Leucine-Induced Hypoglycemia a Review and Speculations

DiGeorge, Angelo M.; Auerbach, Victor H.

doi:10.1097/00000441-196012000-00015

Cited by 34 publications

(16 citation statements)

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“…Thus, the loss of sensitivity to GTP inhibition may potentiate the stimulatory effect of leucine on GDH activity. It is possible that infants and children previously described as having leucinesensitive hypoglycemia actually had the HI/HA syndrome due to mutations of GDH (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators.

Stanley

Fang²,

Kutyna³

et al. 2000

Diabetes

160

126

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and the HI/HA Contributing Investigators Glutamate dehydrogenase (GDH) is allosterically activated by the amino acid leucine to mediate protein stimulation of insulin secretion. Children with the hyperinsulinism/hyperammonemia (HI/HA) syndrome have symptomatic hypoglycemia plus persistent elevations of plasma ammonium. We have reported that HI/HA may be caused by dominant mutations of GDH that lie in a unique allosteric domain that is encoded within GDH exons 11 and 12. To examine the frequency of mutations in this domain, we screened genomic DNA from 48 unrelated cases with the HI/HA syndrome for exon 11 and 12 mutations in GDH. Twenty-five (52%) had mutations in these exons; 74% of the mutations were sporadic. Clinical manifestations included normal birth weight, late onset of hypoglycemia, diazoxide responsiveness, and protein-sensitive hypoglycemia. Enzymatic studies of lymphoblast GDH in seven of the mutations showed that all had reduced sensitivity to inhibition with GTP, consistent with an increase in enzyme activity. Mutations had little or no effect on enzyme responses to positive allosteric effectors, such as ADP or leucine. Based on the three-dimensional structure of GDH, the mutations may function by impairing the binding of an inhibitory GTP to a domain responsible for the allosteric and cooperativity properties of GDH. D i a b e t e s 4 9 :6 6 7-673, 2000

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Section: Discussionmentioning

confidence: 99%

Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators.

Stanley

Fang²,

Kutyna³

et al. 2000

Diabetes

160

126

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“…Second, the response to L-leucine is not uniform in these situations and cannot be demonstrated in all patients with these clinical syndromes (15)(16)(17)(18)(19), nor, as we have shown, in all dogs pretreated with chlorpropamide. Since all the situations in which L-leucine had produced a significant hypoglycemic response seemed to 2 These measurements were obtained with the aid of Dr. S. Kountz, Department of Surgery, Stanford University School of Medicine, Palo Alto, Calif. share in common hyperinsulinism, or hypoglycemia, or both, we had suggested earlier that L-leucine "decreases the hyperglycemic response to hypoglycemia, specifically, hepatic glucose output' (1).…”

Section: Discussionmentioning

confidence: 74%

“…Since the etiology or etiologies of idiopathic infantile hypoglycemia are obscure, the merit of a distinction based on the patient's response to L-leucine is difficult to evaluate. On the other hand, the distinction between "leucine-sensitive" and "leucine-insensitive" seems to have little meaning when applied to patients with insulin-secreting tumors of the pancreas, and avoids the question of why L-leucine produces hypoglycemia only in some patients with organic hyperinsulinism (15)(16)(17). This problem is not confined to clinical situations, and it is as difficult to account for the variable hypoglycemic response to L-leucine that has been observed in experimental leucine hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

Chlorpropamide-Induced Leucine Hypoglycemia*

Lucas¹,

Reaven²

1963

J. Clin. Invest.

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Previous reports from this laboratory have demonstrated that L-leucine-induced hypoglycemia can be experimentally produced in normal dogs during periods of either exogenous (1) or endogenous (2) hyperinsulinism. On the basis of these experiments, it was suggested that L-leucine acts to inhibit hepatic glucose output and that "leucine hypoglycemia" occurs in situations where increased hepatic glucose output is necessary for maintenance of euglycemia. To extend these observations of experimental leucine hypoglycemia, it seemed desirable to investigate the effect of L-leucine in other situations characterized by hypoglycemia, hyperinsulinism, or both. Consequently, we have measured the blood glucose response to L-leucine at varying intervals after both the acute and chronic administration of chlorpropamide. ter a single oral dose of chlorpropamide, 4) 24 hours after 3 consecutive days -of the same oral dose of chlorpropamide, given once daily, and 5) without chlorpropamide pretreatment.Chlorpropamide was given in a dose of 250 or 375 mg. All dogs weighing less than 10 kg were arbitrarily given 250 mg, and 375 mg was used in dogs weighing over 10 kg. Each experiment was performed as follows. A dog was anesthetized with pentobarbital, and two blood samples were drawn 15 minutes apart for glucose determination, with the average of these two values used as a baseline. Then 30 mmoles of L-leucine in 200 ml of distilled water or an equal volume of 0.45 per cent NaCl was given by an intravenous infusion lasting approximately 15 minutes. Blood was then drawn for measurement of glucose concentration 30 and 60 minutes after L-leucine or saline had been administered. The results have been expressed as percentage of fall in glucose concentration (100 X maximal fall observed in blood glucose concentration divided by the baseline value). The percentage of fall in blood glucose due to L-leucine in any given dog under each experimental condition is then expressed as follows: maximal fall in blood glucose after leucine X 100/average baseline minus maximal fall in blood glucose after saline X 100/average baseline. Blood glucose was measured by the Somogyi method as modified by Nelson (3).Serum chlorpropamide levels were measured in eight individual experiments by the method of Toolan and Wagner (4).B. Effect of L-leucine on hepatic metabolism 1. Effect of L-leucine on hepatic-vein and fentoral-vein blood glucose concentration in dogs without prior pretreatment. Five experiments were performed with the following protocol. After the induction of anesthesia with pentobarbital, a radio-opaque catheter was passed percutaneously into the vena cava from the femoral vein and inserted in a hepatic vein under fluoroscopic control. A second catheter was placed in the other femoral vein for collection of peripheral venous blood. After three blood samples were drawn from each catheter over a 15-minute period, each dog received a rapid intravenous infusion of 30 mM of L-leucine in 200 ml of distilled water. Paired blood samples were then drawn fr...

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“…Reports concerning histopathology [3,4,8,9,16,17,18] or ultrastructure [26] of the pancreatic islets in idiopathic neonatal hypoglycemia are rare. Most of the examined pancreata showed a regular islet system [18], whereas only few exhibited islet hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

“…Its general function and its particular significance for the hypoglycemic syndrome are unknown. The findings correspond well with recent observations on the islet cell system in cases of neonatal hypoglycemia with leucine-sensitivity and hyperinsulinism.Key words: Neonatal hypoglycemia, hyperinsulinism, leucine-sensitivity, islet hyperplasia, ultrastructure, A, B, D and type IV cells.Reports concerning histopathology [3,4,8,9,16,17,18] or ultrastructure [26] of the pancreatic islets in idiopathic neonatal hypoglycemia are rare. Most of the examined pancreata showed a regular islet system [18], whereas only few exhibited islet hyperplasia.…”

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confidence: 99%

Morphometric and ultrastructural studies in an infant with leucine-sensitive hypoglycemia, hyperinsulinism and islet hyperplasia

et al. 1974

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Summary.Morphometrie and ultrastruetural studies were performed on biopsy material from the pancreas of an infant with severe leucine-sensitive hypoglycemia and hyperinsulinism, in whom no insulinoma had been found. Qualitatively many large B cells were observed within the pancreatic islets. Quantitatively an about two fold increase of islet tissue proportion (4.2 %) was demonstrated, compared with controls of approximately the same age (1.8%). Differential islet cell counting revealed an increase in A 1 cells whereas the percentage of A 2 and B cells appeared to be unchanged. Ultrastructurally in addition to A, B, and D cells a fourth islet cell type was demonstrated in unusual frequency. Its general function and its particular significance for the hypoglycemic syndrome are unknown. The findings correspond well with recent observations on the islet cell system in cases of neonatal hypoglycemia with leucine-sensitivity and hyperinsulinism.Key words: Neonatal hypoglycemia, hyperinsulinism, leucine-sensitivity, islet hyperplasia, ultrastructure, A, B, D and type IV cells.Reports concerning histopathology [3,4,8,9,16,17,18] or ultrastructure [26] of the pancreatic islets in idiopathic neonatal hypoglycemia are rare. Most of the examined pancreata showed a regular islet system [18], whereas only few exhibited islet hyperplasia. Moreover, as quantitative methods were only rarely applied to islet examination in infants, the diagnosis of islet hyperplasia as a cause of neonatal hypoglycemia remained often doubtful.A recent report of Misugi and coworkers [26] renewed the interest in the islet system in neonatal hypoglycemia. The anthers described islet cell hyperp/asia in three infants with leucine-sensitive hypoglycemia [4] and hyperinsulinism. The ultrastruetural examination revealed a fourth islet cell type in addition to A, B and D cells. The present report of a ease of leucine-sensitive neonatal hypoglycemia confirms the findings of Misugi and associates, and briefly discusses the significance of the observations on the basis of the literature on this subject.

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Leucine-Induced Hypoglycemia a Review and Speculations

Cited by 34 publications

References 0 publications

Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators.

Molecular basis and characterization of the hyperinsulinism/hyperammonemia syndrome: predominance of mutations in exons 11 and 12 of the glutamate dehydrogenase gene. HI/HA Contributing Investigators.

Chlorpropamide-Induced Leucine Hypoglycemia*

Morphometric and ultrastructural studies in an infant with leucine-sensitive hypoglycemia, hyperinsulinism and islet hyperplasia

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