Insulin antagonists, insulin antibodies and insulin resistance.
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Insulin Antagonists↗
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[INSULIN ANTAGONISTS, INSULIN ANTIBODIES AND THEIR PATHOGENETIC SIGNIFICANCE].
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Adrenal Cortex Hormones↗
Insulin antagonistic effects of insulin receptor antibodies on plasma membrane (Ca2+ + Mg2+) ATPase activity: a possible etiology of type B insulin resistance.
The regulatory effect of insulin on plasma membrane (Ca2+ + Mg2+)ATPase activity in target tissues for insulin was proposed to be of importance in mediating the hormone's cellular action. Consequently, polyclonal insulin receptor antibodies from patients with type B insulin resistance (B7 and B10) were used as probes to further explore a possible role for this ATPase in insulin action. The antibodies B7 and B10 obtained during the active phase of the disease manifested insulinomimetic actions in rat renal cortical basolateral membranes by displacing [125I]insulin bound to the membranes and stimulating the tyrosine kinase activity of solubilized insulin receptors in a dose-dependent manner. In contrast, these antibodies had insulin antagonistic effects on the membrane (Ca2+ + Mg2+)ATPase activity. While insulin stimulated, both antibodies inhibited the ATPase basal activity in a dose-dependent manner. Furthermore, the stimulatory effect of insulin on the ATPase was completely abolished by the antibodies. Immunoglobulin fractions obtained from patient B10 in the clinically inactive phase of the disease and from pooled normal human sera did not affect basal or insulin-stimulated ATPase activity. The effects of insulin receptor antibodies on basal and insulin-stimulated (Ca2+ + Mg2+)ATPase activities were specific. The receptor antibody did not affect PTH-stimulated (Ca2+ + Mg2+) ATPase activity, nor did it affect other kidney basolateral membrane ATPase basal activities. The data reveal that insulin receptor antibodies have a direct regulatory effect on the plasma membrane (Ca2+ + Mg2+) ATPase. We suggest that the insulin antagonistic effects of the insulin receptor antibodies on the ATPase might explain in part the impaired insulin action in type B insulin resistance.
Animals↗
Characterization of the insulin-antagonistic effect of growth hormone in insulin-dependent diabetes mellitus.
To characterize its insulin-antagonistic effect, growth hormone (GH) was infused at variable rates (24, 12 or 6 mU kg-1 min-1) for 1 h in 7 IDDM patients. Saline infusion was used as control (C) and all patients participated in all studies. The effect of insulin was measured with the euglycaemic clamp technique for 6 h combined with d-(3-3H)-glucose to evaluate glucose turnover. The insulin levels during the clamps were similar in all studies (23 +/- 3 mU l-1). The infusions produced peak GH levels of (24 rate = 24) 157 +/- 11, (12 rate = 12) 76 +/- 7, and (6 rate = 6) 45 +/- 8 mU l-1 (mean +/- SEM). The insulin-antagonistic effect of GH on glucose uptake was seen after 2 h and was at a maximum 4 to 5 h after the start of the GH infusion (difference in glucose infusion rate between C and 24 was 1.7 +/- 0.4 mg kg-1 min-1, p < 0.01). The resistance was due to a less pronounced effect of insulin to both inhibit rate of appearance and to stimulate rate of disappearance. Infusion of GH at 12 mU kg-1 min-1 induced a less pronounced insulin resistance both with regards to maximal effect (glucose infusion rate C - GH 1.4 +/- 0.5 mg kg-1 min-1, p < 0.05) and duration (3 h). At 6 mU kg-1 min-1, a clear GH-induced insulin-antagonistic effect was only seen during the third hour of the clamp (glucose infusion rate C-GH 1.3 +/- 0.5 mg kg-1 min-1, p < 0.05). GH infusion impaired the effect of insulin to lower both the levels of free fatty acids (NEFA) and glycerol between 2 and 5 h after the start of the infusion (NEFA, C:110 +/- 29, 24:303 +/- 95, p < 0.05: glycerol, C:32 +/- 4, 24:50 +/- 7 mumol l-1, p < 0.05). The present study therefore demonstrates that the insulin-antagonistic effect of GH in IDDM is related to the plasma levels both with regard to duration and response. The results also indicate that GH impairs the effect of insulin on lipolysis in IDDM after physiological peaks.
Adult↗
[Role of insulin antagonists in the pathogenesis of insulin--sensitive and insulin-resistant diabetes mellitus].
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Blood Glucose↗
Circulating factors and insulin resistance. II. The action of the novel myo-inositol cyclic 1,2-inositol phosphate phosphoglycan insulin antagonist from human plasma in regulating pyruvate dehydrogenase phosphatase.
A novel low mol wt inositol phosphoglycan antagonist of insulin action of oxidative glucose metabolism in isolated rat adipocytes was partially purified from normal human plasma and shown to be increased in type II diabetic plasma. It was characterized chemically as a myo-inositol phosphoglycan containing a cyclic 1,2-phosphate. This antagonist, termed fraction V3, is now shown to inhibit the action of an inositol glycan insulin pH 2.0 mediator that stimulates pyruvate dehydrogenase phosphatase in a similar manner to insulin. In addition, fraction V3 inhibits stimulation of the pyruvate dehydrogenase (PDH) phosphatase by Mg2+, the enzyme's required metal, and by spermine, a polyamine. Fraction V3 does not inhibit active PDH itself. The inhibitory effect is dose dependent and apparently noncompetitive or nonsurmountable for the insulin inositol glycan pH 2.0 mediator, thus comparing kinetically with its insulin antagonistic action on intact adipocytes. Its inhibitory action on PDH phosphatase is dose dependent and competitive for Mg2+ stimulation of the phosphatase. Additionally, fraction V3 is shown to inhibit stimulation by Mg2+ of cloned recombinant PDH phosphatase catalytic subunit. Inhibition by fraction V3 of Mg(2+)-stimulated PDH phosphatase and its cloned catalytic subunit helps explain its mechanism of action to inhibit insulin-stimulated oxidative glucose metabolism in adipocytes and its potential clinical significance in insulin resistance.
Animals↗
Characterization of the insulin-antagonistic effect of growth hormone in man.
The insulin-antagonistic effect of growth hormone was characterized by infusing the hormone at three different infusion rates (6, 12 or 24 mU.kg-1.min-1) for one h in 11 healthy subjects. The insulin effect was measured with the euglycaemic clamp technique combined with D-(3-3H)-glucose infusion to evaluate glucose production and utilization. A control study with NaCl (154 mmol.l-1) infusion was also performed. The insulin levels during the clamps were similar in all studies (36 +/- 0.2 mU.l-1). Peak growth hormone levels were reached at 60 min (growth hormone 6 mU.kg-1.h-1: 31 +/- 5; growth hormone 12 mU.kg-1.h-1: 52 +/- 4 and growth hormone 24 mU.kg-1.h-1; 102 +/- 8 mU.l-1). The insulin-antagonistic effect of growth hormone started after approximately 2 h, was maximal after 4-5 h (approximately 39% inhibition of glucose infusion rate between control and growth hormone 24 mU.kg-1.h-1) and lasted for 6-7 h after peak levels. The resistance was due to a less pronounced insulin effect both to inhibit glucose production and to stimulate glucose utilization. Growth hormone infusion of 12 mU.kg-1.h-1 induced a similar insulin-antagonistic effect as the higher infusion rate whereas 6 mU.kg-1.h-1 induced a smaller response with a duration of 1 h between 3-4 h after peak levels of growth hormone. The present study demonstrates that growth hormone levels similar to those frequently seen in Type 1 (insulin-dependent) diabetic patients during poor metabolic control or hypoglycaemia, have pronounced insulin-antagonistic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Insulin-antagonistic effects of pulsatile and continuous glucagon infusions in man--a comparison with the effect of adrenaline.
The insulin-antagonistic effects of pulsatile (3 min pulses every 20 min) and continuous glucagon infusions were studied over 4 h with the euglycemic clamp technique in healthy subjects. Comparisons were made to the effect of a continuous adrenaline infusion. Glucose production and utilization were evaluated with D-3-3H-glucose and somatostatin was used in all studies to inhibit the endogenous release of insulin and glucagon. The amount of glucagon given during the pulsatile infusions (27% of that during continuous infusion) was adjusted so that the peak glucagon levels were the same as during the continuous infusion (372 +/- 22 and 365 +/- 20 ng/L, respectively). The insulin-antagonistic effects of pulsatile and continuous glucagon infusions were similar during the first hour and imparied the insulin effect with 44 +/- 8 and 47 +/- 6%, respectively. However, when infused continuously, the effect of glucagon declined rapidly, whereas the effect of a pulsatile infusion decreased more slowly and was evident for 3 h. Raising the glucagon level 4-fold restored the insulin-antagonistic effect again suggesting that the cells had become desensitized. In contrast, the insulin-antagonistic effect of adrenaline was persistent throughout the 4 h of the study and impaired insulin action with 54 +/- 2%. The effects of pulsatile and continuous glucagon infusions were entirely due to the stimulation of glucose production while that of adrenaline mainly was due to inhibition of peripheral glucose uptake. In conclusion, the acute stimulatory effect of glucagon on glucose production is transient but it is better maintained when given as intermittent pulses rather than as a continuous infusion. In contrast, the insulin-antagonistic effect of adrenaline on glucose uptake is persistent for at least 4 h.
Adult↗
Regulation of insulin receptor kinase activity by insulin mimickers and an insulin antagonist.
Three agents which mimic insulin action in intact cells (concanavalin A, wheat germ agglutinin, and polyclonal insulin receptor antibody), mimicked insulin's ability to stimulate the kinase activity of purified insulin receptors. In contrast, monoclonal insulin receptor antibody, an antagonist of insulin action, did not stimulate the phosphorylation of the insulin receptor either in intact IM-9 cells or in purified receptor preparations. This antibody, however, antagonized the ability of insulin to stimulate the phosphorylation of the receptor both in intact cells and in the purified receptor. These studies with insulin mimickers and an insulin antagonist are consistent with a role for the kinase activity of the receptor mediating the actions of insulin.
Antibodies↗
The insulin-antagonistic effect of the counterregulatory hormones.
The counterregulatory hormones glucagon, adrenaline, cortisol and growth hormone are released during hypoglycaemia, and under other stress conditions. These hormones have insulin-antagonistic effects both in the liver and in the peripheral tissues. The insulin-antagonistic effects of glucagon and adrenaline are of rapid onset, whereas those of cortisol and growth hormone are only observed after a lag period of several hours. Glucagon is the most important hormone for acute glucose counterregulation. When the release of this hormone is deficient, as in patients with insulin-dependent diabetes, adrenaline becomes the most important hormone for glucose recovery during hypoglycaemia. Cortisol and growth hormone contribute to counterregulation during prolonged hypoglycaemia, but adrenaline is also of utmost importance in this condition. Adrenaline induces the early posthypoglycaemic insulin resistance, whereas cortisol and growth hormone are important for the insulin resistance that is observed later following hypoglycaemia. However, the importance of posthypoglycaemic insulin resistance for induction of posthypoglycaemic hyperglycaemia in clinical situations is limited. The pronounced insulin-antagonistic effect of growth hormone indicates that this hormone, in addition to its effect on the dawn phenomenon, could also play a key role in the regulation of other diurnal rhythms of glucose metabolism.
Animals↗
Insulin antagonistic effects of growth hormone in short children.
Growth hormone has several insulin antagonistic effects. To determine the time course of these effects in growth-hormone-treated children, the frequently samples intravenous glucose tolerance test was used to measure insulin sensitivity (SI) and glucose effectiveness (Sg) before, and 1 week, 1 month and 6 months after beginning growth hormone therapy in 3 patients with growth hormone deficiency (GHD), 3 patients with non-growth-hormone-deficient short stature (NGHD) and 3 with Turner syndrome (TS). Pretreatment SI was lower in TS than in the other two groups (p < 0.05), but Sg did not differ between groups. Mean SI levels 1 week and 1 month after starting growth hormone therapy were not different from before growth hormone [1.67 +/- 0.26 x 10(-4) (pmol/l)-1 min-1]. SI after 6 months of growth hormone [0.67 +/- 0.15 x 10(-4) (pmol/l)-1 min-1] was lower than before and 1 week after growth hormone (p < 0.005). SI responses did not differ between groups. Sg, glucose tolerance, blood pressure, triglyceride, and cholesterol levels did not change, but the incremental insulin response increased with growth hormone therapy. Thus, in this small study 6 months of growth hormone therapy decreased SI, but did not affect other cardiovascular risk factors.
Blood Glucose↗
Studies on the insulin-antagonistic effect of catecholamines in normal man. Evidence for the importance of beta 2-receptors.
The insulin-antagonistic effect of adrenaline was studied in seven healthy subjects with the euglycaemic clamp technique using two insulin infusion rates (40 and 1200 mU X (m2)-1 min-1). The adrenergic receptor mediating the adrenaline effect was characterized by concomitant infusion of propranolol (beta 1 + beta 2-antagonist) or metoprolol (beta 1-antagonist). Each subject was studied four times (placebo, adrenaline, adrenaline + propranolol, adrenaline + metoprolol). Glucose turnover was measured with D(3-3H)-glucose. Similar plasma insulin levels were reached in all studies with the two insulin infusion rates (mean; placebo 51 +/- 3 and 7421 +/- 337 mU/l respectively). Glucose production was completely inhibited by the low insulin level during placebo infusion. Adrenaline antagonized this effect so that a significant glucose production was seen at the low but not at the high insulin level. Propranolol, but not metoprolol, reversed this insulin-antagonistic effect of adrenaline. Glucose utilization increased from 2.53 +/- 0.17 to 7.28 +/- 0.88 mg X kg-1 X min-1 during placebo when the insulin levels were increased from 4 +/- 0.3 to 51 +/- 3 mU/l. Increasing the insulin levels 150-fold to approximately 7500 mU/l only doubled the glucose utilization (14.68 +/- 1.14 mg X kg-1 X min-1). Adrenaline induced a pronounced inhibition of glucose utilization at both insulin levels (78% and 37% inhibition respectively). Propranolol, but not metoprolol, prevented this effect of adrenaline. Thus, physiological adrenaline levels exert a pronounced insulin-antagonistic effect which is mediated by beta 2-receptor stimulation. The inhibitory effect on glucose uptake is maintained even at high insulin levels when hepatic glucose production is completely abolished.
Adult↗
Effect of C-terminal chain shortening on the insulin-antagonistic activity of human growth hormone 177--191.
Six synthetic C-terminal shortened fragments of the reduced and S-carbamidomethylated peptide corresponding to residues 177 to 191 of human growth hormone (Cam-hGH 177--191) were assayed for insulin antagonistic activity in vivo. Two of the peptides, Cam-hGH 177--191 and cam-hGH 177--191 were, in nanomolar quantities, both active in that they caused significant hyperglycaemia and insulin resistance in normal rats. The remaining peptides, hGH 177--180, Cam-hGH 177--185, Cam-hGH 177--187 and hGH 177--189 were all inactive even at up to one hundred times the dose employed for the active peptides. The results indicate that an insulin antagonistic core of hGH is contained within amino acid residues 178 to 190 inclusive.
Amino Acid Sequence↗
Human adipose tissue in culture. VIII. Studies on the insulin-antagonistic effect of glucocorticoids.
Biopsies of human adipose tissue were maintained for 1 wk in vitro with physiologic (1.5-30 X 10(-8) M) or pharmacologic (300 X 10(-8) M) concentrations of hydrocortisone or 1000 muU/ml insulin, or both. After this period, the explants were washed and incubated for 2 hr according to techniques generally used to study fat cell metabolism. Physiologic concentrations of hydrocortisone mainly exert an insulin antagonistic effect. Thus, the long-term effects of insulin in increasing lipolysis, as well as glucose metabolism to triglycerides, were reduced, as were the acute effects of insulin on these parameters. At these concentrations, the glucocorticoid itself did not influence the basal metabolic rates when due consideration was given to simultaneous changes in mean fat cell size. At higher concentrations, which may easily be reached during nonspecific glucocorticoid therapy, the glucose metabolism was reduced. Hydrocortisone decreased the number of insulin receptors. However, this cannot solely explain the insulin-antagonistic effect, since it was not overcome by a supramaximal concentration of insulin. Insulin and hydrocortisone together increased the lipoprotein lipase (lpl) activity several times. The resultant changes in LPL appear to depend upon the insulincorticosteroid ratio.
Adipose Tissue↗
Physiological concentrations of growth hormone exert insulin-like and insulin antagonistic effects on both hepatic and extrahepatic tissues in man.
To determine whether increments in circulating GH concentrations within the physiological range would exert insulin-like as well as insulin-antagonistic actions in man and, if so, whether both actions would occur in hepatic and extrahepatic tissues, normal volunteers (n = 6) were infused with human GH (hGH; 100 ng/kg . min) for 6 h along with somatostatin (100 micrograms/h) to suppress insulin, glucagon, and hGH secretion and also with sufficient insulin (100 microU/kg . min) to maintain a constant plasma insulin level. During the final 2 h, glucose (2 mg/kg . min) was infused. In control studies, saline was infused instead of hGH. Infusion of hGH increased plasma hGH to 35 ng/ml. Plasma glucose decreased to 60 +/- 2 mg/dl compared to 67 +/- 1 mg/dl observed in control studies (P less than 0.05); this greater hypoglycemia was due to both greater suppression of hepatic glucose production (P less than 0.05) and greater augmentation of glucose clearance (P less than 0.05). These insulin-like effects of hGH were no longer evident after 2 h. Subsequently, when glucose was infused, plasma glucose increased to 133 +/- 4 mg/dl compared to the 104 +/- 6 mg/dl observed in control studies (P less than 0.01). This greater hyperglycemia was due to both impaired suppression of hepatic glucose production (P less than 0.001) and decreased glucose clearance (P less than 0.01). These results indicate that physiological increments in plasma hGH cause both insulin-like and insulin-antagonistic effects in man and that these actions occur in hepatic as well as extrahepatic tissues. The insulin-like actions of hGH are transient.
Adult↗
Circulating factors and insulin resistance. I. A novel myoinositol 1,2-cyclic phosphate phosphoglycan insulin antagonist from human plasma is elevated in noninsulin-dependent diabetes mellitus.
A novel low mol wt inositol phosphoglycan inhibitor (M tau 1200-1500) of insulin action in rat adipocytes has been partially purified from normal human plasma. This inhibitor, termed fraction V after the first purification step and fraction V3 after the second, is different from other reported serum insulin antagonists. It contains myoinositol, galactosamine, and mannose in approximate molar ratios of 1:1:3.3. The myoinositol has a 1,2-cyclic phosphate substituent, which is essential for the inhibitory activity. Its inhibitory activity is significantly elevated (161%, P < 0.05 for fraction V; 278%, P < 0.05 for fraction V3) in plasma of humans with noninsulin-dependent diabetes mellitus as compared with plasma of nondiabetic controls. These findings represent the first report of a naturally occurring mammalian inositol 1,2-cyclic phosphate containing phosphoglycan related to insulin action.
Adipocytes↗
Enhancement of the insulin antagonistic effect of porcine somatotropin in swine using a monoclonal antibody.
A monoclonal antibody (mAb), PS-7.6, to porcine somatotropin (pST) significantly enhanced the growth responses to pST injections in hypophysectomized (hypox) rats but could not be tested in pigs because of the large quantity of antibody required for a growth trial. Because pST inhibits the hypoglycemic effects of insulin, an insulin tolerance test procedure was established to measure pST activity in jugular-catheterized pigs. Doses of 0, 30, 100, and 300 micrograms/kg per day of pST were split and administered subcutaneously (sc) in equal portions twice daily for 2 d. After a 17-hr fast, plasma samples were obtained at 10-min intervals for 30 min before an intravenous injection of insulin (0.08 IU/kg) and then for an additional 50 min. Because pST increased fasting plasma glucose concentrations, preinsulin glucose values were used as a covariate to adjust the postinsulin concentrations. pST caused a dose-dependent increase in resistance to the insulin injection in these pigs. The areas under the curves (AUC), for plasma glucose were 22.1, 29.0, 39.0, and 47.2 mg/dl per min for the 0, 30, 100, and 300 micrograms/kg pST doses, respectively. Because different doses of pST could be detected, the PS-7.6 enhancement of pST treatment was evaluated. In the first experiment, five pigs/group each received sc injections of either vehicle, pST (75 micrograms/kg; approximately 3.0 mg/d), pST (75 micrograms/kg) + PS-7.6 at 3.75 mg/kg, or pST (75 micrograms/kg) + PS-7.6 at 15 mg/kg for 2 d before the insulin test. The pST and PS-7.6 were combined and incubated for at least 1 hr at room temperature before being injected. The injection of pST alone did not significantly change insulin tolerance activity (23.1 vs. 21.1, AUC), but insulin resistance was enhanced when this dose of pST also included PS-7.6 (27.4 and 29.5, AUC, respectively; P < 0.05). In a second experiment, the effects of PS-7.6 and PS-4.2, a mAb that did not potentiate the pST-stimulated growth of hypox rats, were compared. The five pigs/treatment received either vehicle, pST (75 micrograms/kg), pST (75 micrograms/kg) + PS-7.6 (3.75 mg/kg), or pST (75 micrograms/kg) + PS-4.2 (3.75 mg/kg) for 2 d. The administration of pST increased the resistance to insulin (26.7 vs. 18.8, AUC; P < 0.01), which was markedly potentiated by PS-7.6 (54.3, AUC, P < 0.001) but not affected by PS-4.2 (27.6 AUC). The injection of PS-7.6 at 7.5 mg/kg without exogenous pST did not alter the sensitivity to insulin. These results indicate that PS-7.6, but not PS-4.2, enhanced the insulin antagonistic activity of pST in swine, suggesting that an enhancement of pST-stimulated growth would also occur in PS-7.6-treated pigs.
Animals↗