPases. Naunyn-Schmiedeberg's Arch Pharmacol. 2007;374:399-411
28. Tanemura M, Saga A, Kawamoto K, et al. Rapamycin induces autophagy in islets: Relevance in islet transplantation. Transplantation Proceedings 2009;41:334-338
29. Bussiere CT, Lakey JRT, Shapiro AMJ, Korbutt GS. The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia 2006;49:2341-2349
30. Shanbag P, Pathak A, Vaidya M, Shahid SK. Persistent hyperinsulinemic hypoglycemia of infancy - successful therapy with nifedipine. Indian J Pediatr. 2002 Mar;69(3):271-272
31. Muller D, Zimmering M, Roehr CC. Should nifedipine be used to counter low blood sugar levels in children with persistent hyperinsulinemic hypoglycemia. Arch Dis Child 2004 Jan; 89(1):63-85
32. Bas F, Darendeliler F, Demirkol D, Bundak R, Saka N, Gunoz H. Successful therapy with calcium channel blocker (nifedipine) in persistent hyperinsulinemic hypoglycemia of infancy. J Pediatr. Endocrinol Metab 1999 Nov-Dec;12 (6):873-878
33. Bourcier ME, Sherrod A, Diguardo M, Vinik AI. Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. J Clin Endocrinol&Metabol 2009; 94(9):3157-3162
34. Brown RE, Young RB. A possible role for the exocrine pancreas in the pathogenesis of neonatal leucine-sensitive hypoglycemia. Amercian Journal of Digestive Diseases 1970;15(1):65-72.
35. Sans MD, Tashiro M, Vogel NL, Kimball SR, D'Alecy LG, Williams JA. Leucine activates pancreatic translational machinery in rats and mice through mTOR independently of CCK and insulin. J Nutrition 2006 February;136(7):1792-1799
36. Cohen A, Hall MN. An amino acid shuffle activates mTORC1. Cell 2009;136(3):521-534.