Protein-sensitive hypoglycemia without leucine sensitivity in hyperinsulinism caused by KATP channel mutations

Fourtner, Shannon; Stanley, Charles A.; Kelly, Andrea

doi:10.1016/j.jpeds.2006.02.033

Cited by 35 publications

(35 citation statements)

References 30 publications

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“…In contrast, normal children and those with diffuse K ATP channel hyperinsulinism have little or no insulin response to leucine. 17,18 In the current issue of The Journal, Fourtner et al 19 have shown that in patients with K ATP hyperinsulinism, ingestion of a 1 to 1.5 g per kg protein load, either as a meal or an amino acid hydrolysate, induced a decrease in blood glucose ranging from 17 to 69 mg/dL, similar to the response previously observed in children with GDH hyperinsulinism. 20 It was previously thought that leucine-sensitive hypoglycemia and protein-induced hypoglycemia were synonymous, but Fourtner et al have shown that they are not the same.…”

supporting

confidence: 68%

Understanding protein-sensitive hypoglycemia

Wolfsdorf¹

2006

The Journal of Pediatrics

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supporting

confidence: 68%

Understanding protein-sensitive hypoglycemia

Wolfsdorf¹

2006

The Journal of Pediatrics

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“…Glutamine has emerged as a quantitatively very important fuel stimulant of insulin release as most convincingly demonstrated by studies designed to elucidate the molecular basis of hyperinsulinism syndromes in infants caused by mutations of the SUR1 and the glutamate dehydrogenase genes (38,39). Pancreatic beta cells of SUR1 Ϫ/Ϫ mice and mice overexpressing an activated mutant of glutamate dehydrogenase are markedly hyper-responsive to glutamine stimulation (6,13).…”

Section: Discussionmentioning

confidence: 99%

Elimination of KATP Channels in Mouse Islets Results in Elevated [U-13C]Glucose Metabolism, Glutaminolysis, and Pyruvate Cycling but a Decreased γ-Aminobutyric Acid Shunt

Nissim

Chen

et al. 2008

Journal of Biological Chemistry

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Pancreatic beta cells are hyper-responsive to amino acids but have decreased glucose sensitivity after deletion of the sulfonylurea receptor 1 (SUR1) both in man and mouse. It was hypothesized that these defects are the consequence of impaired integration of amino acid, glucose, and energy metabolism in beta cells. We used gas chromatography-mass spectrometry methodology to study intermediary metabolism of SUR1 knock-out (SUR1 ؊/؊ ) and control mouse islets with D-[U-13 C]glucose as substrate and related the results to insulin secretion. The levels and isotope labeling of alanine, aspartate, glutamate, glutamine, and ␥-aminobutyric acid (GABA) served as indicators of intermediary metabolism. We found that the GABA shunt of SUR1 ؊/؊ islets is blocked by about 75% and showed that this defect is due to decreased glutamate decarboxylase synthesis, probably caused by elevated free intracellular calcium. Glutaminolysis stimulated by the leucine analogue D,L-␤-2-amino-2-norbornane-carboxylic acid was, however, enhanced in SUR1 ؊/؊ and glyburide-treated SUR1 ؉/؉ islets. Glucose oxidation and pyruvate cycling was increased in SUR1 ؊/؊ islets at low glucose but was the same as in controls at high glucose. Malic enzyme isoforms 1, 2, and 3, involved in pyruvate cycling, were all expressed in islets. High glucose lowered aspartate and stimulated glutamine synthesis similarly in controls and SUR1 ؊/؊ islets. The data suggest that the interruption of the GABA shunt and the lack of glucose regulation of pyruvate cycling may cause the glucose insensitivity of the SUR1 ؊/؊ islets but that enhanced basal pyruvate cycling, lowered GABA shunt flux, and enhanced glutaminolytic capacity may sensitize the beta cells to amino acid stimulation.The pancreatic beta cells function as the predominant sensors and regulators of glucose, amino acid, and fatty acid levels of the mammalian organism, including man, by adjusting the minute to minute rate of insulin secretion such that these fuels are maintained at physiologically optimal blood concentrations under all nutritional conditions including feeding and fasting. This process of fuel-sensing and stimulation of insulin secretion requires that the various stimuli are transported into the beta cells and are metabolized to generate coupling factors that trigger and sustain the secretion of the hormone from large stores of insulin granules (1-4). The diverse specific pathways that allow access to metabolism for glucose, amino acids, and fatty acids converge to a complex network of intermediary metabolism represented by the citric acid cycle, a considerable variety of metabolite and cofactor shuttles including the GABA 2 shunt, and the processes of electron transport and oxidative phosphorylation, to mention just a few outstanding features of the biochemical maze of the beta cell.In the present study we have used uniformly labeled D-[13 C]glucose and GC-MS methods to explore the role of intermediary metabolism of pancreatic islets isolated from normal and sulfonylurea receptor 1 (SUR1) knock-out...

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“…Protein sensitivity without leucine sensitivity has also been described [22]. A group of patients presented with K ATP -CHI without leucine sensitivity and it was demonstrated that protein sensitivity is not synonymous with leucine sensitivity and that this non-leucine protein sensitivity can be just as severe as that seen in the HI/HI syndrome.…”

Section: How Do Mutations In Hadh Cause Hh?mentioning

confidence: 93%