Allen M. Glasgow

Adolescent Diabetes Management and Mismanagement

OBJECTIVE To document the existence and prevalence of adolescent-generated diabetes management techniques. RESEARCH DESIGN AND METHODS One hundred forty-four adolescents completed the confidential questionnaire developed for this study. Glycohemo-globin was also obtained for each individual. RESULTS Within the 10 days before their clinic visit, many adolescents admitted to engaging in various mismanagement behaviors, with 25% admitting to missing shots. Parents tend to underestimate adolescent mismanagement. Missing shots was significantly related to poor control (P < 0.01). Older adolescents engaged in more mismanagement than their younger cohorts (P < 0.001). The questionnaire factored into two subscales: blatant mismanagement and faking. CONCLUSIONS This study shows the importance of recognizing the prevalence of mismanagement among adolescents.

Primary systemic carnitine dehciency. II. Renal handling of carnitine

Renal tubular reabsorption rates, reabsorptive maxima, and apparent renal plasma excretory thresholds for carnitine were determined in four children with primary systemic carnitine deficiency (SCD), in two of the mothers of these children, in one patient with muscle carnitine deficiency (MCD), and in seven controls. In SCD the observed values were well below those found in six of seven controls, but one control, a healthy 20-year-old woman with normal muscle carnitine level, also exhibited a renal carnitine leak. In the two mothers of patients with SCD and in the case of MCD some of the parameters of the renal handling of carnitine were slightly altered. Tubular secretion of short-chain acylcarnitines was noted in patients and controls at high plasma free carnitine levels. Augmented excretion of short-chain acylcarnitines occurred at lower plasma free carnitine levels in the patients with SCD than in the other subjects. Free and short-chain acyl-carnitines may compete for the same renal reabsorptive site. A renal defect cannot fully account for primary SCD but may contribute to the carnitine depletion in this disorder.

Production of the Features of Reye's Syndrome in Rats with 4-Pentenoic Acid

Extract: 4-Pentenoic acid, an analog of hypoglycin which is believed to cause Jamaican vomiting sickness, was administered intraperitoneally to rats in an attempt to produce the features of Reyes syndrome in rats. Mean ammonia levels in plasma were found to be elevated approximately four-fold after injection of 200 mg/kg pentenoic acid in fed rats. Pentenoic acid caused hypoglycemia in fasted rats and hyperglycemia in fed rats. In chronic experiments rats were injected intraperitoneally every 4 hr with 50 mg/kg body weight of pentenoic acid for 10 doses, followed by a single dose of 200 mg/kg. The livers of the treated group were enlarged and yellow and showed extensive fatty degeneration. The blood-urea-nitrogen (BUN) was significantly higher and the free fatty acids (FFAs) significantly lower in these rats. This study shows that pentenoic acid administered to rats produces findings similar to those of Reyes syndrome and Jamaican vomiting sickness.Speculation: The similarity of the features of Reyes syndrome, Jamaican vomiting sickness, and pentenoic acid and hypoglycin toxicity suggests that they may be related, perhaps sharing a common pathophysiology.

Hypoglycemia, Hepatic Dysfunction, Muscle Weakness, Cardiomyopathy, Free Carnitine Deficiency and Long-Chain Acylcarnitine Excess Responsive to Medium Chain Triglyceride Diet

Summary: Fraternal twins who had fasting hypoglycemia, hypoketonemia, muscle weakness, and hepatic dysfunction are reported. The hepatic dysfunction occurred only during periods of caloric deprivation. The surviving patient developed a cardiomyopathy. In this sibling, muscle weakness and cardiomyopathy were markedly improved by a diet high in medium chain triglycerides. There was a marked deficiency of muscle total carnitine and a mild deficiency of hepatic total carnitine. Unlike patients with systemic carnitine deficiency, serum and muscle long-chain acylcarnitine were elevated and renal reabsorption of carnitine was normal. It was postulated that the defect in long-chain fatty acid oxidation in this disorder is caused by an abnormality in the mitochondrial acylcarnitine transport.Detailed studies of the cause of the hypoglycemia revealed that insulin, growth hormone, cortisol, and glucagon secretion were appropriate and that it is unlikely that there was a major deficiency of a glycolytic or gluconeogenic enzyme. Glucose production and alanine conversion to glucose were in the low normal range when compared to normal children in the postabsorptive state. The hypoglycemia in our patients was probably due to a modest increase in glucose consumption, secondary to the decreased oxidation of fatty acids and ketones, alternate fuels which spare glucose utilization, plus a modest decrease in hepatic glucose production secondary to decreased available hepatic energy substrates.

Effect of propionic acid on fatty acid oxidation and ureagenesis.

Extract: Propionic acid significantly inhibited 14CO2 production from [1-14C]palmitate at a concentration of 10 μM in control fibroblasts and 100 μM in methylmalonic fibroblasts. This inhibition was similar to that produced by 4-pentenoic acid. Methylmalonic acid also inhibited 14CO2 production from [1-14C]palmitate, but only at a concentration of 1 mM in control cells and 5 mM in methylmalonic cells.Propionic acid (5 mM) also inhibited ureagenesis in rat liver slices when ammonia was the substrate but not with aspartate and citrulline as substrates. Propionic acid had no direct effect on either carbamyl phosphate synthetase or ornithine transcarbamylase.These findings may explain the fatty degeneration of the liver and the hyperammonemia in propionic and methylmalonic acidemia.Speculation: It has been shown that 4-pentenoic acid will produce may of the features of Reyes syndrome in rats. The fact that propionic acid inhibits some of the same reactions as 4-pentenoic acid raises the possibility that other short chain fatty acids less unusual than 4-pentenoic acid could produce the features of Reyes syndrome.

Relationships Between Control and Serum Lipids in Juvenile-onset Diabetes

The relationship between control and serum lipids was examined in 147 children with juvenile-onset diabetes (JOD). Control was assessed by fasting blood glucose, 24-h urine glucose, and fast hemoglobin. There was a significant positive correlation (P < 0.001) between each of the measures of control. Serum cholesterol (P < 0.001), triglycerides (P < 0.001), and low-density lipoprotein plus very low-density lipoprotein cholesterol (P < 0.001) were strongly positively correlated with control for the whole group of patients. High-density lipoprotein was not significantly correlated with control when the data for the whole group were analyzed but was significantly positively correlated with fasting blood glucose when patients were analyzed individually.

Ammonia metabolism in dogs with portacaval shunts.

Plasma ammonia, arginine, citrulline and urine ammonia, total nitrogen, and orotic acid were measured in shunted and control dogs. The progressive rise in plasma ammonia in the experimental group could not be explained solely by shunt hemodynamics. Similarity of control and experimental urinary nitrogen does not implicate nitrogen load. Urea synthesis was similar in experimental and control liver slices and was augmented by ornithine only in the experimental slices. Additionally, elevated urine orotic acid suggests urea cycle compromise at the ornithine transcarbamylase step.

REYE'S SYNDROME: A MODEL AND A HYPOTHESIS

4-Pentenoic acid (P.A.) an analog of hypoglycin, the compound that causes Jamaican vomiting sickness, was given to rats in an attempt to reproduce Reyes syndrome. Twelve rats given a single dose of 200 mg/kg of P.A. intraperitoneally developed hyperventilation, prostration and finally seizures and death. These animals had elevated ammonia (P.A.=162.4 ± 32.9 [S.E.M.] vs control [C]=44.6 ± 3.7 μg/100 ml; p <.01)and, in fasted rats, hypoglycemia (serum glucose P.A.=95.3 ± 14.6 vs C=146.9 ± 6.1 mg/100 ml; p <.01). In long-term experiments 15 rats were given 50 mg/kg of P.A. every 4 hours for 10 doses followed by a single dose of 200 mg/kg. Treated rats had enlarged livers (P.A.=7.49 ± .35 vs C=5.87 ± .16 gm; p <.001) that showed extensive small vacuole fatty degeneration, an elevated SGOT (P.A.=136.1 ± 22.6 vs C=66.4 ± 7.1 IU; p <.02), an elevated BUN (P.A.=29.7 ± 1.0 vs C=16.8 ± .8; p <-001) and normal bilirubin levels. P.A. (1mM) inhibited palmitate oxidation in rat liver slices 47 ± 10%. Evidence indicates the impairment of fatty acid oxidation results in the other metabolic abnormalities caused by P.A. The similarity in clinical and laboratory findings in this animal model, in Jamaican vomiting sickness, and in Reyes syndrome suggests that the pathophysiology, most likely secondary to impaired fatty acid oxidation, may be similar in all three. This model may prove useful for further studies of the pathophysiology and treatment of Reyes syndrome.

1129 SYSTEMIC CARNITINE DEFICIENCY: A CAUSE OF RECURRENT |[ldquo]|REYE'S SYNDROME.|[rdquo]|

A white female had two episodes of protracted vomiting followed by an acute encephalopathy after a “viral” illness at 11 months and 4 9/12 years of age diagnosed as Reyes syndrome on the basis of laboratory data (most abnormal value given; value at 11 months given first) serum glucose-15,12 mg/dl; serum ammonia-97,144 ug/dl (nl<48); SGOT-105,103; prothrombin time-47%, 49%; CSF-normal and at 4 9/12 years a liver biospy showing extensive small vacuole fatty degeneration. A third mild episode occurred at age 5 years. Evaluation following recovery revealed minimal proximal muscle weakness, a non-specific EMG abnormality and no evidence of a urea cycle disorder. A fast had to be terminated after 18 hours when she vomited several times and became very lethargic. A muscle biopsy, obtained at 5½ years at a time of clinical remission, contained excess lipid; a liver biopsy was histologically normal. Free carnitine levels were: serum 8.66 nm/ml (nl range 27.9-67.2) muscle 4.22 nm/mg non-collagen protein (NCP) (nl 7.96-22.86) and liver 0.4 nm/mg NCP (nl 3.3-10.4). In 7 children with single episodes of Reyes syndrome serum (n=4), muscle (n=3) and liver (n=1) free carnitine levels were normal except for one slightly low serem level. Systemic carnitine deficiency may mimic “Reyes syndrome”; the episodes, some initiated by fasting, may be preventale by carnitine therapy.

1217 NEONATAL PROGERIA IN SIBLINGS

Progeria (Hutchinson-Gilford Syndrome) is classified among the very rare childhood diseases (1:8,000,000 births according to De-Busks estimation). After 60 cases had been documented in medical literature by DeBusk in 1972, 5 more cases have been reported. There are only 4 reports in siblings up to this date, only 2 reports (4 cases) that clinical pictures appeared at birth and only 1 of these reports presented as a neonatal progeria in siblings without consanguinity in the family. The rarity of the disease prompted us to report our patient - a 1500 gm white female infant born at 35 wks. gestation with the phenotype typical of progeria patients described in literature along with the radiographic evidence of clavicles resorption at birth. The 1st pregnancy 8 yrs. ago also terminated at 35 wks., 1690 gm male with the same features as our patient, with evidence of clavicles and humeri changes in x-ray at l mo. Our patient developed natal tooth at the lower incisor area on the 5th day (also reported in 4 cases with typical phenotype at birth). She died at 7 days of age from heart failure and sepsis. (Sibling died at 6 wks. of age from congestive heart failure). There are 2 normal children. No consanguinity in the family. Our patient had the lowest birth weight reported. Typical phenotype and x-ray changes at birth, early dentition and early death may represent a new “neonatal progeroid syndrome” or just represent the most severe form of progeria.