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PubMed2003

Insulin secretion and insulin sensitivity pattern is different in isolated impaired glucose tolerance and impaired fasting glucose: the risk factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes study.

OBJECTIVE: Isolated impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two risk categories for type 2 diabetes. This study compared both categories with respect to the degree of insulin secretion abnormalities and insulin resistance. RESEARCH DESIGN AND METHODS: This is a crossover comparison of a population at high risk for type 2 diabetes. The subjects were recruited from the Risk Factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes (RIAD) study. They underwent a 75-g oral glucose tolerance test, with measurement of specific insulin, C-peptide, proinsulin, and free fatty acids at baseline and every 30 min after load for 2 h. Factor analysis was performed to evaluate the importance of insulin resistance and secretion abnormalities in both categories. RESULTS: All categories of prediabetic hyperglycemia had a higher cardiovascular risk factor level when adjusted for sex, age, and BMI compared to control subjects with normal glucose tolerance. Subjects with isolated IFG were more insulin resistant than those with IGT. By contrast, subjects with isolated IGT exhibited a more severe deficit in early- and late-phase insulin secretion versus IFG subjects. As shown with factor analysis, in IFG the insulin resistance factor explained 28.4% of the variance, whereas in IGT the insulin secretion factor was dominant, explaining 31.1% of the total variance. CONCLUSIONS: Our cross-sectional data from the RIAD study demonstrate that isolated IFG and isolated IGT are different with respect to the degree of insulin resistance and anomalies in insulin secretion, and that subjects with IGT exhibit a deficit in the early and late phases of insulin secretion. This finding may be important for a differential approach in primary prevention of type 2 diabetes.

Adult↗

PubMed1977

Role of self-carriers in the immune response and tolerance. II. Parameters of tolerance induced by haptenated lymphoid cells.

The induction of tolerance to the 2,4,6-trinitrophenyl (TNP) hapten has been studied in a system utilizing haptenated syngeneic lymphoid cells. Specific depression of the direct and indirect plaque-forming cell (PFC) responses to TNP-protein conjugates was regularly achieved by pretreatment of Lewis rats with 1 X 10(7) trinitrophenylated spleen cells or TNP lymph node cells. Very low numbers of haptenated lymphocytes were active since tolerance could be induced in vivo with as few as 10(5)-10(6) TNP spleen cells (SC). SC exposed to as little as 10-100 mug of the reactive hapten, trinitrobenzene sulfonic acid, were effective tolerogens in this system. Tolerance induced with 10(7) haptenated spleen cells persisted for at least 4 weeks. Viable intact cells did not seem to be required in this system since the cell-free supernatants from TNP-SC cultured for 24 h were also active. In addition, significant depression of an ongoing immune response could also be imposed by haptenated isologous lymphoid cells. Moderate suppression of the "hapten-specific" delayed hypersensitivity response (measured by the accumulation of 51Cr-labeled bone marrow cells) was also achieved with TNP-SC. These results suggest that haptenated isologous lymphoid cells are potent tolerogenic conjugates capable of inducing tolerance affecting antibody formation and delayed hypersensitivity. However, since we and others have shown that TNP-SC do not adversely affect the generation of hapten-specific cytotoxic T cells, it is postulated that there is a differential recognition of, or response to, hapten-modified self-carriers by functionally distinct lymphocyte subpopulations.

Animals↗

PubMed1977

Role of epitope density in the induction of immunity and tolerance with thymus-independent antigens. IV. Selective tolerance and IgE response by DNP-levan conjugates.

Tolerance induction of IgE antibody-forming cells by dinitrophenylated levan (DNP-LE) conjugates was investigated in CBA mice. Antibody production was measured by passive coutaneous anaphylaxis on rat skin. Specific antibody neutralization was obtained with conjugates of different substitution degrees. Specific inhibition of IgE antibody production was obtained only with highly substituted conjugates. However, the epitope density required for inducing tolerance to antibody synthesis of the IgE class was lower than for other classes of immunoglobulins. The tolerance induced by DNP-LE was shown to affect only the anti-DNP B cells of IgE class without T cell participation. These results demonstrate that B cell precursors of all Ig classes are susceptible to tolerance induction and not to triggering by T-independent antigens.

Animals↗

PubMed1993

Milk whey protein fed as a constituent of the diet induced both oral tolerance and a systemic humoral response, while heat-denatured whey protein induced only oral tolerance.

Milk whey protein fed to mice as a constituent of the diet elicited a systemic humoral response. The serum antibodies were of the IgG class, which recognized mainly beta-lactoglobulin. Feeding whey protein diet also induced tolerance of systemic immunity (oral tolerance). However, when heat-denatured whey protein was fed, the animals showed only a poor serum response, while oral tolerance was induced to a similar degree as that of native whey protein diet. The results demonstrate the difference of antigen recognition between oral tolerance and oral immunization and suggests that our system using mice may be a useful animal model for food allergy.

Administration, Oral↗

PubMed1997

The oral administration of low-dose antigen induces activation followed by tolerization, while high-dose antigen induces tolerance without activation.

The systemic immune response and tolerance induced by oral administration of various doses of bovine alpha s1-casein were examined, focusing on cytokine responses in this study. Spleen cells from mice fed low doses of antigen secreted interferon-gamma and interleukin-2 in response to in vitro antigen stimulation, indicating that a Th1-type response was induced. In these mice, the Th1 responses after subsequent immunization and boosting with the antigen were diminished. In the case of mice fed high doses of the antigen, secretion of Th1 cytokines was minimal, but systemic responses after subsequent immunization and boosting with the antigen were strongly inhibited. Active suppression was not observed at any dose. The results indicate that, in this system, low-dose feeding induced activation of Th1 cells followed by tolerization, while high-dose feeding induced profound tolerance without prior activation. Our results have implications for clinical application of oral tolerance to allergy and autoimmune disease.

Adjuvants, Immunologic↗

PubMed1987

Effect of raphe lesions on the development of chronic tolerance to pentobarbital and cross-tolerance to ethanol.

Sham and electrolytic lesions of the dorsal, median, and median + dorsal raphe nuclei were made in different groups of rats, and the differential patterns of regional 5-HT depletion were verified chemically. One week later, an initial dose-response curve for the motor impairment effect (moving belt test) of pentobarbital was obtained. Matched subgroups of the animals in each lesioned group received daily gavage with either pentobarbital (50 mg/kg) or water for 36 days. Tolerance to the motor impairment effect of pentobarbital was measured at 4-day intervals. Lesions of the dorsal raphe nucleus had no influence on the development of tolerance, whereas median and median + dorsal raphe lesions resulted in slower development of tolerance, though plasma pentobarbital levels were unaltered. The effect of the combined lesion was similar to that of the median raphe lesion alone. A separate study revealed a similar differential effect of median versus dorsal raphe lesions on the development of cross-tolerance to ethanol.

Animals↗

PubMed1983

Glucose tolerance and smoking: a population study of oral and intravenous glucose tolerance tests in middle-aged men.

The oral and intravenous glucose tolerance tests have been compared in middle-aged, normal-weight male non-smokers, ex-smokers and smokers who participated in a general health screening programme in Malmö, Sweden. Subjects with diabetes, previous gastric resection and/or present medication with diuretic agents were excluded. No difference was found when comparing fasting glucose in non-smokers, ex-smokers and smokers. In the oral glucose tolerance test, plasma glucose at 40 and 60 min increased stepwise from non-smokers (8.7 and 7.4 mmol/l) to ex-smokers (8.9 and 7.5 mmol/l), smokers (9.2 and 7.9 mmol/l) and heavy smokers (9.7 and 8.2 mmol/l). Blood glucose levels at 120 min were inversely arranged. Plasma insulin at 120 min was lower in heavy smokers (16.2 mU/l) than in non-smokers (24.8 mU/l). The mean intravenous glucose tolerance test k-value was lower in smokers than in non-smokers. K-values below 1.0 were twice as common in smokers (30%) as in non-smokers. It is concluded that smoking has a clinically significant influence on both the oral and intravenous glucose tolerance tests.

Blood Glucose↗

PubMed1977

An inborn alcohol tolerance in alcohol-preferring rats. The lack of relationship between tolerance to ethanol and the brain microsomal (Na+K+) ATPase activity.

Alcohol tolerance, measured as performance on the tilting plane after ethanol injection (2.5 g/kg body weight i.p.), was examined in the AA strain of rats which voluntarily drink large amounts of alcohol, in the ANA strain which drink very little alcohol, and in ordinary albino rats which consume intermediary amounts of alcohol. The AAs showed the highest innate ethanol tolerance; the ANAs had the lowest innate tolerance. After chronic alcohol administration, both AA and ANA strains increased their tolerance, but the AAs remained superior to the ANAs. The chronic ethanol treatment did not significantly change the (Na+K+) ATPase activity of the crude microsomal fraction of the brains of the strains.

Adenosine Triphosphatases↗

PubMed1981

Self-stimulation and amphetamine: tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate.

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.

Amphetamine↗

PubMed1980

Neonatal tolerance induction across H-2 mutational disparity: induction and specificity of tolerance.

Mutational disparities derived from alleles of the H-2K and H-2D loci vary widely in their ability to induce neonatal tolerance. The more subtle mutations, such as Kbm5 and Kbm8, proved to be excellent tolerogens, but the Kbm3 mutant (M505) turned out to be the poorest tolerogen yet studied of all H-2 alloantigens. By challenging tolerant animals with skin grafts from related mutants, it was found that expression of tolerance was highly specific. Although a minority of tolerant animals failed to discriminate between the Kb, Kbm5 and Kbm8 antigens, they never failed to discern Kb, Kbm1 and Kbm3 as distinctly different alloantigens.

Alleles↗

PubMed1999

Mecamylamine blocks the development of tolerance to nicotine in rats: implications for the mechanisms of tolerance.

Chronic injections of nicotine in rats produce upregulation of nicotinic cholinergic receptors. It has been proposed that this upregulation is a reflection of receptor desensitization and is the basis of functional tolerance. Mecamylamine, a non-competitive antagonist that blocks activation of nicotinic receptors, does not prevent upregulation produced by nicotine injections. This suggests that receptor activation is not a prerequisite for nicotine-induced receptor upregulation. Therefore, the present experiments tested whether mecamylamine would also fail to prevent the development of tolerance to nicotine. Six daily pairings of mecamylamine (1 mg/kg SC) with nicotine did block the development of tolerance to nicotine-induced antinociception (0.35 mg/kg) and to the ability of nicotine to suppress milk intake (0.66 mg/kg). In another experiment, six daily injections of mecamylamine, when given alone, did not alter the effects of a subsequent, acute injection of nicotine (0.35 mg/kg) in inducing antinociception in rats. There was no evidence that after six pairings of mecamylamine with nicotine, the cues associated with mecamylamine delivery took on conditioned antagonistic properties. These findings suggest that, unlike the receptor upregulation that results from either continuous or repeated nicotine administration, the tolerance following a short series of intermittent nicotine injections is dependent on receptor activation.

Analgesics↗

PubMed1985

Unidirectional non-cross-tolerance (UNCT) in rats and an apparent dissociation between narcotic tolerance and physical dependence.

The phenomenon of unidirectional non-cross tolerance (UNCT) to etorphine was observed in adult male rats tolerant to morphine. Using a morphine pellet (four 75 mg morphine pellets) implantation protocol, a 10-fold increase in the analgesic ED50 value, obtained by tail-flick assay, was observed for morphine sulfate, with no alteration in analgesic ED50 value for etorphine. After etorphine pellet (two 60 micrograms pellets) implantation, no significant change in the ED50 value for etorphine was observed, but the ED50 value for morphine increased 15-fold. Both morphine and etorphine pellet-implanted animals, challenged with naloxone, showed similar qualitative signs of precipitated withdrawal. This seeming dissociation obtained by demonstration of physical dependence in the absence of tolerance to etorphine has its basis in the UNCT phenomenon. Thus, appropriate experimental paradigms must be included when evaluating tolerance to avoid specious conclusions.

Analgesia↗

PubMed1986

Effects of footshock stress and morphine on natural killer lymphocytes in rats: studies of tolerance and cross-tolerance.

Exposure to a form of footshock stress known to cause opioid-mediated analgesia suppresses the cytotoxic activity of natural killer (NK) cells in rats. This suppression is blocked by the opioid antagonist, naltrexone and is mimicked by morphine administration, suggesting mediation by opioid receptors. Supporting this hypothesis, we now report that the morphine-induced suppression of NK activity shows tolerance after 14 daily injections. The NK-suppressive effect of stress, however, shows neither tolerance with repetition nor cross-tolerance in morphine-tolerant rats.

Animals↗

PubMed1988

Neonatal tolerance induction to Mlsa. I. Tolerance to Mlsa is restricted by shared MHC determinants.

In this paper we have examined the influence of MHC (major histocompatibility complex) on neonatal tolerance to Mlsa (minor lymphocyte stimulating). By employing a novel approach we have shown that tolerance to Mlsa is restricted by shared MHC determinants. Thus, neonatal Mlsb mice, injected at birth with spleen cells from Mlsa mice, were tested as adults for Mlsa specific responses by interleukin-2 limiting dilution analysis, a technique which allows us to discriminate between responses to MHC + Mlsa and to MHC alone. Tolerance to Mlsa was in the context of any MHC type examined--donor, host, and third-party MHC products. These results show that tolerance to Mlsa is restricted by shared MHC determinants and extend previous studies indicating that activation of Mlsa responses is similarly restricted.

Animals↗

PubMed1983

Development of tolerance and cross-tolerance to the cataleptogenic effects of delta 8-tetrahydrocannabinol and 11-hydroxy-delta 8-tetrahydrocannabinol in mice.

Tolerance developed to the cataleptogenic effects of delta 8-tetrahydrocannabinol (delta 8-THC) and 11-hydroxy-delta 8-THC on daily administration (5 mg/kg per day i.v.) of these substances in mice. Reciprocal cross-tolerance was also demonstrated between both cannabinoids. The ED50S (mg/kg i.v.) for delta 8-THC and 11-hydroxy-delta 8-THC were 13.0 (10.2-16.5) and 5.3 (3.4-8.2), respectively, in delta 8-THC-tolerant mice (7 days' treatment) while the corresponding ED50S were 20.8 (17.6-24.5) and 11.7 (8.5-15.7), respectively, in 11-hydroxy-delta 8-THC-tolerant mice. These values were much higher than those in the vehicle-treated mice [delta 8-THC, 4.1 (2.8-5.9); 11-hydroxy-delta 8-THC, 0.98 (0.53-1.81)].

Animals↗

PubMed1988

Sodium valproate decreases exploratory behaviour in mice: development of tolerance and cross-tolerance with chlordiazepoxide.

Sodium valproate (400 mg/kg) significantly reduced exploratory head-dipping in mice, without significant reductions in locomotor activity or rearing. After 5 daily injections of sodium valproate (50 or 400 mg/kg) there was tolerance to the effects of a test dose of 400 mg/kg. Pretreatment for 5 days with chlordiazepoxide (5 mg/kg) did not change the effects of sodium valproate (400 mg/kg), but 5 days pretreatment with chlordiazepoxide (20 mg/kg) did produce cross-tolerance. Sodium valproate (50 mg/kg) was without significant effect acutely, or after 5 days of pretreatment with sodium valproate (50 or 400 mg/kg) or chlordiazepoxide (5 or 20 mg/kg). Daily injections of the benzodiazepine antagonist, flumazenil (10 mg/kg), immediately after the daily injection of sodium valproate (400 mg/kg) or chlordiazepoxide (20 mg/kg) did not prevent the development of tolerance or cross-tolerance. This suggests that benzodiazepine receptors may not mediate these phenomena; possible roles of GABA and 5-HT are also discussed.

Animals↗

PubMed1989

Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation.

The effects of various mu and kappa opioid agonists were evaluated in three squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine administration. Initially, dose-effect curves for the mu opioid agonists morphine and l-methadone, the kappa opioid agonists U50,488 and tifluadom, the mixed mu/kappa opioid agonist ethylketocyclazocine, and the non-opioid compound pentobarbital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were administered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic position. During the chronic morphine regimen, the l-methadone dose-effect curve shifted to the right approximately 3/4 log unit, while the U50,488 and pentobarbital dose-effect curves did not change. In contrast, the ethylketocyclazocine and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between mu and kappa agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of mu and kappa agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with kappa agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1992

Repeated systemic administration of the mixed inhibitor of enkephalin-degrading enzymes, RB101, does not induce either antinociceptive tolerance or cross-tolerance with morphine.

The potent analgesic responses elicited by systemic administration of RB101, N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopro pyl]- 1-oxopropyl]-L-phenylalanine benzyl ester, a prodrug able to inhibit enkephalin-degrading enzymes completely after in vivo bioactivation, has made it possible to investigate the development of antinociceptive tolerance after chronic potentiation of endogenous enkephalins. The ED50 values of RB101 obtained 10 min after i.v. injection were not significantly different in mice treated for 4 days with i.p. administered vehicle (ED50 = 9.50 (6.37-14.15) mg/kg), or with 80 mg/kg of RB101 twice daily (ED50 = 9.50 (5.86-15.39) mg/kg). In contrast, a parallel rightwards shift of the dose-response curves, corresponding to a significant 1.92 (1.49-2.52)-fold decrease in analgesic potency, was observed after i.v. administration of morphine in mice chronically treated with morphine (3 mg/kg, twice daily for 4 days) (ED50 = 3.10 (2.52-3.81) mg/kg) vs. saline (ED50 = 1.60 (1.22-2.09) mg/kg). No tolerance to RB101 was observed even after a longer period (8 days) of chronic treatment with the prodrug. Moreover, no cross-tolerance between morphine and RB101 appeared to occur since the ED50 values obtained after i.v. administration of RB101 were not significantly different in mice chronically pretreated with vehicle (ED50 = 9.50 (6.37-14.15) mg/kg) or with morphine (ED50 = 10.00 (6.62-15.10) mg/kg). The analgesic effect of RB101 observed in morphine-tolerant mice was antagonized by prior injection of naloxone, but not naltrindole (delta-selective antagonist), supporting a preferential involvement of mu-opioid receptors in the antinociceptive effect of RB101, at least in mice in the hot-plate test.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗