Louis Hagler

Are Abnormalities in Insulin Secretion Responsible for Reactive Hypoglycemia

Seventy patients with reactive hypoglycemia strictly defined by criteria which interpret the low blood glucose value in relationship to clinical and physiologic parameters, were studied to determine if abnormalities in insulin secretion could be demonstrated. These patients were separated into four groups: alimentary (N = 5), diabetic (N = 16), hormonal (N = 5), and idiopathic (N = 44). The findings in these patients were compared to normal control subjects and to weight- and disease-matched patient controls. All of the patients with hormonal and most patients with idiopathic reactive hypoglycemia (thirty-two of forty-four) demonstrated delayed insulin secretion regardless of the control group used for comparison. Diabetic reactive hypoglycemic patients exhibited delayed insulin secretion when compared to normal controls but not when compared to weight-matched diabetic controls. Excessive insulin secretion was consistently found only in the patients with the alimentary variety of reactive hypoglycemia. Using weight- and diseasematched control groups, no abnormalities in insulin secretion could be found to account for the hypoglycemia in the diabetic reactive hypoglycemic patients and some idiopathic reactive hypoglycemic (nine of forty-four) patients. These results help to explain the inconsistent findings of previous investigators and suggest that reactive hypoglycemia is a syndrome having multiple etiologies.

Fructose-1,6-diphosphatase deficiency, hypoglycemia, and response to folate therapy in a mother and her daughter

Abstract Symptomatic fasting and reactive hypoglycemia in association with low iejunal and hepatic fructose-1,6-diphosphatase (FDPase) activity were found in an adult patient and her 19-month-old daughter. Plasma glucose response to glycerol ingestion was abnormal in both, showing little change in the adult and a decline in the child. FDPase activity was low in tissues from both patients. This reduced enzyme activity defines a new variant of the fructose-1,6-dipphosphatase deficiency state(s) which is mild in its manifestations and thus more resistant to the hypoglycemia-provoking effects of fructose and alanine. No difference was detected between the FDPase from these patients and unaffected individuals by polyacrylamide gel electrophoresis. The K m of the jejunal enzyme for fructose diphosphate in the adult was similar to the normal control. Glucagon rapidly increased the activity of hepatic FDPase in both patients. Folic acid, 15 mg/day, increased hepatic and jejunal FDPase activity in both patients. After folate therapy, there was improvement in the adults symptoms and improvement in the childs ability to maintain normal plasma glucose levels. The interrelationship between the hypoglycemia, FDPase deficiency, and the response to folate therapy was discussed.

Biopsy of the small intestine with the Crosby-Kugler capsule: Experience in 3,866 peroral biopsies in children and adults

Experience with 3,866 peroral intestinal biopsies performed over 6-1/2 years is presented. Fifty-five infants and children had 101 biopsies performed. Initial attempts at obtaining tissue in three children were unsuccessful, but tissue was obtained in all three on the second attempt. One infant receiving heparin experienced significant bleeding, which stopped spontaneously when the heparin was discontinued. Tissue was obtained in 93–98% of all biopsies performed on 3,765 adult individuals and six had significant bleeding. Only one required transfusion and no perforations were encountered. We find that peroral intestinal biopsy is a relatively easy and safe procedure in both adults and children. It should be performed under the direction of those experienced in intestinal biopsy techniques because of occasional complications.

Effects of insulin, tolbutamide, and glucagon on activities of jejunal carbohydrate-metabolizing enzymes in humans

The activities of jejunal carbohydrate-metabolizing enzymes show adaptive drugs, and sex hormones. To learn whether insulin, tolbutamide, and glucagon had effects on these enzymes, we performed serial peroral jejunal biopsies in normal young men and in obese patients, before and after treatment with these agents. Jejunal mucosa was assayed for glycolytic enzyme activities, pyruvate kinase (PK), hexokinase (HK), and fructose-1,6-diphosphate aldolase (FDPA), and the nonglycolytic enzyme activity, fructose diphosphatase (FDPase). Insulin significantly increased the activity of jejunal PK (+48% change from control) and HK (+6%), decreased the activity of FDPase (-36%),and had no effect on FDPA. Glucagon had opposite effects; the activity of PK was decreased (-33%) and FDPase was increased (+50%). Tolbutamide significantly increased the activities of PK (+47%), HK (+14%), and FDPA (+7%), and decreased the activities of FDPase (-36%). The results of tolbutamide on glycolytic enzyme activities were independent of endogenous insulin. The data support the concept that jejunal carbohydrate-metabolizing enzymes in man respond to hormones and drugs similar to responses observed in rat liver. This is important because it now gives us a means of studying the actions of these hormones directly in human tissue.

Adaptive Response of Humans to Changes in Dietary Calcium: Relationship Between Vitamin D Regulated Intestinal Function and Serum 1,25-Dihydroxyvitamin D Levels

We developed intestinal biopsy procedures in chicks that were extended to humans to study the role of vitamin D in regulating intestinal adaptation to dietary calcium. By comparing biopsy specimens from rachitic chicks (D–) to those from vitamin Dsupplemented chicks (D+) on otherwise identical diets, we observed that (a) the rates of calcium and phosphate accumulation by D+ duodenal or jejunal mucosa were ~50% greater than those by comparable D– mucosa, (b) alkaline phosphatase activity was three times greater in D+ duodenal mucosa brush border preparations than D- preparations, and (c) calcium binding activity was 10 times greater in the cytosol from D+ duodenal mucosa than from D– duodenal mucosa. We then evaluated the calcium and phosphate uptake and alkaline phosphatase activity of duodenal mucosal specimens obtained each week from 15 subjects ingesting, in successive weeks, 100 mg calcium per day (week 1) and 1000 mg calcium per day (week 2). Serum levels of 1,25-dihydroxyvitamin D, immunoreactive parathyroid hormone, calcium, and phosphorus were determined on the day the biopsy specimens were obtained. The subjects were prospectively selected to provide a range of basal 1,25-dihydroxyvitamin D levels from low to high, and included four osteoporotic, five control, and six hyperparathyroid subjects. The change from the 100-mg to 1000-mg calcium diet resulted in a fall of serum 1,25-dihydroxyvitamin D levels and duodenal calcium and phosphate uptake and alkaline phosphatase activity, with no change in serum calcium in the control subjects. Similar effects were observed in the osteoporotic subjects. The hyperparathyroid subjects experienced an increase in serum calcium and failed to reduce their serum 1,25-dihydroxyvitamin D levels on the high calcium diet. These hyperparathyroid subjects had the highest duodenal alkaline phosphatase activities and serum 1,25-dihydroxyvitamin D levels and the least consistent response of any intestinal function to the change in dietary calcium. We observed a strong correlation between duodenal alkaline phosphatase activity and serum 1,25-dihydroxyvitamin D levels on the low calcium diet (r = 0.777, P

Acute effects of oral and intravenous ethanol on rat hepatic enzyme activities

1. Oral administration of ethanol (3 ml) of 95% in 12 ml total volume over a two day period) significantly decrease plasma glucose and insulin levels and the activities of two key gluconeogenic enzymes, pyruvate carboxylase (pyruvate: CO2 ligase (ADP), EC 6.4.1.1) and fructose diphosphatase, (D-Fru-1,6-P2 1-phosphohydrolase, EC 3.1.3.11), and one glycolytic enzyme, fructose-1,6-P2 aldolase (Fru-1,6-P2 D-glyceraldehyde-3-P lyase, EC 4.1.2.13). In each instance, the administration of 2400 mug daily of oral folate in conjuction with the ethanol prevented these alterations in carbohydrate metabolism. 2. Intravenous injection of ethanol produced a rapid decrease (within 10--15 min) in the activities of hepatic phosphofructokinase, (ATP:D-fructose-6-phosphate 6-phosphotransferase, EC 2.7.1.11), pyruvate kinase, (ATP:pyruvate phosphotransferase, EC 2.7.1.40), fructose diphosphatase and fructose-1,6-P2 aldolase. 3. Intravenous ethanol significantly increased hepatic cyclic AMP concentration approximately 60% within 10 min, while oral ethanol did not alter hepatic cyclic AMP concentrations. 4. These data confirm the known antagonism ethanol and folate and suggest that oral folate might offer a protective effect against hypoglycemia in rats receiving ethanol.

Hormonal regulation of hepatic and jejunal formiminotransferase activity in man and rat

Abstract 1. 1. Glucagon, insulin and epinephrine produce rapid changes (within minutes) in hepatic and jejunal formiminotransferase ( N- formimino- L -glutamate: tetrahydrofolate 5-formiminotransferase, EC 2.1.2.5) activity in the rat. Limited evidence in human subjects and patients demonstrate that similar effects also occur in man. 2. 2. Intravenous glucagon (0.0015–0.5 mg) and isnulin (0.015–1.5 units/kg) produced rapid increases and decreases, respectively, in hepatic formiminotransferase activity which were unaltered by pretreatment of the rats with either actinomycin D or puromycin. Intravenous insulin and glucagon significantly decreased and increased, respectively, rat jejunal formiminotransferase activity, as well. Intravenous epinephrine (1.0–2.0 μg/min) also produced a rapid increase in hepatic formiminotransferase activity. The stimulatory effects of glucagon and epinephrine on hepatic formiminotransferase activity were mimicked by intravenous cyclic AMP suggesting that these hormonal responses may be mediated through increased cyclic AMP production. 3. 3. In four children with fasting-induced hypoglycemia, intravenous glucagon (1 mg/min) significantly increased hepatic formiminotransferase activity within 2–3 min. In five normal human subjects, the administration of subcutaneous insulin (15 units) for three consecutive days significantly decreased jejunal formiminotransferase activity. 4. 4. We suggest that the rapid insulin, glucagon and epinephrine effects on formiminotransferase activity may be due to dephorylation— phosphorylation mechanisms analogous to that involved in the regulation of glycogen metabolism.

Familial life-long persistent fever of unknown origin responding to dexamethasone and uronic acids☆

Abstract A patient of Lebanese ethnic origin was found to have a persistent temperature of 102 °F. with no diurnal variation. He gave a history of persistent life-long fever in himself and a twin brother. His family history was notable for multiple consanguineous marriages. Thorough study uncovered no apparent cause for his fever. Thyroid and adrenal function were normal as was the urinary etiocholanolone excretion. Sweat function also was normal. There was a further increase in his temperature after the administration of killed typhoid bacilli. His temperature could be decreased in twelve hours by the oral administration of dexamethasone and within one to five hours by the oral administration of glucuronic acid, its precursors, its metabolites and galacturonic acid. These various uronic acids, including the nonphysiologic galacturonic acid, are inhibitors of beta-glucuronidase. It is postulated that in this patient the defect in beta-glucuronidase is such that larger than normal physiologic amounts of natural inhibitors are necessary to inhibit beta-glucuronidase action. Beta-glucuronidase, therefore, is thought to be more active than normal, converting nonpyrogenic conjugated etiocholanolone to the pyrogenic free form. Glucuronic acid had no effect on etiocholanolone-induced fever in normal male volunteer subjects. It is suspected that beta-glucuronidase is important in regulating body temperature by controlling the level of free intrahepatic etiocholanolone and that this patient has a hitherto unknown defect of this mechanism.