Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Tolerance”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources
PubMed1998

Antigen persistence and time of T-cell tolerization determine the efficacy of tolerization protocols for prevention of skin graft rejection.

We studied antigen-specific T-cell tolerization therapy using skin transplantation across a defined minor histocompatibility antigen difference. Specific tolerization protocols using short-lived peptide or long-lived spleen cells presenting the peptide as antigen prevented graft rejection without immunosuppression when started before or as long as 10 days after transplantation. Peptide-induced T-cell tolerance was transient, and antigen presentation by the graft was not sufficient to maintain tolerance. In contrast, transfer of antigen-expressing lymphoid cells induced long-lasting tolerance correlating with donor cell chimerism. These findings show that antigen-specific tolerization can induce graft acceptance even when begun after transplantation and that long-term graft survival depends on persistence of the tolerizing antigen.

Animals↗
PubMed1972

Induction of immunity and tolerance in vitro by hapten protein conjugates. 3. Hapten inhibition studies of antigen binding to B cells in immunity and tolerance.

The capacity of dissociated spleen cell suspensions to be immunized by dinitrophenylated polymeric flagellin (DNP POL), in the absence of thymus-dependent lymphocytes or macrophages, provided a simple experimental system to investigate the mechanism of binding of antigen molecules to nonthymus-dependent lymphocyte (B cell) receptors during the induction of immunity or tolerance. Various nonimmunogenic DNP compounds were used to inhibit the anti-DNP response to DNP POL. By performing inhibition experiments of brief duration at 4 degrees C, it was established that the inhibition of the anti-DNP response by nonimmunogenic compounds was due to competitive blockade of receptors, and not tolerance or receptor modulation. It was found that univalent DNP compounds were much less efficient inhibitors of the antibody response than multivalent DNP conjugates. The difference in inhibitory capacity between univalent and multivalent DNP human globulin (DNP HgG) suggested the importance of interaction with both combining sites of a single receptor antibody molecule. Nonimmunogenic highly conjugated DNP(3)POL was a more efficient inhibitor of the anti-DNP response to immunogenic DNP(1)POL than DNP(12)HgG, indicating that interactions at more than one receptor molecule are involved in immunization of B cells. Recent demonstrations of the rapid metabolic turnover of receptor antibody molecules suggests that the requirement for multipoint binding (to different receptors) may simply be to maintain the antigen at the cell surface in a dynamic system. Competitive inhibition experiments were also performed to investigate the mechanism of binding of DNP(3)POL in the induction of B cell tolerance. It was found that monovalent DNP compounds or multivalent DNP(12)HgG did not prevent the induction of tolerance, unlike their capacity to inhibit immunity, suggesting that a tolerance-inducing antigen binds more avidly to the cell membrane than an immunogen. The inhibition data obtained here, together with prior results describing the differential immunogenicity of DNP conjugates of different structure, and the importance of epitope density on DNP POL conjugates, permit certain conclusions about the details of antigen-receptor interaction in immunity and tolerance. Distinctions between the mechanisms of immune and tolerance induction are discussed.

Animals↗
PubMed1977

Role of IgD in the immune response and tolerance. I. Anti-delta pretreatment facilitates tolerance induction in adult B cells in vitro.

Adult spleen cells from C57BL.Ige mice, which generally are resistant to in vitro tolerance induction in the B-cell compartment, became hyporesponsive (tolerant) when cultured with antigen in the presence of an anti-allotype serum. Both antigen and anti-delta had to be present for this effect, which was hapten-specific and did not occur in C57BL/L mice, which lack the Ig5-1 allotype of the delta-chain detected in this system. Preculture with anti-mu serum plus antigen, in contrast, did not cause tolerance induction in adult spleen B cells of either strain. These results suggest that the surface IgD may act as a failsafe receptor to prevent tolerance induction in adult B cells. Tolerance studies with spleen cells from mice with markedly reduced numbers of IgD+ve cells, because of regimen of repeated injections of anti-delta serum beginning at birth (delta-suppressed mice), confirmed the importance of membrane IgD in preventing tolerance, because such delta-suppressed mice were hypersusceptible to tolerance by antigen alone. Inasmuch as immature B cells lack IgD on their surface, these studies suggest that acquisition of IgD is an important maturational step in the ability of murine B cells to discriminate tolerogenic and immunogenic signals.

Animals↗
PubMed1979

Tolerance to non-H-2 histocompatibility antigens. Transplantation tolerance to the H-4 and H-7 histocompatibility antigens.

There have been several reports of observations which suggest that transplantation tolerance may be a result of positive immunoregulation rather than simply unresponsiveness attributable to a lack of competent effector cells. In particular, several investigators have reported that tolerance of the H-Y and H-1 histocompatibility antigens is mediated by a population of thymus-derived lymphocytes. In a companion report, we have presented evidence that supports the existence of a suppressor cell to the H-Y antigen. Furthermore, we have observed that female mice rendered tolerant of the H-Y antigens by neonatal exposure to male lymphoid cells or by multiparity accept male skin grafts indefinitely, but inactivate male peritoneal exudate cells (PEC) in a second-set fashion. This observation has led us to investigate whether tolerance of other non-H-2 antigens is controlled by a similar mechanism. Using mice congenic with C57BL/10 at the H-4 and H-7 loci, we have shown that mice rendered tolerant of the H-7a and H-4b antigens by neonatal exposure to histoincompatibe lymphoid cells are incapable of rejecting either skin or peritoneal cell allografts, suggesting that identical histocompatibility antigens are present on skin and peritoneal cells. Tolerance induced in neonatal mice to the H-4b and H-7a antigens could not be adoptively transferred to syngeneic recipients. These results suggest that tolerance involving the H-4 and H-7 antigens is most likely because of a clonal inactivation of alloantigen-reactive cells as a consequence of neonatal exposure to antigen.

Animals↗
PubMed1983

Analysis of neonatally induced tolerance of H-2 alloantigens. III. Ease of abolition of tolerance of class I, but not class II, antigens with infusions of syngeneic, immunocompetent cells.

Neonatally-induced tolerance of class I H-2 alloantigens can be abolished in adult, long-term-tolerant mice by infusions of immunocompetent cells from donors syngeneic with the recipient. By contrast, neonatally-induced tolerance of Ia alloantigens can not be abolished easily, indicating that the Ia-specific tolerant state is maintained by an active process that can be impressed upon mature alloreactive lymphoid cells in the tolerant environment. This finding is concordant with previous observations that tolerance of Ia alloantigens can readily be transferred adoptively by inoculating lymphoid cells from tolerant mice into syngeneic, naive recipients. It is concluded that class II H-2 antigens induce a type of unresponsiveness that class I antigens fail to evoke, an unresponsiveness that is actively maintained among mature immunocompetent cells. It is proposed that, in addition to a central process of clonal deletion/inactivation that both class I and class II H-2 antigens induce in neonatal mice, Ia alloantigens also evoke a secondary, fail-safe mechanism that operates to prevent alloreactivity from emerging when cells with alloreactive potential escape the central mechanism, or mutate to alloreactivity at a later stage of maturation.

Animals↗
PubMed1989

The nature of tolerance in adult recipient mice made tolerant of alloantigens with supralethal irradiation followed by syngeneic bone marrow cell transplantation plus injection of F1 spleen cells.

The length of time after syngeneic bone marrow reconstitution when tolerance to alloantigens can be induced in adult mice during T cell differentiation from bone marrow cells was studied by exposing those T cells to (recipient x donor)F1 spleen cells. Supralethally irradiated C3H/He Slc(C3H; H-2k) mice were reconstituted with 1 x 10(7) syngeneic T cell-depleted bone marrow cells and then injected intravenously with 5 x 10(7) (C3H x C57BL/6[B6])F1 (B6C3F1; H-2bxk) or (C3H x AKR/J[AKR])F1 (AKC3F1; H-2kxk) spleen cells at various intervals. In the fully allogeneic combination of B6C3F1----C3H, EL-4 tumor originating from B6 was accepted, and survival of grafted B6 skin was significantly prolonged in the tolerant C3H mice treated with irradiation on day -1 followed by injection of syngeneic bone marrow cells on day 0 plus B6C3F1 spleen cells on days 0, 5, or 10, in a tolerogen-specific manner. In the multiminor histocompatibility antigen-disparate combination of AKC3F1----C3H, AKR skin grafts were permanently accepted in the tolerant C3H mice treated with AKC3F1 spleen cells on days 0, 5, 10, or 15. Immunological parameters, including cytotoxic T lymphocyte activity and delayed foot-pad reaction (DFR), were almost completely suppressed in C3H mice made tolerant of B6 or AKR antigens. A chimeric assay using a direct immunofluorescence method revealed that the tolerant C3H mice given B6C3F1 spleen cells on day 0 were mixed-chimeric for at least 8 weeks after syngeneic bone marrow reconstitution, but not definitely chimeric thereafter. The C3H mice given AKC3F1 spleen cells on day 0 were chimeric even 43 weeks after syngeneic bone marrow reconstitution, but the C3H mice given AKC3F1 spleen cells on day 15 showed temporal chimerism that disappeared within 43 weeks. The untolerant mice were never detectably chimeric. These data suggest that the earlier the timing of the injection of F1 spleen cells after syngeneic bone marrow reconstitution was, the more profound tolerance was induced. Moreover, the stronger the antigenic disparity between donor and recipient, the earlier the injection of F1 spleen cells was required to induce tolerance.

Aging↗
PubMed1994

Tolerance induction to cultured islet allografts. II. The status of antidonor reactivity in tolerant animals.

Murine islet tissue cultured in 95% O2 to eliminate/inactivate donor antigen-presenting cells can function indefinitely and induce a state of tolerance in nonimmunosuppressed, allogeneic recipients. Such cultured grafts represent a model of antigen presentation in which antigen (signal 1) is presented without the delivery of appropriate costimulatory activity (signal 2) necessary for T cell activation. As T cell inactivation has been proposed to result from this form of antigen presentation, we determined whether the tolerance generated in response to such cultured grafts was due to a passive (clonal deletion/inactivation) mechanism. We have shown that, although tolerant in vivo, animals bearing long-term cultured islet allografts are donor-reactive in vitro as assessed by (1) CTL precursor frequency, (2) antidonor proliferative and cytotoxic responses, and (3) lymphokine production (IL-2, IL-3, TNF, and IFN-gamma). In addition, tolerance does not appear to be tissue (islet)-specific in that primed, donor-reactive T cells from tolerant animals react to islet cells in vitro and are capable of destroying donor-type islet grafts in vivo. Thus, the notion that "signal 1" antigen presentation, as represented by cultured islet allografts, leads to the clonal deletion or inactivation (anergy) of donor-reactive T cells is not supported by these results. Since this form of tolerance does not appear to be an intrinsic property of the donor-specific lymphocyte, these results are more consistent with a model of active regulatory tolerance in vivo.

Animals↗
PubMed2000

Mixed chimerism, heart, and skin allograft tolerance in cyclophosphamide-induced tolerance.

We elucidated the possible role of chimerism in skin and heart allograft tolerance using cyclophosphamide (CP)-induced tolerance. When C3H (H-2k; Thy1.2, Mls-1b) mice were i.v. primed with 1x10(8) spleen cells (SC) from H-2 matched AKR (H-2k; Thy1.1, Mls-1a) mice and then treated i.p. with 200 mg/kg of CP, the survivals of both AKR skin grafts and heart grafts (HG) were permanently prolonged in a tolerogen-specific fashion. After this treatment, a minimal degree of mixed chimerism, the clonal destruction of Mls-1a-reactive CD4+Vbeta6+ T cells in the periphery, and the clonal deletion of Vbeta6+ thymocytes were all observed. When AKR SC and 100 mg/kg CP were used for conditioning, the AKR HG were permanently accepted, but the survival of the AKR skin grafts was only mildly prolonged. The clonal destruction of CD4+Vbeta6+ T cells in the periphery and the intrathymic clonal deletion of Vbeta6+ thymocytes were induced in both the SC and the 100 mg/kg CP-treated C3H mice. A minimal degree of mixed chimerism was detectable at 4 and 12 weeks after AKR SC and 100 mg/kg CP treatment, and still did not disappear at 40 weeks. The degree of mixed chimerism induced with SC and 100 mg/kg CP was significantly lower than that with SC and 200 mg/kg CP during the observation. No posttransplant cardiac allograft vasculopathy (CAV) was observed to develop, while both the Th1 type (interferon-gamma) and Th2 type (interleukin-4 and -10) cytokine expressions decreased in the AKR HG of the tolerant C3H mice treated with both AKR SC plus 200 mg/kg CP, and AKR SC plus 100 mg/kg CP. A second set of skin grafts from donor AKR mice survived for more than 100 days in a tolerogen-specific fashion in all C3H mice treated with AKR SC and 200 mg/kg CP and also accepted the AKR HG for over 200 days, while 80% of the C3H mice treated with AKR SC and 100 mg/kg CP and accepted the AKR HG for more than 200 days. These results strongly suggested the following conclusions: 1) the degree of chimerism can strongly influence the induction of skin and heart allograft tolerance, 2) posttransplant CAV does not develop in the donor HG maintained by chimerism-based CP-induced tolerance, 3) the mRNA expression of both Th1 and Th2 type cytokine decreased in the donor HG maintained by chimerism-based CP-induced tolerance, and 4) the induction of skin allograft tolerance is more difficult than the prevention of posttransplant CAV.

Animals↗
PubMed2005

Is B cell tolerance essential for transplantation tolerance?

In some transplantation settings, achieving B cell as well as T cell tolerance will be essential in order to ensure long-term graft survival. However, in other situations, although B cell tolerance could potentially offer advantages to the long-term function of the graft and may therefore be desirable, there is no evidence that inducing B cell tolerance alongside T cell tolerance is essential. This overview forms part of a debate discussing the potential role of B cell tolerance in transplantation and uses selected examples in the literature to address the question: is B cell tolerance essential for transplantation tolerance?

Acute Disease↗
PubMed2005

Differential effects of CpG-DNA in Toll-like receptor-2/-4/-9 tolerance and cross-tolerance.

Lipopolysaccharide (LPS) tolerance is a state of refractoriness towards a second stimulation by LPS after a preceding stimulation. LPS is recognized by Toll-like receptor-4 (TLR-4), which belongs to a group of pattern recognition receptors mediating activation of innate immunity by microbial components. To date, it is not known in detail to what extent other TLR-dependent stimuli also induce tolerance and whether preceding and challenging stimuli are interchangeable. We have examined tolerance induction in detail for lipoteichoic acid (LTA), LPS and CpG-DNA, which are recognized by TLR-2, -4 and -9, respectively. In RAW264.7 macrophages, all three stimuli induced tolerance towards a subsequent challenge with the same stimulus used for priming, as well as cross-tolerance towards subsequent challenge with other stimuli signalling via different TLRs. However, whereas LPS/LTA cross-tolerance was also functional in an in vivo model of galactosamine (GalN)-primed liver damage, pretreatment with CpG only protected against GalN/CpG challenge and failed to induce cross-tolerance for LPS and LTA. CpG-DNA pretreatment even enhanced tumour necrosis factor (TNF)-alpha production and liver damage upon subsequent challenge with LPS or LTA. Stimulation with CpG-DNA resulted in a peculiar sensitization for interferon (IFN)-gamma secretion. The data indicate that, in contrast to in vitro macrophage desensitization, the in vivo consequences of repeated TLR stimulation greatly differ amongst different TLR ligands.

Animals↗
PubMed2004

Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance.

AIMS: To determine the effects of rosiglitazone on insulin sensitivity, glucose tolerance and ambulatory blood pressure when administered to subjects with persistent impaired glucose tolerance (IGT). METHODS: Eighteen subjects with persistent IGT were randomized to receive rosiglitazone 4 mg twice daily or matching placebo for 12 weeks. Evaluation at baseline and at the end of treatment included measurement of whole body insulin sensitivity during a euglycaemic hyperinsulinaemic clamp and deriving an insulin sensitivity index. Changes in glucose and insulin concentration were determined after oral glucose tolerance test (OGTT) and mixed meal tolerance tests, and 24-h ambulatory blood pressure was monitored. RESULTS: Rosiglitazone significantly improved the insulin sensitivity index by 2.26 micro g/kg per min per pmol/l relative to placebo (P = 0.0003). Four of nine subjects receiving rosiglitazone reverted to normal glucose tolerance and 5/9 remained IGT, although four of these had improved 2-h glucose values. In the placebo group, 1/9 subjects progressed to Type 2 diabetes and 8/9 remained IGT. Following OGTT and meal tolerance test, glucose and insulin area under curve were reduced over 3 and 4 h, respectively. Compared with placebo, ambulatory blood pressure decreased significantly in the rosiglitazone group by 10 mmHg systolic (P = 0.0066) and 8 mmHg diastolic (P = 0.0126). CONCLUSIONS: Consistent with its effects in patients with Type 2 diabetes, rosiglitazone substantially improved whole body insulin sensitivity and the glycaemic and insulinaemic responses to an OGTT and meal tolerance test in subjects with persistent IGT. Furthermore, rosiglitazone reduced systolic and diastolic ambulatory blood pressure in these subjects.

Adult↗
PubMed1991

Tolerance pattern to GABAmimetic analgesics and their influence on morphine tolerance and dependence.

The possible development of acute and chronic tolerance to 4, 5, 6, 7-tetrahydroisoxazole-(5, 4-C)pyridin-3-ol (THIP) and muscimol-induced analgesia was tested using the acetic acid induced writhing assay. Acute tolerance developed to their analgesic actions on repeated exposure at a 4-h interval which was sensitive to naloxone. Chronic tolerance gradually developed to these agents from the 4th day and was appreciable after 10 days of treatment. Injection of THIP or muscimol prior to morphine attenuated the acute tolerance developed to morphine analgesia. These findings reveal that acute and chronic tolerance developed to THIP and muscimol induced analgesia and are suggestive of a role for opioidergic system in the development of acute tolerance to their analgesic effect. However, these agents per se did not produce any dependence phenomena and failed to affect morphine dependence indicating that different mechanisms might be operating in the development of tolerance and dependence.

Analgesics↗
PubMed1980

Absence of cross-tolerance to heroin in morphine-tolerant mice.

Mice implanted with morphine pellets demonstrated a 30-fold increase in tolerance to subcutaneously administered morphine but showed no cross-tolerance to subcutaneously administered heroin. When given morphine intracerebroventricularly, the mice showed no tolerance to morphine or cross-tolerance to heroin. These observations depended on the presence of the morphine pellet. If the pellets were removed prior to determinations of potency, the expected responses--tolerance to morphine and cross-tolerance to heroin--were obtained. The blood-brain barrier may be a prime site for the expression of morphine tolerance in mice.

Animals↗
PubMed2004

Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance.

Recent studies suggest that mitochondrial aldehyde dehydrogenase (ALDH-2) plays a central role in the process of nitroglycerin (glyceryl trinitrate, GTN) biotransformation in vivo and that its inhibition accounts for mechanism-based tolerance in vitro. The extent to which ALDH-2 contributes to GTN tolerance (impaired relaxation to GTN) and cross-tolerance (impaired endothelium-dependent relaxation) in vivo remain to be elucidated. Rats were treated for three days with GTN. Infusions were accompanied by decreases in vascular ALDH-2 activity, GTN biotransformation, and cGMP-dependent kinase (cGK-I) activity. Further, whereas in control vessels, multiple inhibitors and substrates of ALDH-2 reduced both GTN-stimulation of cGKI and GTN-induced vasodilation, these agents had little effect on tolerant vessels. A state of functional tolerance (in the GTN/cGMP pathway) was recapitulated in cultured endothelial cells by knocking down mitochondrial DNA (rho(0) cells). In addition, GTN increased the production of reactive oxygen species (ROS) by mitochondria, and these increases were associated with impaired relaxation to acetylcholine. Finally, antioxidants/reductants decreased mitochondrial ROS production and restored ALDH-2 activity. These observations suggest that nitrate tolerance is mediated, at least in significant part, by inhibition of vascular ALDH-2 and that mitochondrial ROS contribute to this inhibition. Thus, GTN tolerance may be viewed as a metabolic syndrome characterized by mitochondrial dysfunction.

Aldehyde Dehydrogenase↗
PubMed1995

Oral tolerance to ovalbumin in mice as a model for detecting modulators of the immunologic tolerance to a specific antigen.

Oral tolerance is thought to have a role in preventing allergic responses and immune-mediated diseases. Modulation of this tolerance by drugs and chemicals can cause or suppress them. An improved model of oral tolerance to ovalbumin (OVA) in mice was developed to detect modulators of the tolerance and to apply it to selected immunomodulating substances, cyclophosphamide (CP), Escherichia coli lipopolysaccharide (LPS) and cadmium chloride (Cd). Male C3H/HeN mice given an oral administration of 20 mg OVA were immunized 7 d later with an i.p. injection of 0.1 mg OVA in complete Freund's adjuvant. Effects of oral OVA and agents on systemic immunity were assessed by enzyme-linked immunosorbent assay (ELISA) of immunoglobulin (Ig) levels in serum collected 7 or 14 d after immunization. Oral tolerance was adequately induced on day 7 after immunization and was more effective in C3H/HeN mice than in BALB/c mice. It was primarily associated with the decreased serum levels of anti-OVA IgG (including both IgG1 and IgG2a subclasses regulated differently by T-helper subpopulations, Th2 and Th1 cells, respectively). The C3H model of oral tolerance was further examined to detect modulators of the tolerance. An i.p. injection of CP prior to oral OVA, or 5 consecutive daily oral administrations of LPS after oral OVA elevated or reduced serum levels of anti-OVA IgG in C3H mice hyposensitized by the oral OVA, respectively. Concerning IgG subclasses, CP restored anti-OVA IgG2a but not IgG1 levels, while LPS caused greater suppression of both anti-OVA IgG1 and IgG2a levels. Oral administrations of Cd for 5 d after oral OVA also suppressed anti-OVA IgG1 levels further.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed1989

[Tolerance and reverse tolerance of nicotine on spontaneous motor activity].

Repeated administration of nicotine induces tolerance and/or reverse tolerance of spontaneous motor activity in rodents. These effects of nicotine on the spontaneous motor activity have been shown to be influenced by drug factors (e.g., doses, elapsed time after injection, period of treatment), circadian rhythm, age, sex, strain and species of animals. Although nicotinic acetylcholine receptors in the brain participate in the effects of nicotine, the development of tolerance and reverse tolerance is not sufficiently explained by changes in the receptor sites. Recently, neurochemical and behavioral studies have shown the possibility that reverse tolerance of nicotine on the spontaneous motor activity is probably concerned with the dopaminergic system through nicotinic acetylcholine receptors in the striatum or mesolimbic dopaminergic system of the rat brain. The present knowledge about the tolerance and reverse tolerance of nicotine on spontaneous motor activity is discussed in this review.

Animals↗
PubMed2005

In vivo activation of a mutant mu-opioid receptor by naltrexone produces a potent analgesic effect but no tolerance: role of mu-receptor activation and delta-receptor blockade in morphine tolerance.

Opioid analgesics are the standard therapeutic agents for the treatment of pain, but their prolonged use is limited because of the development of tolerance and dependence. Recently, we reported the development of a mu-opioid receptor knock-in (KI) mouse in which the mu-opioid receptor was replaced by a mutant receptor (S196A) using a homologous recombination gene-targeting strategy. In these animals, the opioid antagonist naltrexone elicited antinociceptive effects similar to those of partial agonists acting in wild-type (WT) mice; however, development of tolerance and physical dependence were greatly reduced. In this study, we test the hypothesis that the failure of naltrexone to produce tolerance in these KI mice is attributable to its simultaneous inhibition of delta-opioid receptors and activation of mu-opioid receptors. Simultaneous implantation of a morphine pellet and continuous infusion of the delta-opioid receptor antagonist naltrindole prevented tolerance development to morphine in both WT and KI animals. Moreover, administration of SNC-80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide], a delta agonist, in the naltrexone-pelleted KI animals resulted in a dose-dependent induction in tolerance development to both morphine- and naltrexone-induced analgesia. We conclude that although simultaneous activation of both mu- and delta-opioid receptors results in tolerance development, mu-opioid receptor activation in conjunction with delta-opioid receptor blockade significantly attenuates the development of tolerance.

Animals↗
PubMed2004

Short-term low-dose growth hormone administration in subjects with impaired glucose tolerance and the metabolic syndrome: effects on beta-cell function and post-load glucose tolerance.

OBJECTIVE: Modest elevations in circulating IGF-I levels have been suggested to protect against the development of glucose intolerance in insulin-resistant subjects. To further understand the interactions of GH and IGF-I on beta-cell function and post-load glucose tolerance in glucose-intolerant subjects predisposed to diabetes, we performed a pilot study in 12 subjects with impaired glucose tolerance and the metabolic syndrome using a low GH dose (1.7 microg/kg per day) known to increase endogenous IGF-I production. DESIGN: Fourteen daily GH or placebo injections in a double-blind cross-over study. METHODS: Baseline and post-treatment oral glucose tolerance tests were performed. The homeostasis model assessment and the insulinogenic index was used to estimate fasting insulin sensitivity (S(I)) and beta-cell function respectively, whereas changes in the incremental area under the curve were used to estimate post-load glucose tolerance (DeltaAUC(glu)) and post-load insulin levels (DeltaAUC(ins)). RESULTS: GH increased total IGF-I (P<0.02), free IGF-I (P<0.04) and fasting insulin (P<0.04) levels, but did not modify plasma IGF-binding proteins (IGFBPs)-1 and -3, fasting glucose, non-esterified fatty acid and C-peptide levels, and fasting S(I). After oral glucose intake, glucose tolerance improved (P<0.03), but post-load insulin levels and beta-cell function remained unchanged. CONCLUSION: Short-term low-dose GH administration induced fasting hyperinsulinaemia possibly by reducing insulin clearance but improved post-load glucose tolerance, suggesting that increased bioavailable IGF-I enhanced post-load S(I) without altering beta-cell function. Longer-term studies are required to ascertain whether these positive effects on post-load glucose tolerance and the preservation of beta-cell function can be sustained by this GH dose in these high-risk subjects.

Adult↗