Correlation between Hypoglycemia and Positive Rate of Inborn Error of Metabolism in Neonatal Intensive Care Unit

Objective

To investigate the correlation between hypoglycemia and positive rate of inborn error of metabolism (IEM) in neonatal intensive care unit.

Methods

160 patients from a neonatal intensive care unit were enrolled. Blood glucose was measured by Roche Modular chemistry. The dry blood on filter papers, collected from 160 patients, was tested by tandem mass spectrometry to detect 35 inborn errors of metabolism. Clinical follow-up of all the patients was at least in an interval of 12 months. The mean observation period was 13.5 months per child.

Findings

Based on the ROC curve, the optimal cut-off value of hypoglycemia as an indicator for screening for IEMs was projected to be 2.8 mmol/L, which yielded a sensitivity of 71.4% and a specificity of 76.5%. The patients were divided into two groups: hypoglycemia group (48 cases) and the control group (112 cases). 5(10.4%) of the 48 patients in the hypoglycemia group were positive, while only 2(1.8%) of the 112 patients in the control group were positive. The difference of the positive rate in the screening for IEMs between the two groups was significant (χ²=4.10, P<0.05); the relative risk (RR) was 5.83 (95% CI: 1.06–32.12).

Conclusion

The risk of patients with hypoglycemia suffering from IEMs was significantly higher than that of the non-hypoglycemia patients in NICU, based on cut-off value of 2.8mmol/L.     

Symptoms of hypoglycemia — A comparison between porcine and human insulin

Summary For more than 2 years now it has been controversially debated whether awareness of hypoglycemia is reduced when type I diabetic patients are switched from porcine to human insulin. In order to address this question, we studied nine C-peptide negative diabetics (age 27.6 years, Broca index 106%, duration of diabetes 5.7 years, HbA₁, 8.8%) in comparison with eight healthy volunteers (age 22.4 years, Broca index 104%). Following euglycemic monitoring overnight, a controlled hypoglycemia was induced by altering the algorithms of the Biostator. This was done in a double-blind, cross-over fashion using porcine or human insulin on 2 nonconsecutive days. There were no differences between the results obtained with respect to the time course of the study, blood glucose, amount of insulin infused, and concentration of venous free insulin achieved. Of the nine diabetics, eight were aware of hypoglycemia at a higher blood glucose level under porcine insulin. The first symptom of hypoglycemia was percieved at a mean blood glucose level of 61.1±5.4 mg/dl under porcine insulin and of 44.4 ± 5.3 mg/dl under human insulin (P0.05). Thirty symptoms were noted under porcine insulin exclusively or preferentially as opposed to only eight which were observed exclusively or preferentially under human insulin. The healthy volunteers evidenced fewer symptoms at lower blood glucose concentrations than the diabetics. The clear difference between human and porcine insulin could not unequivocally be reproduced in this group. We conclude that type I diabetic patients, who are maintained on a treatment regimen with human insulin, perceive symptoms of hypoglycemia at higher blood glucose concentrations when hypoglycemia is induced by porcine insulin as compared with human insulin. As every single patient and healthy volunteer was aware of at least one symptom of hypoglycemia under both insulins, it is possible to react appropriately to counteract this situation. Nevertheless, diabetic patients should be informed about this phenomenon.Abbreviations P porcine insulin - H human insulin - IU international units Supported by Nordisk Deutschland     

Acute self-poisoning with phenformin

Summary The case is reported of a non-diabetic young woman who attempted suicide by ingesting 2,500 mg of phenformin. The most marked clinical and laboratory findings during the first 24 hrs included nausea, vomiting, anxiety, agitation, polydipsia, polyuria, increased appetite, tachycardia, tachypnea, persistent lactic acidosis, hypoglycemia and hypokalemia. Treatment at the ICU 10 hrs after ingestion of the overdose was essentially symptomatic and included measures to correct acidosis and hypoglycemia. The patient recovered completely.     

Prevalence of hypoglycemia during oral glucose tolerance testing in adults with cystic fibrosis and risk of developing cystic fibrosis-related diabetes

Background

Hypoglycemia in cystic fibrosis (CF) patients during the oral glucose tolerance test (OGTT) has been reported; however, these patients have not been well-characterized. Few studies have examined whether hypoglycemia during the OGTT increases the risk of developing CF-related diabetes (CFRD). Objectives of this study were to describe the characteristics of CF patients with hypoglycemia during the OGTT and to determine the incidence and time to development of CFRD in those with hypoglycemia.

Modification of glutamate binding sites in newborn brain during hypoglycemia

We have shown that acute insulin-induced hypoglycemia leads to specific changes in the cerebral NMDA receptor-associated ion channel in the newborn piglet. The present study tests the hypothesis that exposure to acute hypoglycemia in the newborn will alter the glutamate binding site of both NMDA and kainate receptors. Studies were performed in 3-6 days-old piglets randomized to control (n=6) or hypoglycemic (n=6) groups. Hypoglycemia was maintained for 120 min using insulin infusion. Saturation binding assays were performed in cerebral cell membranes using (3)H-glutamate or (3)H-kainate to determine the characteristics of the glutamate binding sites of the NMDA and kainate receptors, respectively. The concentration of glucose in cerebral cortex was 10-fold less in hypoglycemic piglets than in controls (P<0.05). Brain ATP was not significantly decreased during hypoglycemia, but phosphocreatine decreased from control of 6.6 +/- 1.3 micromoles/g brain to 3.2 +/- 1.9 micromoles/g brain in hypoglycemic piglets. The B(max) for NMDA-displaceable (3)H-glutamate binding was 992 +/- 64 fmol/mg protein in hypoglycemic animals, significantly higher than the control value of 746 +/- 42 fmol/mg protein. However, the dissociation constant for glutamate was unchanged during hypoglycemia. The (3)H-kainate binding studies demonstrated no change in B(max) of high-affinity kainate receptors during hypoglycemia. In contrast, the affinity of the kainate receptor glutamate binding site significantly increased compared to control. Thus, acute hypoglycemia in the newborn piglet had specific effects on the glutamate binding sites of the NMDA and kainate receptors that could be due to alterations in cell membrane lipids or modification of receptor proteins.     

Adenosine triphosphate accelerates recovery from hypoxic/hypoglycemic perturbation of guinea pig hippocampal neurotransmission via a P(2) receptor

The present study was designed to assess the effects of adenosine triphosphate (ATP) on hippocampal neurotransmissions under the normal and hypoxic/hypoglycemic conditions. ATP reversely depressed population spikes (PSs), which were monitored in the dentate gyrus of guinea pig hippocampal slices, in a dose-dependent manner at concentrations ranged from 0.1 micro M to 1 mM. A similar depression was obtained with the P(2) receptor agonist, alpha,beta-methylene ATP (alpha,beta-MeATP), and the effect was inhibited by the P(2) receptor antagonists, suramin and PPADS. The inhibitory action of ATP or alpha,beta-MeATP was inhibited by the gamma-aminobutyric acid(A) (GABA(A)) receptor antagonist, bicuculline, but it was not affected by theophylline, a broad inhibitor of adenosine (P(1)) receptors, tetraethylammonium, a broad inhibitor of K(+) channels, or ecto-protein kinase inhibitors. ATP or alpha,beta-MeATP enhanced GABA release from guinea pig hippocampal slices, that was inhibited by deleting extracellular Ca(2+) or in the presence of tetrodotoxin, while ATP had no effect on GABA release from cultured rat hippocampal astrocytes or postsynaptic GABA-gated channel currents in cultured rat hippocampal neurons. Twenty-minutes deprivation of glucose and oxygen from extracellular solution abolished PSs, the amplitude recovering to about 30% of basal levels 50 min after returning to normal conditions. ATP or alpha,beta-MeATP accelerated the recovery after hypoxic/hypoglycemic insult (approximately 80% of basal levels). Adenosine diphosphate and adenosine monophosphate accelerated the recovery, but to a much lesser extent, and adenosine had no effect. The results of the present study thus suggest that ATP inhibits neuronal activity by enhancing neuronal GABA release via a P(2) receptor, perhaps a P2X receptor, thereby protecting against hypoxic/hypoglycemic perturbation of hippocampal neurotransmission.     

Carnitine levels and the ketogenic diet

PURPOSE: To determine the long-term effect of the ketogenic diet (KD) on carnitine levels and whether carnitine depletion is a significant cause of clinical complications during KD initiation or treatment. METHODS: Carnitine levels at 0, 1, 6, 12, and 24 months of diet treatment, carnitine antiepileptic drug (AED) history, lowest blood glucose and time to achieve ketosis during diet initiation, and diet complications were analyzed for 38 consecutive patients who initiated the KD from May 1997 to March 2000. Carnitine levels at follow-up were analyzed for eight patients started on the diet before to May 1997. RESULTS: Total carnitine (TC) at diet initiation correlated negatively with the number of AEDs at diet initiation but not with number of past AEDs, lowest blood glucose, or time to ketosis. TC decreased in the first months of diet treatment and then stabilized or increased slightly with long term treatment. Only 19% of patients were supplemented with carnitine for low TC. No patient showed clinical signs of carnitine deficiency. CONCLUSIONS: Multiple AED exposure lowers TC, but actual TC deficiency in patients initiating the KD is not common, and TC levels do not appear to predict hypoglycemia or problems achieving ketosis. Mild carnitine depletion may occur early in KD treatment and occasionally TC decreases out of the normal range, without clinical symptoms. TC stabilizes or increases back toward baseline with long-term treatment, and most patients do not require carnitine supplementation.     

Tyrosinose

Zusammenfassung Die biochemischen und klinischen Veränderungen eines Patienten mit Tyrosinose wurden über 2 Jahre verfolgt. Die Reduktion der Phenylalanin- und Tyrosinaufnahme führte zur Heilung der Rachitis sowie zur Normalisierung der Hypophosphatämie, der tubulären Phosphatreabsorption und der Methioninämie. Dieser Effekt war bei Auslaßversuchen reproduzierbar. Die Störungen im Methioninabbau besserten sich jedoch auch später unabhängig von der Tyrosinämie. Diese spontane Besserung, eher unabhängig von der Therapie und im Verlauf der Erkrankung oder mit zunehmendem Alter erfolgend, ließ sich gleichfalls an anderen Symptomen, wie der Thrombocytopenie, den Gerinnungsstörungen und dem verzögerten Phenylalaninabbau beobachten. Der fehlende oder nicht reproduzierbare Einfluß des normalisierten Tyrosinstoffwechsels auf diese Symptome spricht dafür, daß sie eher unabhängig neben der Tyrosinämie bestehen und nicht durch diese bedingt sind. Das Ausmaß der Tyrosinämie war in allen Krankheitsphasen abhängig von der Menge des aufgenommenen Phenylalanin und Tyrosin, die Belastungen mit Phenylalanin ergeben unabhängig vom Alter etwa gleiche Konzentrationskurven für Tyrosin. Die Störungen im Glucosestoffwechsel scheinen durch die Methioninämie verursacht, da Hypoglykämie und fehlender Anstieg des Blutzuckers nach Glukagoninjektion nur bei erhöhten Methioninserumkonzentrationen auftraten, bei isolierter Tyrosinerhöhung hingegen nicht gefunden wurden und beides durch eine Methioninbelastung provoziert werden konnte.

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TyrosinosisPrimary and secondary metabolic disturbances

A child with so-called tyrosinosis was treated with a reduced phenylalanine and tyrosine intake (100 mg/kg/day) for two periods of 2 and 9 months each. Healing of rickets, normalization of phosphate in the serum and increased tubular reabsorption of phosphate occurred during treatment achieving normal tyrosine levels, whilst these parameters, worsened when the tyrosine in the palsma rose. Methioninemia disappeared and reappeared together with tyrosinemia during and after the first period of treatment (methionine intake was unchanged). Later on these symptoms were no longer correlated, and high levels of methionine were only found during a period of vomiting, loss of weight, failure to grow and normal blood tyrosine levels. Thus the delayed methionine degradation seems be influenced by age, rate of protein synthesis and tyrosinemia. Thrombocytopenia, disturbed liver functions and other symptoms also improved with advancing age or during the natural course of the disease and did not seem to be directly related to dietary treatment. By contrast, the degree of tyrosinemia remained unchanged, depending on the amount of phenylalanine and tyrosine in the food. Hypoglycemia and methioninemia were correlated, the difference in blood sugar between periods with and without methioninemia being statistically significant. Furthermore, there was no rise in the glucose level after glucagon injection when the methionine level was elevated, whilst the results of the glucagon tests were approximately normal at low methionine levels. These findings indicate that hypoglycemia and rickets are secondary symptoms, whereas the other abnormalities seem be more independent of the disturbed tyrosine metabolism.

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