Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications.
BACKGROUND
Amino-acids stimulate the mammalian target of rapamycin complex(mTORC)1; mTORC1 integrates amino-acid and energy-sensing pathways in beta-cells. Rapamycin inhibits mTORC1. We examined the mTOR pathway and cell cycle data in the exocrine pancreas in diffuse persistent hyperinsulinemic hypoglycemia of infancy (PHHI).


METHODS
Tissues from two diffuse PHHI cases, one pediatric control and from adult pancreatic tissue microarray were analyzed. The case studies are newborns of non-diabetic mothers, one with SUR1 mutation, and the other with a family history of PHHI. Immunostaining for (p)-mTOR(Ser2448), phospholipase(PLD)1, cell cycle analytes ( Ki67, Skp2, p27Kip1), and insulin were performed. Cell cycle analytes were assessed by automated cellular imaging or visual quantification. Multispectral imaging of double immunostaining for insulin/p-mTOR and transmission electron microscopy (TEM) were performed.


RESULTS
Hematoxylin-eosin and insulin-staining showed beta-cell hyperplasia in the exocrine pancreas, without mass effect. Overexpression of (p)-mTOR on the plasmalemmal, but not nuclear compartment, consistent with mTORC1, was noted in acinar elements. Residual expression was noted in islets. Double immunostaining revealed occasional exocrine cells co-expressing mTOR and insulin. No such co-expressions were seen in the control. TEM showed acinar cells containing zymogen and hormone-secreting granules. No nuclear Skp2 was noted. Obversely, p27Kip1 was expressed. Mitotic index was 1/40 (0.25/10) HPF.


CONCLUSIONS
Morphoproteomic, histopathologic and morphometric findings in this study of diffuse PHHI coincide with existing genomic and signal transduction data in: 1) supporting a role for a constitutively activated and overexpressed mTORC1 pathway in the acinar pancreas in its pathogenesis; 2) reaffirming transdifferentiation of acinar-to-islet cells; 3) raising the possibility of rapamycin as a therapeutic option in PHHI.
Alexandrescu
Sanda
S
Department of Pathology and Laboratory Medicine, University of Texas Health Science Center-Medical School at Houston, Houston, TX 77030, USA.
Tatevian
Nina
N
Olutoye
Oluyinka
O
Brown
Robert E
RE
D054338:Cell Transdifferentiation / Q000502:physiology*; D044903:Congenital Hyperinsulinism / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D007328:Insulin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases