Ian M. Burr

Continuous Nocturnal Intragastric Feeding for Management of Type 1 Glycogen-Storage Disease

The clinical and biochemical abnormalities associated with Type 1 glycogen-storage disease can be reversed by avoidance of hypoglycemia and secondary hormonal flux. Three patients with Type 1 disease were treated with intragastric infusions of a high glucose formula at night with three-hour starch feedings during the day. This regimen stabilized blood glucose levels above 70 mg per deciliter and decreased serum uric acid, triglyceride, lactate and serum oxalacetic transaminase levels, as well as hepatic size, in all patients. Increased linear growth rate (mean 1 cm per month) was associated with a decrease in mean plasma glucagon (from 190 to 40 pg per milliliter) and an increase in mean plasma insulin (from 19 to 43 muU per milliliter, [two patients]). These changes occurred within four weeks of beginning of treatment and continued with home treatment for 13 months. No complications resulted from tube placement daily by the patients. Type 1 disease can be managed by nighttime intragastric feeding and frequent daytime high starch meals.

Protection against streptozotocin-induced diabetes by superoxide dismutase.

SummarySuperoxide dismutase was administered intravenously to rats 50 min prior to intravenous administration of a diabetogenic dose of streptozotocin. A dose of 45 mg/kg streptozotocin alone produced marked glucose intolerance and a decrease in pancreatic insulin content to less than 10% of control; both of these effects were abolished by prior administration of 105 u/g of superoxide dismutase. Superoxide dismutase (105 u/g) administered 50 min before 65 mg/kg intravenous streptozotocin did not prevent the development of diabetes. The fall in pancreatic insulin content seen with streptozotocin alone was, however, partially reversed by superoxide dismutase.

Diencephalic syndrome revisited

This report details the histories of five patients with clinical diencephalic syndrome who collectively demonstrate the variability found in the syndrome with respect to: (1) clinical course, (2) site of the tumor, and (3) ease of obtaining radiologic confirmation of the presence of a tumor. A review of an additional 67 patients indicates that the observations are not unique. The anatomic variability combined with the fact that the course of those who are treated is infinitely better than those left untreated adds urgency to the establishment of precise anatomic diagnosis. These considerations led to a critical review of the histories of the 72 patients. From this it can be stated that anteriorly and posteriorly placed tumors do exhibit subtle but significant differences in their clinical course, and roentgenograms of the optic foramina and analysis of the CSF cell and protein content appear warranted early in the investigation of emaciation from unknown cause. Further, an evaluation is made of the role of various radiologic techniques and of endocrine studies in establishing the diagnosis. Similarly, the relative merits of radiotherapy and/or surgery in the treatment of the disease are defined. Finally, the adequacy of the term diencephalic syndrome is discussed.

Modification of chemically induced diabetes in rats by vitamin E. Supplementation minimizes and depletion enhances development of diabetes.

Administration of the antioxidant vitamin E to rats, prior to administration of either streptozotocin or alloxan, provided protection against the diabetogenic effect of both these agents. This was demonstrated by their response to a glucose load, their pancreatic insulin content and light microscopy findings. In addition, rats whose antioxidant state was depleted, by being maintained on a vitamin E and selenium-deficient diet, demonstrated increased diabetogenic susceptibility to normally nondiabetogenic doses of streptozotocin. These findings provide indirect support for the suggestion that the chemical agents streptozotocin and alloxan may exert their diabetogenic effect by acting as oxidants or free radical producers.

Type I glycogen storage disease: Five years of management with nocturnal intragastric feeding

It has been five years since the original report indicating that intragastric feedings could reverse most of the clinical and metabolic abnormalities present in patients with type I glycogen storage disease. We have now treated seven patients with nocturnal intragastric feedings for five years. All patients have shown marked improvement in blood chemical values (urate, lactate, triglyceride, cholesterol) as well as linear growth. The only serious complication has been symptomatic hypoglycemia and acidosis resulting from acute gastroenteritis and vomiting. Results indicate that nocturnal intragastric feeding is a practical, safe, and effective form of long-term treatment for patients with type I glycogen storage disease.

Acceleration of Growth Rate in Growth Hormone-Deficient Children Treated with Human Growth Hormone-Releasing Hormone

ABSTRACT: Twenty-four growth hormone-deficient children were treated with growth hormone releasing hormone-40 (GHRH) for 6 months or longer. GHRH (1 to 4 μg/kg of body weight per dose) was administered subcutaneously every 3 h (n = 10); or every 3 h overnight only (n = 10); or by twice daily injections (n = 4). Twenty-one children had an increase in growth rate during GHRH treatment. The growth velocities (mean ± SD; cm/yr) before and during treatment were, respectively: every 3 h 3.5 ± 1.4 versus 10.0 ± 2.2, p = 0.0001; overnight only 3.4 ± 1.0 versus 6.2 ± 2.1, p = 0.008; twice daily injections 3.2 ± 1.8 versus 7.9 ± 2.4, p = 0.06. Using these three modes of GHRH administration, different total daily amounts of GHRH were administered. Regression analysis of average daily dose versus growth velocity revealed a correlation coefficient (r) value of 0.57, p = 0.004. Sixteen children received extended treatment for periods varying from 9 to 30 months. Of these, seven children were treated continuously for 9 months with pump overnight only and 5 for 12 months with pump every 3 h. Their growth velocities were sustained at a similar rate as those observed at 6 months. Six children received both twice daily and three hourly treatments consecutively. The growth velocities were similar during both treatments. Eleven children developed circulating antibodies to GHRH during treatment, however, all 11 had accelerated growth rates during GHRH therapy. GHRH can stimulate growth hormone secretion and its biologic effects to accelerate linear growth in children with growth hormone deficiency. Further studies are required to characterize the optimal dose and frequency of administration.

Cholinergic Modification of Glucose-Induced Biphasic Insulin Release in Vitro

An in vitro system for perifusion of rat pancreatic islets has been utilized to define the effects of cholinergic agents on the dynamics of insulin release. In the absence of glucose the effects of either acetylcholine or acetyl-beta-methylcholine were minimal at concentrations up to 10(-5) mM. In the presence of low glucose concentration (2.4 mM), both of the muscarinic agents produced dose-dependent biphasic insulin release. Under these conditions significant insulin release was observed over both phases at concentrations of the muscarinic agents as low as 10(-8) mM. Further, the dose response curves relating muscarinic concentration to the total amount of insulin released in each of the two phases showed lack of parallelism between the curves. Nicotinic acid in concentrations up to 10(-5) mM had no effect on insulin release in the presence of 2.4 mM glucose. When the glucose concentration was increased to 16.4 mM, the effects of the muscarinic agents were significantly less than those observed in the presence of 2.4 mM glucose. This held true whether the effect was defined as absolute increment due to the muscarinic agent or as percentage of enhancement. Atropine inhibited insulin release induced by both acetylcholine and by 16.4 mM glucose. These data indicate that cholinergic stimulation can play a significant role in modifying insulin release patterns.

ATP Depletion, a Possible Role in the Pathogenesis of Hyperuricemia in Glycogen Storage Disease Type I

Other investigators have shown that fructose infusion in normal man and rats acutely depletes hepatic ATP and P(i) and increases the rate of uric acid formation by the degradation of preformed nucleotides. We postulated that a similar mechanism of ATP depletion might be present in patients with glucose-6-phosphatase deficiency (GSD-I) as a result of ATP consumption during glycogenolysis and resulting excess glycolysis. The postulate was tested by measurement of: (a) hepatic content of ATP, glycogen, phosphorylated sugars, and phosphorylase activities before and after increasing glycolysis by glucagon infusion and (b) plasma urate levels and urate excretion before and after therapy designed to maintain blood glucose levels above 70 mg/dl and thus prevent excess glycogenolysis and glycolysis. Glucagon infusion in seven patients with GSD-I caused a decrease in hepatic ATP from 2.25 +/- 0.09 to 0.73 +/- 0.06 mumol/g liver (P <0.01), within 5 min, persisting in one patient to 20 min (1.3 mumol/g). Three patients with GSD other than GSD-I (controls), and 10 normal rats, showed no change in ATP levels after glucagon infusion. Glucagon caused an increase in hepatic phosphorylase activity from 163 +/- 21 to 311 +/- 17 mumol/min per g protein (P <0.01), and a decrease in glycogen content from 8.96 +/- 0.51 to 6.68 +/- 0.38% weight (P <0.01). Hepatic content of phosphorylated hexoses measured in two patients, showed the following mean increases in response to glucagon; glucose-6-phosphate (from 0.25 to 0.98 mumol/g liver), fructose-6-phosphate (from 0.17 to 0.45 mumol/g liver), and fructose-1,6-diphosphate (from 0.09 to 1.28 mumol/g) within 5 min. These changes, except for glucose-6-phosphate, returned toward preinfusion levels within 20 min. Treatment consisted of continuous intragastric feedings of a high glucose dietary mixture. Such treatment increased blood glucose from a mean level of 62 (range 28-96) to 86 (range 71-143) mg/dl (P <0.02), decreased plasma glucagon from a mean of 190 (range 171-208) to 56 (range 30-70) pg/ml (P <0.01), but caused no significant change in insulin levels. Urate output measured in three patients showed an initial increase, coinciding with a decrease in plasma lactate and triglyceride levels, then decreased to normal within 3 days after treatment. Normalization of urate excretion was associated with normalization of serum uric acid. We suggest that the maintenance of blood glucose levels above 70 mg/dl is effective in reducing serum urate levels and that transient and recurrent depletion of hepatic ATP due to glycogenolysis is contributory in the genesis of hyperuricemia in untreated patients with GSD-I.

Differential effect of denervation on free radical scavenging enzymes in slow and fast muscle of rat

Abstract: To determine the effect of denervation on the free‐radical scavenging systems in relation to the mitochondrial oxidative metabolism in the slow‐twitch soleus and fast‐twitch extensor digitomm longus (EDL) muscles, the sciatic nerve of the rat was crushed in the mid‐thigh region and the muscle tissue levels of five enzymes were studied 2 and 5 weeks following crush. Recently developed radioimmunoassays were utilized for the selective measurement of cuprozinc (cytosolic) and man‐gano (mitochondrial) superoxide dismutases. Total tissue content of cuprozinc superoxide dismutase showed a mild decrease after denervation in slow but not in fast muscle. Manganosuperoxide dismutase and fumarase decreased markedly at 2 weeks and returned toward control levels by 5 weeks, the changes appearing to be greater in slow than in fast muscle. At 2 weeks, cytochrome c oxidase decreased significantly in slow, but not in fast muscle. GSH‐peroxidase at baseline was 10‐fold higher in slow than in fast muscle, markedly decreased at 2 weeks in slow muscle, and returned toward control levels at 5 weeks, whereas the total enzyme activity in fast muscle did not change through 5 weeks. These data represent the first systematic report of free radical scavenging systems in slow and fast muscles in response to denervation. Selective modification of cuprozinc and manganosuper‐oxide dismutases and differential regulation of GSH‐peroxidase was demonstrated in slow and fast muscle.

Chemiluminescence as an Index of Drug-induced Free Radical Production in Pancreatic Islets

Chemiluminescence induced in isolated islets from rat pancreas by the diabetogenic drugs, alloxan and streptozotocin, has been measured. The assay system consisted of 3 μM of luminol, 10 islets, and 100 μM of alloxan or 500 μM of streptozotocin in 5 ml Krebs-Ringer bicarbonate buffer containing 16 mM of Hepes (pH 7.4). Alloxan-induced chemiluminescence appeared very rapidly and lasted more than 5 min. On the other hand, streptozotocin failed to produce chemiluminescence over a period of 60 min after addition. The presence of Superoxide dismutase (1000 U/ml) and/or catalase (100 U/ml) markedly suppressed alloxan-induced chemiluminescence. These results suggest that alloxan acts as an exogenous free radical generator in pancreatic islets, but that streptozotocin does not. The involvement of Superoxide anion and hydrogen peroxide in production of chemiluminescence by alloxan suggests that the hydroxyl radical may mediate this chemiluminescence.