Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. (25/62)

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Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia. (26/62)

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Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications. (27/62)

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). DESIGN: 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. CONCLUSION: 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.  (+info)

Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. (28/62)

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Familial focal congenital hyperinsulinism. (29/62)

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The clinical problem of hyperinsulinemic hypoglycemia and resultant infantile spasms. (30/62)

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The contribution of rapid KATP channel gene mutation analysis to the clinical management of children with congenital hyperinsulinism. (31/62)

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In vitro recovery of ATP-sensitive potassium channels in beta-cells from patients with congenital hyperinsulinism of infancy. (32/62)

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