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Biomedical subjects

K H Gabbay

Publications and source records attributed to K H Gabbay.

At least 73 records · Page 4Linked to original sources
PubMed1980

Isolation and characterization of immunoreactive somatostatin from fish pancreatic islets.

Using a radioimmunoassay with labeled synthetic tetradecapeptide somatostatin, a large amount of immunoreactive somatostatin was found in the principal pancreatic islet of the channel catfish (Ictalurus punctata). The purpose of these experiments was to isolate and characterize the somatostatin-like material. Extracts of islets were chromatographed on a Bio-Gel P-30 column, and over 90% of the immunoreactive somatostatin migrated with proteins at least twice the size of synthetic tetradecapeptide somatostatin. This fraction was further purified by ion-exchange chromatography on carboxymethyl-cellulose and DEAE-cellulose columns. Two peptides were obtained with identical immunoreactivity, which was approximately 25% that of the synthetic somatostatin. Each peptide was judged to be >95% pure by thin-layer electrophoresis, polyacrylamide gel electrophoresis at pH 8.9, and highpressure liquid chromatography. Further criteria of purity included amino-terminal analysis of fraction IV yielding only aspartic acid. A total of 1.3 mg of fraction II, and 3.8 mg of fraction IV somatostatin-like peptides were obtained from 10 g of fresh frozen islets. Characterization of the two peptides revealed both peptides slightly more acidic than synthetic tetradecapeptide somatostatin. Fraction II had an isoelectric point of 8.0-8.3, and fraction IV 8.3-9.0. Molecular weight estimation by sodium dodecyl sulfate-urea polyacrylamide gel electrophoresis revealed similar mobility of both peptides, between pancreatic polypeptide (mol wt 4,500) and glucagon (mol wt 3,500). The mobility was not altered by reduction, and was approximately twice the size of synthetic tetradecapeptide somatostatin (mol wt 1,800). This confirmed that the peptides were single polypeptide chains and not aggregates, or somatostatin bound to larger proteins. Molecular weight determination by gel filtration chromatography on Bio-Gel P-6 in 8 M urea gave an estimated mol wt of 3,700. Amino acid analysis of the two immunoreactive somatostatins indicated that they were very similar in composition. Both pancreatic somatostatins (1 muM) had full biological activity relative to synthetic somatostatin measured as inhibition of growth hormone release from rat anterior pituitary cells.

Amino Acids↗
PubMed1980

Effects of E coli endotoxin on pancreatic hormones and blood flow.

Studies were performed on anesthetized dogs to determine the relationship between endotoxin-induced alterations in pancreatic blood flow (PBF) and hormones that originate partially or completely from the pancreas. PBF was estimated in six dogs by radioactive microspheres (praeendoxin, 25 and 240 minutes postendotoxin). Insulin, glucagon, pancreatic polypeptide (PP), and somatostatin-like immunoreactivity (SLI) were assayed in arterial and portal venous blood. Cardiac output and mean arterial blood pressure (MABP) decreased 25 minutes after endotoxin administration (50% and 40%, respectively) and returned toward normal levels by four hours. However, there was 74% decrease in PBF at 25 minutes and a further drop four hours after endotoxin. Hormonal responses were characterized by a short-lived increase in arterial insulin, corresponding to a transient increase in blood glucose. Insulin release increased shortly after endotoxin. Arterial glucagon and PP increased two to five hours after endotoxin. There was a suggestion that the increase in PP was of nonpancreatic origin. Little change in plasma SLI was noted following endotoxin. Thus, it appears that endotoxin altered the release of different pancreatic hormones with a variable time courses.

Animals↗
PubMed1979

The infant of the diabetic mother: correlation of increased cord C-peptide levels with macrosomia and hypoglycemia.

C peptide is secreted by pancreatic beta cells in amounts equimolar with insulin, and its levels provide a direct indication of endogenous fetal levels of insulin despite the presence of maternal insulin antibodies. To determine the presence of hyperinsulinemia and its relation to the development of complications in infants of diabetic mothers, we measured cord serum levels of C peptide in 79 infants of diabetic mothers and 62 infants of nondiabetic mothers. Infants of diabetic mothers had higher cord levels of C peptide, which were significantly associated with neonatal hypoglycemia and macrosomia (P less than 0.001) but not with hyaline-membrane disease. Cord levels of C peptide in infants of diabetic mothers were elevated at the earliest gestational age studied (less than 34 weeks) and were directly related to the severity of maternal diabetes, as assessed by the White classification. We conclude that hyperinsulinemia is present in infants of diabetic mothers and that it is related to some major complications in such infants.

Birth Weight↗
PubMed1979

Genetic marker for insulin-dependent diabetes mellitus.

A rare genetic type (Bf F1) of properdin factor B is found in 22.6% of patients with insulin-dependent diabetes mellitus but in only 1.9% of the general population, yielding a relative risk of 15.0. This indicates that a genetic locus for insulin-dependent diabetes mellitus is very close on chromosome 6 to Bf, and that Bf F1 is a marker for nearly 1 out of 4 insulin-dependent diabetic patients.

Adult↗
PubMed1979

Aldose reductase inhibition: studies with alrestatin.

Studies with the aldose reductase inhibitor alrestatin in animal models have suggested that the sorbitol pathway may be of etiologic significance in the pathogenesis of peripheral neuropathy in diabetes. In normal subjects and in highly selected diabetic patients with severe peripheral neuropathy, alrestatin given either intravenously (50 mg/kg body weight) or orally (1 gm q.i.d.) produced no acute toxicity. The serum half-life of alrestatin was approximately 1 hr, and 99% was recovered in the urine within 24 hr. Two diabetic patients receiving alrestatin intravenously reported subjective improvements in clinical symptoms 2 days following the start of infusions. These improvements lasted approximately 3 wk after infusions were discontinued. However, there were no significant objective changes in peripheral nerve condition velocities, or on neurologic examination. In a 30-day oral trial with alrestatin in 4 diabetics, there were no subjective improvements in clinical symptoms nor were there objective improvements on neurologic examination or in peripheral nerve conduction velocities. In this study, peak serum levels of alrestatin were approximately 3 times lower than those obtained on intravenous administration, and it is possible that a high peak serum level is critical to the attainment of adequate tissue drug concentrations. Furthermore, the patients were suffering from severe clinical peripheral neuropathy, which could represent a stage of permanent irreversible nerve damage. Studies with alrestatin in newly diagnosed diabetics with peripheral nerve conduction velocity deficits but without clinical neuropathy might provide a better test of the sorbitol pathway hypothesis.

Absorption↗
PubMed1979

Familial hyperproinsulinemia: partial characterization of circulating proinsulin-like material.

Familial hyperproinsulinemia is an autosomal dominant defect that is associated with strikingly elevated levels of serum proinsulin-like material. Our studies show that trypsin converts familial hyperproinsulinemia proinsulin to insulin more slowly than it converts a 131I-labeled porcine proinsulin marker. Molar yields of insulin indicated that the material may be an intermediate proinsulin. Studies with two human C-peptide antisera that differ in their relative immunoreactivity with human C-peptide and proinsulin showed that the two antisera reacted equally with familial hyperproinsulinemia proinsulin, suggesting that it is a partially cleaved proinsulin intermediate. Sulfitolysis of highly purified material to break the inter- and intra-chain disulfide bridges and subsequent adsorption on a specific B-chain antibody covalently bound to Sepharose beads showed that the C-peptide was still connected to the B-chain. These data indicate that familial hyperproinsulinemia proinsulin is normally cleaved at the C-peptide-A-chain linkage site. A structural abnormality appears to underlie familial hyperproinsulinemia proinsulin, which impairs its cleavage at the B-chain-C-peptide linkage site.

Amino Acid Sequence↗
PubMed1979

Glycosylated hemoglobins: increased glycosylation of hemoglobin A in diabetic patients.

The components of the hemoglobin-A1 fraction--hemoglobins A1a--c--arise from nonenzymatic glycosylation of hemoglobin A at the beta-chain N-terminal amino groups and can be resolved from hemoglobin A by cation exchange chromatography. Glycosylation can also occur at the alpha-chain N-terminals as well as the epsilon-amino groups of lysine residues of both alpha- and beta-chains; this results in glycosylated species appearing in the hemoglobin-A fraction. In this study, we determined the extent of hemoglobin-A glycosylation using a colorimetric chemical method specific for the detection of ketoamine-linked hexoses in proteins. We demonstrate increased glycosylation of the main hemoglobin-A fraction in diabetic patients, which correlates significantly (r = 0.72, P less than 0.001) with the hemoglobin-A1 percentage determined by column chromatography in the corresponding hemolysates. This finding provides the basis for the application of this chemical procedure to the measurement of total glycosylation of hemoglobin.

Chemical Phenomena↗
PubMed1979

Somatostatin and pancreatic polypeptide secretion: effects of glucagon, insulin, and arginine.

The isolated perfused canine pancreas with duodenal exclusion was used to examine islet hormone output in response to arginine and exogenous glucagon and insulin. Exogenous glucagon (100 ng/ml) stimulated insulin and somatostatin secretion, which occurred in a biphasic pattern. The insulin response to glucagon was markedly enhanced by increased perfusate glucose, unlike the somatostatin response, which was little affected. The insulin and somatostatin responses were seen between 15 and 45 s after the glucagon stimulus. Pancreatic polypeptide secretion was uninfluenced by exogenous glucagon. Biphasic release of glucagon, somatostatin, and pancreatic polypeptide was evoked by 10 mM arginine, the responses first being apparent within less than 30 s. Exogenous insulin (50 mU/ml) infused for 10 min had no statistically significant effect on glucagon, somatostatin, or pancreatic polypeptide secretion. This study suggests that these four islet hormones may all be involved in the dynamic mechanisms of nutrient metabolism. In addition, potential intra-islet paracrine effects are identified.

Animals↗
PubMed1978

The glycosylation of hemoglobin: relevance to diabetes mellitus.

Glucose reacts nonenzymatically with the NH2-terminal amino acid of the beta chain of human hemoglobin by way of a ketoamine linkage, resulting in the formation of hemoglobin AIc. Other minor components appear to be adducts of glucose 6-phosphate and fructose 1,6-diphosphate. These hemoglobins are formed slowly and continuously throughout the 120-day life-span of the red cell. There is a two- to threefold increase in hemoglobin AIc in the red cells of patients with diabetes mellitus. By providing an integrated measurement of blood glucose, hemoglobin AIc is useful in assessing the degree of diabetic control. Furthermore, this hemoglobin is a useful model of nonenzymatic glycosylation of other proteins that may be involved in the long-term complications of the disease.

Blood Glucose↗
PubMed1977

Hypoglycemia of infancy and nesidioblastosis. Studies with somatostatin.

We treated a two-month-old infant with servere intractable hypoglycemia and nesidioblastosis with continuous glucose infusions (0.75 g per kilogram per hour) via a central venous catheter. Preprandial glucose levels on this regimen were 37+/-2 mg per deciliter (+/-S.E.M.). Basal serum insulin levels were within normal fasting levels for this age group but inappropriately elevated for the blood glucose levels. The beta cells were exquisitely sensitive to infusions of synthetic cyclic somatostatin, with a dose-dependent rise in blood glucose and concomitant suppression of serum insulin levels. There was only minimal suppression of plasma glucagon levels. Single subcutaneous injections of 50 microng of protamine zinc somatostatin raised preprandial blood glucose levels to 83+/-3 mg per deciliter for four to five days although preprandial hormone levels were unchanged. These findings indicate that hypoglycemia of infancy is a hyperinsulin state with abnormal basal regulation of insulin secretion.

Adenoma, Islet Cell↗
PubMed1977

"Somatostatinoma": a somatostatin-containing tumor of the endocrine pancreas.

We studied the pancreatic and enteric hormone profile of a 46-year-old woman who had hyperglycemia and a pancreatic tumor. Before operation, there was no evidence of overproduction of glucagon or insulin. The tumor's ultrastructure had a distinctive endocrine morphology, resembling D cells. Prompted by the recent demonstration of somatostatin in D cells of pancreatic islets, we analyzed the tumor and found a large quantity of immunoreactive somatostatin (301 ng per milligram of tissue). Insulin, glucagon, gastrin, vasoactive intestinal polypeptide and human pancreatic polypeptide were present in only trace quantities. The tumor cells were cultured in monolayers, which remained viable up to 51 days and released somatostatin into the culture medium. In seven insulinomas and two glucagonomas, we found the somatostatin content either much lower (less than 0.6 ng per milligram of tissue) or undetectable. After complete resection of the tumor, our patient became euglycemic and has remained so for the past 20 months.

Cells, Cultured↗
PubMed1977

Ultrastructural localization of pancreatic polypeptide in human pancreas.

Human pancreatic polypeptide (HPP) was localized in surgically obtained human pancreas by immunocytochemical electron microscopy. HPP was localized to the secretory granules of cells distinct from the alpha, beta, or delta cells of endocrine islets. The PP cells in 10 patients surveyed were most frequently located in the periphery of the islets. Immunolocalization distinguishes a fifth endocrine cell type in human islets which distinct ultrastructurally by its smaller granule diameter and lack of PP immunoreactivity.

Humans↗
PubMed1977

Glycosylated hemoglobins and long-term blood glucose control in diabetes mellitus.

The glycosylated minor hemoglobin components Hb A1a+b and HbA1c are elevated in insulin-dependent juvenile diabetic patients, 3.2+/-0.7 (+/-1 SD) and 10.0+/-1.9% of total hemoglobin respectively, versus 2.1+/-0.4 and 4.9+/-0.7% in a normal non-diabetic control population. Total glycosylated hemoglobin components, Hb A1a+b+c, correlated with the degree of diabetic blood glucose regulation as measured by antecedent 24-h urinary glucose excretion determined in 220 diabetic patients immediately before, 1, 2, and 3 months prior to the HB A1a+b+c measurement. This assay for long-term blood glucose regulation was utilized to determine the effect of hyperglycemia on plasma cholesterol levels in 112 diabetic patients. Hb A1a+b+c levels correlated with plasma cholesterol levels, suggesting that long-term hyperglycemia is associated with hypercholesterolemia. It is suggested that glycosylated hemoglobin measurement is a good index of long-term blood glucose levels in diabetic patients.

Adolescent↗
PubMed1977

Aldose reductase in retinal mural cells.

Cultured mural cells (intramural pericytes) from adult rhesus retinal capillaries were examined for the presence of the sorbitol pathway. A radioimmunoassay for human aldose reductase, cross-reactive with rhesus lens aldose reductase, showed the presence of this enzyme in our cultured cells. Mural cells grown in culture media containing normal (10 mM) and high (40 mM) levels of glucose were examined for polyol accumulation by gas-liquid chromatography. Cells incubated in high glucose medium showed a threefold increase in sorbitol concentration over cells grown at low glucose levels. After 30 days in high glucose medium, mural cells formed dense multilayered areas with extensive cellular debris. These findings suggest the presence of the sorbitol pathway in cultured retinal mural cells and cellular degeneration in high glucose medium; this may have possible implications in the pathogenesis of diabetic retinopathy.

Alcohol Oxidoreductases↗
PubMed1976

Familial hyperproinsulinemia. An autosomal dominant defect.

We describe a genetic defect in a kindred in whom proinsulin or a proinsulin-like material constitutes the major fraction of circulating insulin immunoreactivity in both the fasting and stimulated states. The defect, familial hyperproinsulinemia, affects eight males and 10 females in four generations of the kindred, with an autosomal dominant mode of transmission. Familial hyperproinsulinemia is asymptomatic in the affected progeny, with no apparent relation to hypoglycemia or to the development of diabetes mellitus. This genetic defect may represent either a deficiency in the proinsulin cleaving enzyme (or enzymes) within the beta cell, or more probably, an abnormal species of proinsulin.

Adolescent↗