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Biomedical subjects

A Rubenstein

Publications and source records attributed to A Rubenstein.

At least 37 records · Page 2Linked to original sources
PubMed1984

Biosynthetic human insulin and proinsulin have additive but not synergistic effects on total body glucose disposal.

Recent studies from our laboratory have demonstrated that human biosynthetic proinsulin has a much slower MCR than insulin as well as a greater effect on hepatic than on peripheral tissues. Since both of these features make proinsulin potentially useful as an adjunct to insulin, the present study was undertaken to characterize the biological effects of combined infusions of insulin and proinsulin. As an initial study, multiple euglycemic clamp studies were performed in six normal subjects to construct dose-response curves for insulin- and proinsulin-mediated glucose disposal. Insulin infusion rates of 0.63, 1.67, 5, and 10 micrograms/M2 X min were compared to proinsulin infusion rates of 2.75, 7.5, 22.5, and 45 micrograms/M2 X min. Analysis of these dose-response curves indicated that proinsulin-mediated glucose disposal was approximately 7% that of insulin. Each subject also received a combined infusion of insulin (0.63 micrograms/M2 X min) and proinsulin (2.75 micrograms/M2 X min). The mean (+/- SE) glucose disposal rate obtained during the combination study (319 +/- 21 mg/M2 X min) was similar to that predicted by adding the results from the individual hormone infusions (307 +/- 21 mg/M2 X min). Analysis of the dose-response curves for insulin and proinsulin was also useful in predicting the glucose disposal rate during the combination study (290 +/- 19 mg/M2 X min). Thus, using either approach to predict the glucose disposal rates, insulin and proinsulin appeared to have additive effects on total body glucose disposal.

Adult↗
PubMed1984

The effects of biosynthetic human proinsulin on carbohydrate metabolism.

Large quantities of biosynthetic human proinsulin have recently become available through recombinant DNA technology. Since the in vivo effects of human proinsulin have not been studied in man, we compared the dose-response relationship for stimulation of glucose disposal and suppression of hepatic glucose output by proinsulin and insulin. Ten normal subjects were studied using the euglycemic glucose clamp technique. The human proinsulin and insulin infusion rates were chosen to achieve steady-state proinsulin levels 10-fold higher than insulin levels on a molar basis, based on previous observations that porcine proinsulin has approximately 10% the potency of insulin. Proinsulin infusion rates of 2.75, 7.5, 22.5, and 45 micrograms/m2/min were compared with insulin infusion rates of 0.63, 1.67, 5, and 10 micrograms/m2/min. Primed, continuous infusions of insulin yielded steady-state levels within 25 min, whereas proinsulin levels did not reach a steady state for 120-180 min. The metabolic clearance rate of insulin was 11-12 ml/kg/min at the lower infusion rates but fell to 8.4 ml/kg/min at the highest infusion rate. The metabolic clearance rate of proinsulin was 3.0-3.5 ml/kg/min at all infusion rates. Dose-response analysis demonstrated that proinsulin-mediated glucose disposal was approximately 8% that of insulin. In contrast, proinsulin-mediated suppression of hepatic glucose output was approximately 12% that seen with insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Seventh-Day Adventist adolescents--life-style patterns and cardiovascular risk factors.

The life-style of adolescents attending a Seventh-Day Adventist boarding school was evaluated as it related to cardiovascular risk factors. The diet contained 34% calories as fat, with 11% derived from saturated fat. Total serum cholesterol levels were low (mean, standard deviation=138+/-15 mg per dl), and apolipoprotein B level was low as well (46+/-9 mg per dl). The high-density lipoprotein cholesterol level was within the usual range (52.4+/-13.3 mg per dl). Mean blood pressures were also low (systolic, 104.1+/-9.6 mm of mercury; diastolic, 65.7+/-9.7 mm of mercury). There was no self-reported use of cigarettes. If this life-style were to continue through adulthood, the incidence of premature atherosclerotic disease, particularly coronary artery disease, for this group might well be reduced, compared with other North Americans, as suggested by findings from previous studies of adult Seventh-Day Adventists.

Adolescent↗
PubMed1983

Three mutant insulins in man.

We have previously identified a structurally abnormal insulin in the serum and pancreas of a middle-aged man with diabetes mellitus which arose from a leucine for phenylalanine substitution at position 24 or 25 of the insulin B chain; further analysis of the patient's leukocyte DNA showed that one of the patient's insulin alleles had undergone mutation resulting in loss of an MboII restriction site normally present in the human insulin gene. Two additional and unrelated patients with the same clinical syndrome have now been identified (ref. 4 and unpublished results). All of these patients showed hyperglycaemia typical of diabetes and with marked hyperinsulinaemia typical of insulin resistance, but all three show normal tolerance to exogenously administered insulin. As the opportunity of examining pancreatic tissue from patients suspected of secreting insulin variants is rare, we have developed a method combining HPLC and radioimmunoassay to identify insulin variants isolated from human sera. By this method we have shown that all three patients noted above secrete structurally variant and chemically distinct insulins. In correction of our original assignment, one is identified as [LeuB25]insulin.

Amino Acid Sequence↗
PubMed1983

Characteristics of binding of a low affinity, noncooperative insulin [( LeuB25]insulin) to IM-9 lymphocytes.

[Leu-B25]insulin is a low affinity insulin analog which does not increase the rate of dissociation of 125I-insulin from insulin receptors (i.e. does not display negative cooperativity). We have studied the characteristics of binding of this analog to IM-9 cultured lymphocytes, in order to determine the contribution of negative cooperativity to the curvilinear nature of Scatchard plots typical of insulin binding data. The affinity of [LeuB25]insulin for receptors was approximately 1% that of insulin, as determined by its ability to inhibit 125I-insulin binding. Monoiodinated preparations of insulin and of [LeuB25]insulin were produced, labeled in the tyrosine at position 14 of the A chain. These 125I-TyrA14-labeled species were used in all studies. Both native insulin and a serum containing antiinsulin receptor antibodies were equally potent at inhibiting binding of 125I-[LeuB25]insulin and 125I-native insulin, suggesting that they bind to the same population of receptors. Native insulin (100 ng/ml) increased the rate of dissociation of both 125I-insulin and 125I-[LeuB25]insulin. However, [LeuB25]insulin (2.5 micrograms/ml) did not increase the rates of dissociation of either 125I-insulin or 125I-[LeuB25]insulin (i.e. it did not display negative cooperativity). Competition curves and Scatchard plots were constructed using 125I-[LeuB25]insulin and unlabeled analog. Half-maximal inhibition of 125I-[LeuB25]insulin binding was seen at a [LeuB25]insulin concentration of approximately 500 ng/ml. More importantly, the Scatchard plot of these binding data was markedly curvilinear, as is typical of insulin binding data. In summary, a non-cooperative insulin analog, [LeuB25]insulin, yielded curvilinear Scatchard plots, indicating that negative cooperativity is not the full explanation of the curvilinear nature of Scatchard plots of insulin binding data. Therefore, an alternative explanation, such as the existence of heterogeneous receptor states, with differing affinities for the hormone, must contribute to the nonlinearity of these plots.

Cell Line↗
PubMed1982

Relation of counterregulatory responses to hypoglycemia in type I diabetics.

We compared counterregulatory metabolic and hormonal responses in 8 normal controls with responses in 16 Type I (insulin-dependent) diabetics, 7 of whom had had repeated attacks of severe hypoglycemia, in an effort to determine whether these responses are related to the occurrence of hypoglycemia in the latter group. In response to insulin-induced hypoglycemia, peak values for glucose production (5.7 +/- 0.5 vs. 2.5 +/- 0.3 mg per kilogram of body weight per minute) (P less than 0.0001), glucagon (195 +/- 26 vs. 93 +/- 18 pg per milliliter) (P less than 0.0001), and growth hormone (63 +/- 8 vs. 37 +/- 5 ng per milliliter) (P less than 0.006) were significantly higher in the controls than in the diabetics. However, peak values for glucose production, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone were similar in the diabetics with and without clinical hypoglycemia. Thus, with the present dose and method of insulin administration we were unable to predict the presence of severe hypoglycemic reactions in a group of Type I diabetics. Although deficient counterregulatory hormone responses are important in the pathogenesis of hypoglycemic reactions, we conclude that other factors in the daily lives of such patients also play a major part in determining whether reactions will occur.

Adolescent↗
PubMed1982

Hepatic ultrastructure in leprechaunism. Hepatic ultrastructural evidence suggesting a syndrome with defective hepatic glucose release.

Leprechaunism is a congenital syndrome with characteristic habitus and facies, with fasting hypoglycemia and hyperinsulinism. In response to a glucose challenge there is prolonged severe hyperglycemia with an increased hyperinsulinemia. Our studies on such a patient showed a normal response of the serum glucose to glucagon stimulation in the fed state but no response in the postabsorptive state. Ultrastructural studies on the hepatocytes demonstrated that a lack of hepatic glycogen was not responsible for the biochemical features, since there was abundant normal beta-glycogen in both the fed and fasting state, the granules being smaller in the fasted state. We speculate that carbohydrate intolerance in leprechaunism may be due to a relative insulin resistance of cell receptors in the fed state. Reactive hyperinsulinemia persisting into the postabsorptive phase appears to antagonize the usual glycogenolytic response to glucagon during fasting, resulting in hypoglycemia despite the presence of large hepatic glycogen stores.

Child, Preschool↗
PubMed1982

The selective lipid-lowering effect of vegetarianism on low density lipoproteins in a cross-over experiment.

In a cross-over experiment the effect of short-term vegetarianism on serum lipids, lipoproteins and apoproteins was studied. The experimental diet was free of animal products, with the exception of skim milk, and consequently low in saturated fat and cholesterol. Fifteen free-living individuals were randomly assigned to 3-week periods on either the experimental diet or a control diet which closely approximated the usual intake in the U.S.A. Significant reductions in total cholesterol (12.5%), low density lipoprotein cholesterol (14.7%), and apo B (13.2%) were observed, accompanied by a non-significant decrease in high density lipoprotein cholesterol (10%), apo A-I (3%) and a non-significant increase in apo-II (4%). These data suggest that a fat-modified diet low in total fat, saturated fat and cholesterol, and moderate (not high) in polyunsaturated fat may not lower HDL-C or its apoproteins as much as a diet high in polyunsaturated fat, while having similar effects on LDL-C, and would therefore be preferable as the basis for primary prevention of atherosclerosis.

Adult↗
PubMed1982

Evidence for the presence of somatostatin 28 in plasma.

Somatostatin-like immunoreactivity (SLI) from dog and rat plasma eluted from Biogel P-6 columns as three distinct peaks. A large-molecular-weight peak was present in the void volume of the column, an intermediate-sized peak (SLI28) coeluted with synthetic somatostatin 28 (S-28), and a small-molecular-weight peak (SLI14) coeluted with SRIF. Material from the SLI28 peak diluted in parallel to the S-28 standard in the radioimmunoassay and behaved identically to S-28 on high pressure liquid chromatography (HPLC). Levels of SLI28 in the portal vein were consistently greater than the simultaneously measured peripheral levels (portal peripheral ratio 2.2 +/- 0.2). Venous samples drawn from multiple sites suggested that SLI28 is segregated by the duodenum and/or pancreas and the intestine. This data is consistent with the possibility that S-28 is a hormone distinct from SRIF.

Animals↗
PubMed1982

Endocrine-metabolic relationships in patients with leprechaunism.

Leprechaunism is a rare, heritable syndrome, associated with multiple dysmorphic and pathologic features, suggestive of an endocrine dysfunction. Few endocrine and metabolic studies have been obtained because of the rarity of the syndrome, and the small size and early demise of these infants. The authors present here the clinical, anatomic, and endocrine-metabolic studies of three patients, with a view toward careful delineation of the syndrome and further characterization of the metabolic defect.The most striking and consistent metabolic derangements present in all of these patients were fasting hypoglycemia (less than 20 mg/dL), postprandial hyperglycemia (more than 250 mg/dL), marked hyperinsulinemia (more than 2000 μU/mL), and severe insulin resistance (less than a 20 percent decrease in blood sugar with 0.3 to 1.0 U/kg of regular insulin IV). Hyperinsulinemia was observed in response to oral feedings and glucose infusion, and after tolbutamide. Insulin secretion was less marked with amino acid infusions. Normal increments in blood glucose occurred following alanine, galactose, and glycerol. Glucagon caused a rise in glucose 4 hours after a meal, but no response was seen after a 12-hour fast. Pituitary, gonadal, and adrenal hormone levels were normal, and there was a normal response pattern to GnRH and TRH. Hyperinsulinemia would appear to be the biochemical hallmark of this disease. Our previous studies were suggestive of a postreceptor defect in insulin action. The present endocrine-metabolic studies are compatible with this hypothesis. Interaction of supraphysiologic concentrations of plasma insulin with growth factor receptors, this may provide a partial explanation for some of the dysmorphic features seen in the disorder.

Adult↗
PubMed1981

Simultaneous inhibition of insulin and somatomedin-C binding to cultured IM-9 lymphocytes by naturally occurring antireceptor antibodies.

A 53-y4-old male patient with insulin-resistant diabetes was found to have circulating inhibitors of both insulin and somatomedin-C binding. Serum obtained from the patient at the time of initial presentation inhibited 50% of both 125I-insulin and 125I-SM-C binding to IM-9 lymphocytes at dilutions of 1:150. Spontaneous improvement in the patient's diabetic state was associated with a simultaneous and equal decrease in the serum inhibitory titers for both radioligands. Scatchard analysis indicated that the observed serum-induced decrease in both insulin and SM-C binding was due to decreased receptor affinity, with no alteration in receptor number. The serum inhibitors of both insulin and SM-C binding were precipitated equally by Staph-A and also by 40% ammonium sulfate, suggesting they were immunoglobulins. The observation of naturally occurring autoantibodies against both the insulin and SM-C receptors suggests a structural homology between the two receptors.

Antibodies↗
PubMed1980

Semisynthesis and biological activity of porcine [LeuB24]insulin and [LeuB25]insulin.

Two analogs of porcine insulin with substitutions of leucine for phenylalanine in the COOH-terminal region of the insulin B chain have been prepared by a combination of solid-phase synthesis and semisynthesis. Solid-phase synthesis of the substituted octapeptides B23-B30 bearing the trifluoracetyl group on lysine-B29, enzymatic coupling of the octapeptides to bis(tertiary-butyloxycarbonyl)desoctapeptide insulin by trypsin, and deprotection of the corresponding adducts in formic acid and piperidine resulted in two insulin derivatives, one with leucine at position B24 and the other with leucine at position B25. These analogs had only about 10% and 1%, respectively, of the activity of porcine insulin in competing for the binding of [125I]iodoinsulin to both rat adipocytes and human IM-9 lymphocytes. The relative potencies of the analogs in stimulating glucose oxidation by rat adipocytes decreased in the order porcine insulin > [LeuB24]insulin > [LeuB25]insulin. However, at high concentrations both analogs had full agonists activity. Experiments in which the semisynthetic insulins were mixed with the native hormone showed that [LeuB24]insulin, but not [LeuB25]insulin, was an active antagonist of insulin action. These results suggest that the antagonistic activity of a human insulin variant having leucine at position B24 or B25 can be assigned to the molecule with the sequence Gly-Leu-Phe-Tyr (residues B23-B26) in its active site.

Adipose Tissue↗
PubMed1980

Glucose kinetics in leprechaunism: accelerated fasting due to insulin resistance.

Postprandial and postabsorptive glucose metabolism was studied in a 3-yr-old girl with leprechaunism by substrate and hormonal measurements and by quantifying hepatic glucose output during continuous infusion of D-[6-6-2H2]-glucose. Hepatic glucogen content and the activity of glycogen synthase and phosphorylase were also measured in the post-prandial state on a separate occasion. During the 4-h postprandial state, plasma glucose, alanine, lactate, beta-hydroxybutyrate, and glycerol were normal, as were hepatic glycogen, glycogen synthase, phosphorylase, and hepatic glucose output of 7.5 mg kg-1 min-1. Intravenous injection of glucagon (30 micrograms kg-1) caused an immediate almost 3-fold rise in glucose production consistent with brisk glycogenolysis. During the 8- to 12-h postabsorptive state, however, the patient had elevated levels of glycerol (330-508 microM) and beta-hydroxybutyrate (3291-3801 microM) and decreased levels of glucose 24-29 mg/dl) and alanine (121-135 microM) consistent with a much longer period of fasting in the normal child. Furthermore, hepatic glucose output was reduced to 3.9 mg kg-1 min-1, and iv glucagon injection failed to increase this rate; both of these observations are consistent with a hepatic state generally found only later in fasting in the normal child. From these observations we conclude that the hypoglycemia reported in the leprechaunism syndrome is due to an accelerated fasting state secondary to insulin resistance. As with long-fasted, glycogen-depleted normal children, gluconeogenesis alone is often not capable of adequately meeting the child's large noninsulin-dependent cerebral glucose requirements.

Abnormalities, Multiple↗
PubMed1979

A structurally abnormal insulin causing human diabetes.

Insulin isolated from the pancreas of a diabetic patient with fasting hyperinsulinaemia showed decreased activity in binding to cell membrane insulin receptors and in stimulating cellular 2-deoxyglucose transport and glucose oxidation. Chemical studies suggest that the isolated hormone is a mixture of normal insulin and an abnormal variant which contains a leucine for phenylalanine substitution at position 24 or 25 of the insulin B-chain.

Amino Acid Sequence↗