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At least 19 recordsLinked to original sources
PubMed1978

Change of insulin dosage, circulating free and bound insulin and insulin antibodies on transferring diabetics from conventional to highly purified porcine insulin.

Fifty-eight patients on long term conventional mainly bovine insulins have been transferred to highly purified porcine insulin preparations. There was an overall reduction of 22% in daily insulin dosage and improved diabetic control as shown by decreased blood glucose concentration. Increased concentrations of serum free insulin and falls in serum bound insulin levels were also found. There were reductions in the serum binding capacities and affinity constants on changeover from conventional to highly purified insulin due to a combination of the effects of differential conventional/purified porcine binding and the substitution of a low antigenicity insulin. However, 12 of the patients receiving higher doses of insulin experienced marked hypoglycaemic reactions immediately on insulin changeover despite initial dosage reductions of 30% and prior to any changes in antibody characteristics.

Adolescent↗
PubMed1979

Insulin action in isolated fat cells. II. Effects of divalent cations on stimulation by insulin of protein synthesis, on inhibition of lipolysis by insulin, and on the binding of 125I-labelled insulin to isolated fat cells.

The effects of ommission of Ca2+ and Mg2+ from the incubation medium on three aspects of insulin action in isolated fat cells have been investigated. In the (Ca2+ + Mg2+)-free incubation medium incorporation of L-[14C]leucine into fat cell protein was reduced in the absence of insulin. Insulin stimulated L-[14C]leucine incorporation only in the presence of added CaCl2 or MgCl2. Incubation of the cells in the (Ca2+ + Mg2+)-free medium reduced but did not abolish the ability of adrenaline to stimulate lipolysis or the ability of insulin to inhibit the adrenaline-stimulated lipolysis. Specific binding of 125I-labelled insulin to the fat cells was reduced in the absence of Ca2+ and Mg2+ but was not abolished, even in the presence of EDTA. Ca2+ was routinely the most effective divalent cation in supporting these aspects of insulin action, but similar responses were obtained with Mg2+, Sr2+ and Ba2+. Since insulin still binds to the cells under conditions in which some of the cellular effects of the hormone are abolished, it is suggested that divalent cations may have a role, either direct or indirect, in the processes linking the insulin-insulin receptor complex to certain effector systems in the cells. It is tentatively suggested that this action occurs at the level of the fat cell plasma membrane.

Adipose Tissue↗
PubMed1978

The relationship between circulating free and bound insulin, insulin antibodies, insulin dosage and diabetic control in insulin treated diabetics.

Free and bound insulin concentrations, blood glucose and anti-insulin antibody binding characteristics have been determined in 100 insulin treated diabetics; medium serum free insulin was 11 mU/l when fasting and rose to 30 mU/l after the mid-day meal. Significant correlation between blood glucose and serum free (but not bound) insulin was found. No relationship between insulin antibodies and daily insulin dose or diabetic control were found, nor a relationship between free insulin and antibody characteristics.

Adolescent↗
PubMed1977

Structure and activity of insulin, XV[1-5]. Further evidence for the importance of arginine residue B22 in the activity of insulin. Semisyntheses of despentapeptide-(B23 - 30)-insulins varied in B22 using desnonapeptide-(B22 - 30)-insulin and tetrapeptides.

Insulin hexamethyl ester was digested by trypsin. The resulting desoctapeptide-(B23 - 30)-insulin pentamethyl ester was purified. This compound was digested by carboxypeptidase B to remove the arginine residue B22 at the end of the B chain. Then the N-terminal amino groups of the remaining desnonapeptide-(B22 - 30)-insulin pentamethyl ester were protected with the Boc residue. The free carboxyl group of the glutamic acid residue B21 of this product was coupled to the following synthetic tetrapeptide esters: Arg-Gly-Phe-Phe-OMe, Lys(Boc)-Gly-Phe-Phe-OMe, Orn(Boc)-Gly-Phe-Phe-OMe, Cit-Gly-Phe-Phe-OMe, Ala-Gly-Phe-Phe-OMe and Gly-Gly-Phe-Phe-OMe. The syntheses of these peptide esters are described. After removal of all protecting groups, despentapeptide-insulin (B22-Arg) and analogues of this product with variation in position B22 could be obtained. They were purified by column chromatography. The biological activities of these components were determined by the mouse fall test. In the case of despentapeptide insulin (C-terminus Arg-Gly-Phe-Phe), the activity rose to the expected value of 34%. The insulin variants with amino acid residues other than arginine in position B22 had much lower activities: with lysine 13%, with ornithine 12%, with citrulline 9%, with alanine 8% and with glycine 6%. Desnonapeptide-insulin by itself posses an activity of 3%. These results demonstrate once more the essential nature of arginine residue B22 for insulin activity.

Animals↗
PubMed1979

Effect of cytochalasin B and D on groups of insulin receptors and on insulin action in rat adipocytes. Possible evidence for a structural relationship of the insulin receptor to the glucose transport system.

The possible physiological importance of the groups of insulin receptors on rat adipocytes and the relationship of these groups to insulin action were investigated. The effect of cytochalasin B and D on biological actions of insulin was measured and compared with the effect of these agents on the ultrastructural distribution of groups of insulin receptors. Cytochalasin B had no effect on epinephrine-stimulated lipolysis, insulin inhibition of epinephrine-stimulated lipolysis, or insulin stimulation of protein synthesis. Cytochalasin B, over a concentration range of 50 nM to 5 muM, progressively inhibited the basal glucose transport system, as measured by glucose oxidation, 2-deoxyglucose transport, and 3-O-methylglucose transport. Insulin was capable of fully stimulating remaining basal transport at submaximal concentrations of cytochalasin B. Insulin pretreatment of adipocytes partially protected the glucose transport system from inhibition by cytochalasin B. Cytochalasin B markedly altered the distribution pattern of insulin receptors, which caused an increase in the number of single receptor molecules by decreasing the number of larger groups. A significant correlation (r = 0.964; P < 0.001) was found between the percent increase in single receptors and the percent decrease in glucose transport. Ferritin-insulin pretreatment of adipocytes prevented disruption of the groups of insulin receptors by cytochalasin B. Cytochalasin D had no effect on the biological actions of insulin or on the groups of insulin receptors. These data suggest that the ability of insulin to affect adipocyte metabolism is independent of the hormone occupying adjacent, grouped receptor sites. The marked contrast in effects of cytochalasin B and D on groups of insulin receptors and glucose transport suggests that the microfilament system is not involved in insulin action or in holding the groups of insulin receptors together, as both agents are known disrupters of microfilaments and inhibitors of actin gelation. The correlation between the effects of cytochalasin B on insulin receptor distribution and glucose transport leads to the speculation that the glycoprotein molecules containing the insulin receptor are functionally linked with the glucose transport system.

Adipose Tissue↗
PubMed1977

[Clinical effects of monocomponent insulin and commercial insulin preparations on insulin requiring diabetics (author's transl)].

Diurnal variation of blood sugar, C-peptide immunoreactivity (CPR), free insulin and total insulin were measured in 10 insulin requiring diabetics after obtaining adequate control of diabetes with commercial lente insulin treatment. Following these tests, insulin treatment were changed to monocomponent insulin (MC-insulin) from commercial lente insulin treatment in all subjects and the same tests were performed at 7th day of MC-insulin treatment. Diurnal variations of blood sugar in both groups were not changed significantly. Also changes in CPR of both groups were nearly same magnitude and endogenous insulin secretion in these insulin treated diabetics were suggested except a case of juvenile diabetic subject. However personal variation were great in diabetics with high antibody titer, diurnal variations of total extractable insulin in both groups were quite comparable. And mean diurnal changes in free insulin were resemble to that of CPR. All of these data suggested that clinical effects of MC-insulin and commercial insulin treatment on insulin requiring diabetics were comparable except insulin antibody or proinsulinspecific antibody production.

Adult↗
PubMed1977

Phylogeny of insulin. Some evolutionary aspects of insulin production with particular regard to the biosynthesis of insulin in Myxine glutinosa.

Preceding phylogenetic studies on the occurrence of insulin have shown--e.g. by bioassays and immunocytochemical procedures--that insulin producing B-cells are present in all vertebrates and even in several invertebrates, both protostomian and deuterostomian. The most original B-cells are obviously endocrine cells of open type, situated in the mucosa of the alimentary tract. Moreover, the results of these studies show that insulin is not only a polypeptide hormone of considerable age but also that the insulin molecule seems to have been kept surprisingly stable during evolution. Best known of all non-mammalian insulins is that from the hagfish, Myxine glutinosa. It is probably the most original insulin of all in the vertebrate series. Both the amino-acid sequence and the three-dimensional structure of the dimer of hagfish insulin differ only little from those of pig insulin. The biosynthesis occurs via proinsulin and is also in most respects similar to mammalian insulin biosynthesis. There are, however, some differences. Although it readily crystallizes as tetragonal bipyramids, hagfish insulin does not form hexamers. In a test system, with isolated rat fat cells, its binding affinity is 23% and its potency 5% of that of pig insulin, a discrepancy indicating a "partial antagonism" on the receptors. Although the conversion of proinsulin to insulin seems to occur in the secretion granules, they contain no crystalline cores. Since a strictly tryptic-like enzyme was found to destroy hagfish insulin rapidly, the enzyme converting proinsulin to insulin must--in addition to a carboxy-peptidase-B-like activity--have a different specificity in Myxine.

Amino Acid Sequence↗
PubMed1977

Insulin secretion in insulin-requiring diabetics before and during insulin treatment.

Endogenous insulin secretion after different stimuli was determined in insulin requiring diabetics without circulating insulin antibodies. Four groups of non-obese diabetics were investigated and compared with 111 controls. Group I: 14 patients with mild diabetes, not yet requiring insulin; diagnosis before the age of 30 years. Group II: 19 ketonuric patients just before being started on insulin treatment. Group III: 18 patients during remission after an average of 16.5 months' insulin treatment. Group IV: 13 patients with no remission period or relapse after an average of 19.5 months on insulin treatment. Blood glucose and immunoreactive insulin were measured during fasting and after iv secretin, iv tolbutamide, iv GTT, and oral GTT, followed by combined iv tolbutamide and glucagon stimulation. A considerable insulin secretion could be demonstrated in group I, whereas in group II only a very low insulin peak was obtained after secretin and the combined injection of glucagon and tolbutamide. In group III considerable insulin secretion was demonstrated, whereas in group IV only a very low insulin peak was obtained. A significant correlation between the degree of metabolic control and endogenous insulin secretion was found.

Adult↗
PubMed1979

Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations.

The liver and beta cells function in a negative feedback loop, which appears to have a predominant role in regulating both the basal plasma glucose and insulin concentrations. The degree of basal hyperglycemia in diabetes probably provides a bioassay of both the effect of a reduction in insulin secretory capacity and the degree of insulin resistance. A mathematic model of the interaction of insulin deficiency and insulin resistance has been constructed, based on the known response characteristics of the beta cells to glucose, and of plasma glucose and insulin control of hepatic and peripherpal glucose flux. The degree to which beta cell deficiency increases basal plasma glucose reflects the hyperbolic shape of the normal insulin secretory response to different glucose concentrations. The height of basal plasma insulin is a function of the degree of insulin resistance. From the basal plasma insulin and glucose concentrations, the model provides an estimate of the degree to which both beta cell deficiency and insulin resistance contribute to diabetes. The predictions arising from the model are in accord with experimental data in man and in animals. In normal-weight diabetics who do not have increased insulin resistance, the model predicts that more than 85% of beta cell function has to be lost for the basal plasma glucose to rise to 6 mmol/liter, but a further 5%--10% loss increases the basal plasma glucose to over 10 mmol/liter. In a third of a consecutive series of 65 newly presenting, uncomplicated diabetics, both normal weight and obese, the analysis from the model suggested that insulin resistance, rather than beta cell deficit, was the predominant feature.

Blood Glucose↗
PubMed1976

Effect of "fractionated" insulins on total plasma insulin binding capacity and insulin requirements in severe diabetes.

Serial observations of insulin requirement and total plasma insulin binding capacity have been carried out on six xevere diabetics whose treatment was changed from standard soluble and isophane (NPH) insulins to "fractionated" preparations (Nordisk Insulin Ltd). No correlation was found between initial insulin dose and binding capacity, but changes in these two functions during the study period were closely correlated, both for the group as a whole and for individual patients in whom falls in insulin dose occurred. It is concluded that highly purified insulins could be valuable in the treatment of insulin-resistant cases, that their use is frequently associated with a gradual reduction in insulin dose, and that estimation of total plasma insulin binding capacity may indicate which patients are most likely to benefit from fractionated insulin. No sudden change in insulin requirement was seen on changing to purified insulin preparations.

Adult↗
PubMed1977

Pulmonary insulin responsivitiy: in vivo effects of insulin on the diabetic rat lung and specific insulin binding to lung receptors in normal rats.

Adult rats were rendered diabetic by a single iv injection of streptozotocin (70 or 75 mg/kg). In these rats, serum insulin fell to minimal levels during the 48 h following drug treatment, and this was roughly paralleled by a progressive decrease in the ability of the lung to oxidize glucose. The addition of insulin to diabetic rat lung slices in vitro had no restorative effect on the depressed glucose oxidative rate during a 2 h incubation period; however, two daily treatments of the rats with 1 unit of protamine, zinc insulin completely restored lung glucose oxidation rate to normal, without significantly reducing the hyperglycemic state of the rats. An examination of the temporal changes in glucose utilization by the rat lung after acute insulin treatment revealed that the diabetic lung responded directly to serum levels of insulin, whereas the normal lung appeared to be unaffected by serum insulin levels as hihg as 87 ng/ml. The reduced rate of glucose oxidation in the diabetic lung was apparent after perfusion of the lung with glucose-free medium, and was characterized by a significant reduction in Vmax without an alteration in Km. This was attended by a depressed ability of the lung to incorporate [3H]leucine into protein and an increased ability to produce lactate, but hexose monophosphate shunt activity was normal. Specific receptors for insulin have been identified and partially characterized in crude membrane preparations of normal rat lung. The interaction of insulin with these receptors was rapid, reversible, saturable, and was dependent upon time and temperature. The binding of labeled insulin was inhibited by low concentrations of unlabeled insulin and by high concentrations of proinsulin, whereas it was unaffected by the presence of glucagon, gastrin, prolactin, ACTH, or growth hormone in microgram amounts. These observations suggest that insulin regulates the transport and utilization of glucose in the rat lung, and that this tissue contains specific receptors for insulin.

Animals↗
PubMed1979

Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents.

In view of the potent influences of the central nervous system on glucose metabolism and on its hormonal regulators, and our recent finding of insulin and insulin receptors throughout the central nervous systsem, we have examined extreme conditions of hyperinsulinemia (obese mice) and hypoinsulinemia (streptozotocin-treated rats) with respect to changes in brain insulin and receptor content. Sprague-Dawley rats given streptozotocin (100 mg/kg body wt) developed severe diabetes and by 48 h showed no change in brain insulin. Rats given 65 mg/kg streptozotocin also had severe diabetes, but survived longer. Both at 7 d and at 30 d after streptozotocin treatment there was no significant change in brain insulin or in brain content of insulin receptors, despite the fact that peripheral hepatic receptors were elevated and pancreatic insulin was markedly depleted. The obese mice were studied at 8-10 wk when peripheral plasma insulin concentrations were 50-fold elevated and receptors on peripheral target cells were reduced to congruent with40-50% of normal; brain insulin concentrations and receptor content were indistinguishable from those of thin littermates. Thus, brain insulin, which is typically 10 times higher than plasma insulin concentrations, and brain receptor content, which is equivalent to receptor content on peripheral tissues, appears to be regulated entirely independently of hormone and receptor in the periphery. These findings are consistent with the hypothesis that insulin in the central nervous system is synthesized by the neural elements, and plays a role in the central nervous system which is unrelated to peripheral glucose metabolism.

Animals↗
PubMed1979

Carbohydrate inhibitors of concanavalin A that inhibit binding of insulin-sepharose to fat cells and antagonize and mimic insulin's bioactivity. A possible role for membrane carbohydrate in insulin's action.

A consistent pattern of insulin-like properties is expressed by a variety of glycoside inhibitors of concanavalin A (Con A), and is suggestive of a common mechanism of action to explain these effects. Various exogenously added glycoside derivatives inhibit the binding of insulin-Sepharose beads to insulin receptors on isolated intact rat fat cells with a specificity resembling that for Con A-Sepharose binding to these cells. A more limited number of glycosides tested were also found to inhibit the binding of 125I-insulin, although some enhancement of binding that preceded the inhibition was observed for some of these saccharides. The glycosides also antagonize insulin-stimulated glucose utilization by the cells, but in some cases also mimic the hormone by stimulating glucose utilization. A few glycosides mimic insulin without appearing to antagonize its bioactivity. Radiolabeled glycoside inhibitors fail to bind to insulin in equilibrium dialysis experiments although they readily bind to Con A, indicating that the glycosides act directly on the cell rather than on the insulin molecule. The latter observation is consistent with the ability of those glycosides that act like insulin to do so independent of the hormone. In view of the known insulin-like properties of Con A, the effects of the glycosides seen in the present study suggest roles for a membrane carbohydrate and a carbohydrate binding site in the mechanisms of action of both insulin and Con A. In addition to various alternative explanations, a working hypothesis is presented to rationalize the present observations. It proposes that the effects of the exogenously added glycosides (and Con A) may reflect the presence on the membrane of a native carbohydrate moiety by either mimicking or competitively inhibiting its ability to interact reversibly with a lectin-like carbohydrate binding site associated with the function of the insulin receptor.20

Adipose Tissue↗
PubMed1976

Autoregulatory system of insulin degradation in liver. II. Relationship between blood insulin levels and GSH-dependent insulin degrading activity in liver and blood.

An autoregulatory system of insulin degradation in the liver in which the rate of insulin metabolism changes in response to fluctuation in its blood levels, was investigated. In the plasma of rats and man in the absence of reduced glutathione (GSH), insulin degradation was not observed, but when a sufficient amount of reduced glutathione was added, the plasma did degrade insulin. This GSH-dependent insulin degrading activity in plasma was quite similar to that in liver in its nature. In rats, this GSH-dependent insulin degrading activity in the liver and plasma was fluctuated in response to fluctuation in the blood insulin levels, and the GSH-dependent insulin degrading activity in plasma was well correlated with that in the liver. Similarly, in man the GSH-dependent insulin degrading activity in plasma was changed in response to fluctuation in the blood insulin levels. In plasma under the physiologic conditions, there is an insufficient amount of reduced glutathione to elicit the insulin degrading activity, but in the liver there is a sufficient amount of reduced glutathione to manifest this activity. This evidence further supports the concept that an autoregulatory system of insulin degradation in the liver exists in man.

Animals↗
PubMed1975

Determination of total insulin (TIRI) in plasma of insulin-treated diabetics and newborn infants of insulin-treated diabetic mothers.

Plasma of insulin-treated diabetics and of newborn infants of insulin-treated diabetic mothers contains insulin antibodies which invalidates the radioimmunoassay of insulin. Therefore, the endogenous insulin antibody complex must be splitted at a pH lower than 5 and the total IRI (TIRI) is separated by ethanol extraction. It was investigated the recovery rate in dependence upon plasma volume used for extraction. By reduction of used plasma volume from 500 to 200 mul per extraction the recovery rate was increased from 65.1 +/- 8.4 to 88.3 +/- 4.2% (mean +/- SEM). The low plasma volume of 200 mul for TIRI extraction made it possible to determine TIRI during glucose loads of newborn infants. To eliminate different conditions of incubation for standard and unknown plasma samples the TIRI levels were computed by means of so-called "extracted" standard curve, obtained with extracted insulin from standard insulin dilution in insulin-free pooled human plasma. Using the described method a temporary regeneration of insulin secretion of a newly diagnosed juvenile diabetic after insulin treatment could be shown. In contrast to newborn infants of healthy mothers a biphasic/insulin release was found during the intravenous glucose loads in newborn infants of insulin-treated diabetic mothers.

Adult↗
PubMed1979

Insulin secretion and peripheral insulin sensitivity in obese children. Evidence of deficient glucose-stimulated early insulin release despite hyperinsulinemia.

Insulin secretion and peripheral insulin sensitivity were studied in 19 grossly-obese girls and 17 age-matched non-obese girls by means of the intravenous glucose tolerance test (IVGTT) and the simulated early insulin response test (SERT) respectively. SERT measures the fall in fasting blood glucose after a short infusion of insulin, performed so as to simulate the early phase of insulin release to the acute stimulus of an intravenous glucose load (ERex). In the IVGTT, the obese girls showed significantly increased early insulin response (ERend) in comparison with the non-obese girls. The glucose disappearance rate (KG) was similar in the two groups, although four obese girls had borderline low values. In the SERT, the rise in plasma insulin caused a much smaller decrease in blood glucose in the obese girls, than in the reference girls over the whole range of insulin levels studied. The relationship between insulin sensitivity and insulin secretion of each subject was evaluated from the plot of the ERex/ERend ratio vs blood glucose decrement. This showed that the hyperinsulinemia of the obese girls did not match the degree of peripheral resistance.

Blood Glucose↗
PubMed1979

Free insulin, bound insulin, C-peptide and the metabolic control in juvenile onset diabetics: comparison of C-peptide secretors and non-secretors during 24 hours conventional insulin therapy.

In two groups of juvenile onset diabetics similar in age, weight, diet and daily insulin dosage (eight without C-peptide, group I; eight with C-peptide, group II) the serum levels of free and antibody bound insulin, C-peptide, glucose, lactate, alanine and FFA were determined over 24 h. In addition the affinity and binding capacity of the insulin antibodies were determined in vitro. No correlation was found between free or bound insulin and glucose. This holds true for the individual profiles as well as for the averaged profiles of the two groups. Free insulin and lactate or alanine were positively correlated in the C-peptide secreting group. C-peptide secretion followed the flucturations of the glucose level during 24 h in each individual patient. As a group, C-peptide secretors were better controlled than non-secretors with respect to mean blood glucose, M-value and the lability index and showed higher free insulin levels despite a similar daily insulin dosage. The possible reasons for this fact are discussed. No correlation was found between the affinity characteristics of the insulin antibodies and the degree of metabolic control or the daily insulin dosage.

Adolescent↗
PubMed1976

Aspects of the secondary antibody response to ox insulin in the Hartley guinea-pig; the use of chemically modified ox insulin to delineate the antigenic determinants of ox insulin.

The use of a quinea-pig model to study the immunogenicity of the insulin molecule is presented. The Hartley guinea-pig has been shown consistently to form antibody to ox insulin, when given in a water-in-oil emulsion containing pertussis vaccine as adjuvant. After log transformation of standardized antibody titres to iodo-ox insulin, a valid statistical comparison of the antibody response to different ox insulin preparations could be made. Antibody cross-reacting with ox insulin, but not iodo-ox insulin, was also detected. The quantity of one type of antibody was complementary to the other, an observation compatible with determinant competition having occurred during the immune response. From the results of cross-reactivity experiments using N-triacylated ox insulins and human insulin, it was shown that antibody cross-reacting with iodo-ox insulin had most probably been produced to a localized area of the molecule.

Animals↗