Sirolimus: Efficacy and Complications in Children With Hyperinsulinemic Hypoglycemia: A 5-Year Follow-Up Study.

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Abstract

Sirolimus, a mammalian target of rapamycin inhibitor, has been used in congenital hyperinsulinism (CHI) unresponsive to diazoxide and octreotide. Reported response to sirolimus is variable, with high incidence of adverse effects. To the best of our knowledge, we report the largest group of CHI patients treated with sirolimus followed for the longest period to date.

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Multiple phenotypes in phosphoglucomutase 1 deficiency.

Laura C Tegtmeyer, Stephan Rust, Monique van Scherpenzeel … (2014)

Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest.

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Glucose Metabolism in 105 Children and Adolescents After Pancreatectomy for Congenital Hyperinsulinism

Jacques Beltrand, Marylène Caquard, Jean-Baptiste Arnoux … (2012)

OBJECTIVE To describe the long-term metabolic outcome of children with congenital hyperinsulinism after near-total or partial elective pancreatectomy. RESEARCH DESIGN AND METHODS Patients (n = 105: 58 diffuse and 47 focal congenital hyperinsulinism) received operations between 1984 and 2006. Follow-up consisted of periodic measurements of pre- and postprandial plasma glucose over 24 h, OGTT, and IVGTT. Cumulative incidence of hypo- or hyperglycemia/insulin treatment was estimated by Kaplan-Meier analysis. RESULTS After near-total pancreatectomy, 59% of children with diffuse congenital hyperinsulinism still presented mild or asymptomatic hypoglycemia that responded to medical treatments and disappeared within 5 years. One-third of the patients had both preprandial hypoglycemia and postprandial hyperglycemia. Hyperglycemia was found in 53% of the patients immediately after surgery; its incidence increased regularly to 100% at 13 years. The cumulative incidence of insulin-treated patients was 42% at 8 years and reached 91% at 14 years, but the progression to insulin dependence was very variable among the patients. Plasma insulin responses to IVGTT and OGTT correlated well with glycemic alterations. In focal congenital hyperinsulinism, hypoglycemia or hyperglycemia were rare, mild, and transient. CONCLUSIONS Patients with focal congenital hyperinsulinism are cured of hypoglycemia after limited surgery, while the outcome of diffuse congenital hyperinsulinism is very variable after near-total pancreatectomy. The incidence of insulin-dependent diabetes is very high in early adolescence.

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Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets.

Tara C. Marshall, Guim Kwon, Maria Remedi … (2004)

Mammalian target of rapamycin (mTOR) is a protein kinase that integrates signals from mitogens and the nutrients, glucose and amino acids, to regulate cellular growth and proliferation. Previous findings demonstrated that glucose robustly activates mTOR in an amino acid-dependent manner in rodent and human islets. Furthermore, activation of mTOR by glucose significantly increases rodent islet DNA synthesis that is abolished by rapamycin. Glucagon-like peptide-1 (GLP-1) agonists, through the production of cAMP, have been shown to enhance glucose-dependent proinsulin biosynthesis and secretion and to stimulate cellular growth and proliferation. The objective of this study was to determine if the glucose-dependent and cAMP-mediated mechanism by which GLP-1 agonists enhance beta-cell growth and proliferation is mediated, in part, through mTOR. Our studies demonstrated that forskolin-generated cAMP resulted in activation of mTOR at basal glucose concentrations as assessed by phosphorylation of S6K1, a downstream effector of mTOR. Conversely, an adenylyl cyclase inhibitor partially blocked glucose-induced S6K1 phosphorylation. Furthermore, the GLP-1 receptor agonist, Exenatide, dose-dependently enhanced phosphorylation of S6K1 at an intermediate glucose concentration (8 mmol/l) in a rapamycin-sensitive manner. To determine the mechanism responsible for this potentiation of mTOR, the effects of intra- and extracellular Ca2+ were examined. Glyburide, an inhibitor of ATP-sensitive K+ channels (K(ATP) channels), provided partial activation of mTOR at basal glucose concentrations due to the influx of extracellular Ca2+, and diazoxide, an activator of KATP channels, resulted in partial inhibition of S6K1 phosphorylation by 20 mmol/l glucose. Furthermore, Exenatide or forskolin reversed the inhibition by diazoxide, probably through mobilization of intracellular Ca2+ stores by cAMP. BAPTA, a chelator of intracellular Ca2+, resulted in inhibition of glucose-stimulated S6K1 phosphorylation due to a reduction in cytosolic Ca2+ concentrations. Selective blockade of glucose-stimulated Ca2+ influx unmasked a protein kinase A (PKA)-sensitive component involved in the mobilization of intracellular Ca2+ stores, as revealed with the PKA inhibitor H-89. Overall, these studies support our hypothesis that incretin-derived cAMP participates in the metabolic activation of mTOR by mobilizing intracellular Ca2+ stores that upregulate mitochondrial dehydrogenases and result in enhanced ATP production. ATP can then modulate KATP channels, serve as a substrate for adenylyl cyclase, and possibly directly regulate mTOR activation.

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Journal

Journal ID (iso-abbrev): J Endocr Soc

Title: Journal of the Endocrine Society

Publisher: The Endocrine Society

ISSN (Electronic): 2472-1972

ISSN (Print): 2472-1972

Publication date (Electronic): Apr 01 2019

Volume: 3

Issue: 4

Affiliations

[1 ] Endocrinology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

[2 ] Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, University College London Great Ormond Street Hospital Institute of Child Health, London, United Kingdom.

[3 ] Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.

[4 ] Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom.

Article

Publisher Item ID: js_201800417

DOI: 10.1210/js.2018-00417

PMC ID: 6411415

PubMed ID: 30882046

SO-VID: d84c7c6c-7647-4951-9703-4c7e661f849e

History

Keywords: ABCC8 gene,hyperinsulinemic hypoglycemia,mTOR inhibitors,side effects,sirolimus

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Keywords: ABCC8 gene, hyperinsulinemic hypoglycemia, mTOR inhibitors, side effects, sirolimus

Sirolimus: Efficacy and Complications in Children With Hyperinsulinemic Hypoglycemia: A 5-Year Follow-Up Study.

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Most cited references 28

Multiple phenotypes in phosphoglucomutase 1 deficiency.

Glucose Metabolism in 105 Children and Adolescents After Pancreatectomy for Congenital Hyperinsulinism

Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets.

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