Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adipocyte membrane G protein pattern, beta-adrenergic receptor activity, and adenylyl cyclase were determined in adipocyte membranes of the db/db mouse, a mutant that is a model of diabetes preceded by hyperinsulinemia, hyperglycemia, and extreme obesity. These studies were undertaken to determine whether the alterations already noted in the ob/ob mouse and those in the db/db mouse are similar and related to the hormonal defects, particularly the hyperinsulinemia and hyperglycemia prevalent in these animals (cf. Ref. 11). The ADP ribosylation data show that Gs alpha was more highly labeled in the tissues of the db/db mutant than in the homozygous control, but there was no significant difference in the amount of ADP-ribose incorporated in the Gi alpha-subunits. Quantification of the proteins by immunodetection revealed that the long (46-kDa) form of Gs alpha was significantly less abundant in the db mutant than in its control, whereas there was no difference in the short (42-kDa) form. Gi alpha-peptides corresponding to Gi alpha 2 and Gi alpha 1 were both less abundant in the db mutant than in the homozygous control. These data contrasted with those obtained for ob mutants and their lean homozygous controls reported previously (4) and confirmed here. It is concluded on the basis of these studies that factors other than the hormonal status are responsible for the G protein patterns in the ob and db mutants. Differences in G protein patterns noted in between the control groups (B/Ks or B/6 homozygotes) correlated strongly with the quantitative differences in adenylyl cyclase response in the two strains.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha-subunits of Gs and Gi in adipocyte plasma membranes of genetically diabetic (db/db) mice. 132 37

All of the components of the neuropeptide vasoactive intestinal peptide (VIP) signal transduction system were underexpressed in rat prostatic membranes 6 weeks after streptozotocin-induced diabetes. Binding studies with [125I]VIP showed decreases of 86% and 62% in the binding capacity of the high and low affinity classes of VIP receptors in diabetes. Affinity labeling experiments indicated that the main form of VIP receptor was 51 kilodaltons in control rats and 45 kilodaltons in diabetic animals. The efficacy of VIP and forskolin in stimulation of adenylyl cyclase activity as well as the potentiating effect of GTP on VIP action were also reduced in diabetes, as was the expression of the alpha-subunit of the guanine nucleotide-binding regulatory proteins Gs and Gi (studied by ADP ribosylation with cholera and pertussis toxins). Gi function was lost in diabetes, as assessed with experiments on guanyl-5'-yl-imidodiphosphate potentiation of forskolin activity. These disturbances together with previous findings argue for VIP playing a role in the diabetic neuropathy of the genitourinary tract.
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PMID:The effect of streptozotocin diabetes on the vasoactive intestinal peptide receptor/effector system in membranes from rat ventral prostate. 132 26

beta 3-Adrenergic receptors (beta 3AR) mediate lipolytic and thermogenic responses in rodent adipose tissues in vitro, and "atypical" beta AR agonists that active these receptors have potent therapeutic effects in in vivo rodent models of adult-onset diabetes and obesity. However, experiments with rodent cells that natively express the beta 3AR, as well as those with cells that express cloned rodent beta 3AR, have suggested that the pharmacological properties of the rodent and human beta 3AR differ. Given that rodent models of obesity and diabetes are used to develop human therapeutic agents, we sought to compare directly the ligand-binding and functional properties of the rat and human beta 3AR in parallel studies using Chinese hamster ovary cells expressing the recombinant receptors. The endogenous catecholamines epinephrine (EPI) and norepinephrine (NE) were found to have low affinities (micromolar) for the beta 3AR of both species. The rank orders of potency of various agonists in stimulating adenylyl cyclase were clearly different, i.e., for the human beta 3AR, CGP12177 (CGP) > isoproterenol (ISO) > or = BRL34377 (BRL) = Pindolol > NE > EPI; for the rat, CGP > or = BRL > ISO > or = NE > Pindolol > EPI. The intrinsic activities of various agonists were also different, with the following rank orders (compared with ISO): for the human beta 3AR, NE > EPI > BRL = CGP > Pindolol; for the rat beta 3AR, BRL > NE > EPI > CGP > Pindolol. Competition binding studies with 125I-cyanopindolol and these agonists gave similar rank orders of potency. Thus, although the human and rat receptors exhibited similar properties with respect to catecholamine agonists, numerous differences in the potency and efficacy of synthetic noncatecholamine agonists were noted, indicating that the action of atypical agonists at rodent beta 3AR may not be predictive of therapeutic potential in humans.
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PMID:Functional properties of the rat and human beta 3-adrenergic receptors: differential agonist activation of recombinant receptors in Chinese hamster ovary cells. 133 54

It has been proposed that the cytokine interleukin-1 beta (IL-1 beta), secreted by islet-infiltrating macrophages, may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. Addition of IL-1 beta to isolated pancreatic islets in vitro results in cytotoxic effects on beta-cell function, but there is little information on the intracellular events that convey the actions of the cytokine. In the present study, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture to IL-1 beta. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis, insulin secretion and cyclic AMP content. In order to explore whether the decrease in cAMP resulted from IL-1 beta interaction with GTP-binding proteins coupled to adenylyl cyclase, islets were treated for 24 h with pertussis toxin prior to addition of cytokine. While this treatment restored the decrease in cAMP, the reduced DNA synthesis and insulin secretion persisted. Pertussis toxin treatment without the addition of IL-1 beta resulted in increases in cAMP, DNA synthesis and insulin secretion. Addition of the stimulatory cAMP analog Sp-cAMPS also increase DNA synthesis and insulin secretion, but failed to affect the decrease in these functions evoked by IL-1 beta. The protease inhibitor N alpha-p-tosyl-L-lysine chloromethyl ketone, recently shown to protect completely against IL-1 beta-induced suppression of insulin production and secretion, was found to markedly reduce DNA synthesis without affecting insulin secretion. When the protease inhibitor was combined with IL-1 beta, the suppressed secretion was counteracted while DNA synthesis inhibition was not. It is concluded that cAMP stimulates DNA synthesis and insulin secretion in beta-cells, but that the inhibitory effect of IL-1 beta on these functions cannot be ascribed to the decrease in cAMP evoked by the cytokine. However, the repressive effect of the cytokine on insulin secretion, but not DNA synthesis, may be prevented by protease inhibition.
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PMID:Inhibition of fetal rat pancreatic beta-cell replication by interleukin-1 beta in vitro is not mediated through pertussis toxin-sensitive G-proteins, a decrease in cyclic AMP, or protease activation. 165 27

The authors wanted to test the long-term effectiveness of immunoisolation in the NOD mouse, an adequate model of Type I diabetes. Recipients were diabetic female NOD mice with sustained plasma glucose levels above 400 mg/100 ml. They were grafted intraperitoneally with permselective hollow fibers seeded with human insulinoma (n = 6), rodent insulinoma (n = 6), or human islets (n = 6). Controls were 15 nontreated diabetic females and 10 nondiabetic male NOD mice implanted with nonseeded macrocapsules. Electron microscopy (rectangular crystalline nucleoids characteristic of B-cells), in vitro release of insulin (during abrupt changes in glucose concentration from 40 to 400 mg/dl and return, M +/- SD insulin levels were 122 +/- 5 uu/ml and 315 +/- 17 at low and high glucose), evidence of binding hormone receptors (VIP and GIP, the binding sites being coupled with adenylyl cyclase stimulation) were used to assess the quality of the transplant. Survival was always prolonged in grafted animals. Taking complete and long-term (less than 3 months) correction of hyperglycemia as the criterion, the success rate was about 50% as observed in streptozotocin rats. Splenocytes isolated from cured and not cured recipients and injected into irradiated nondiabetic male NOD mice were always able to transfer the disease. Our bioartificial pancreas is efficient in preventing the recurrence of the disease in autoimmune diabetes.
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PMID:Bioartificial pancreas in autoimmune nonobese diabetic mice. 284 60

Glucagon may play a role in the metabolic derangements of overt Type 2 (non-insulin-dependent) diabetes mellitus. We therefore have evaluated the early steps in glucagon action by investigating the hormone-sensitive adenylyl cyclase system in liver membranes from seven Type 2 diabetic patients with fasting hyperglycaemia and two-fold elevations in plasma glucagon. The comparison was made with seven control subjects matched for age, sex and body weight. Glucagon receptor binding was almost identical in the two groups. There were, however, marked alterations in the adenylyl cyclase activity in membranes from the diabetic patients. This activity was reduced by 35-50% when compared to control activity. Basal cyclase activity, as well as the activity after stimulation with glucagon or with agents (i.e., sodium fluoride and forskolin) that act beyond the glucagon receptor, was significantly decreased (p less than 0.05, p less than 0.001 respectively). In conclusion, uncontrolled Type 2 diabetes in associated with an over-all loss of responsiveness of the hormone-sensitive adenylyl cyclase in human liver, which apparently results from post-receptor alterations. This change may provide a mechanism for reducing the effect of hyperglycagonaemia in Type 2 diabetes mellitus.
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PMID:Altered action of glucagon on human liver in type 2 (non-insulin-dependent) diabetes mellitus. 303 42

The impact of diabetes on cyclic nucleotide-associated mechanisms regulating skeletal muscle protein and amino acid metabolism was assessed using epitrochlaris preparations from streptozotocin-induced diabetic rats. 1 nM epinephrine inhibited alanine and glutamine release from control preparations, but no inhibition was observed from diabetic preparations with <0.1 mM. 10 nM epinephrine stimulated lactate production from control muscle but stimulation in diabetic preparations was observed only at 0.1 mM. Serotonin inhibited amino acid release and stimulated lactate production equally in control and diabetic muscle. 0.1 mM epinephrine increased cyclic (c)AMP levels by 360% in control muscles, but these levels were increased only 83% in diabetic muscle. Basal-, fluoride-, and serotonin-stimulated adenylyl cyclase activities were equal in membrane preparations of diabetic and control muscle, but epinephrine-stimulated adenylyl cyclase was reduced by 60% in diabetic muscle. Carbamylcholine stimulation of alanine and glutamine release was blunted in diabetic preparations. Carbamylcholine increased cGMP levels in control but not in diabetic muscle. In diabetic muscle, guanylyl cyclase activity was 65% of control and the stimulation of cyclase activity by sodium azide was less in diabetic than control preparations. Added cGMP stimulated alanine and glutamine release from control, but not from diabetic muscle. These data suggest a loss of adrenergic and cholinergic responsiveness in diabetic muscle. Because amino acid release also showed a decreased responsiveness to added cAMP and cGMP, the presence of other derangements in the mechanism(s) of cyclic nucleotide regulation of muscle amino acid metabolism also seems likely.
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PMID:The impact of streptozotocin-induced diabetes mellitus on cyclic nucleotide regulation of skeletal muscle amino acid metabolism in the rat. 624 11

Glucagon receptor levels, glucagon-stimulated and other forms of adenylyl cyclase activity, and regulatory component activity of adenylyl cyclase were determined in hepatic plasma membranes of rats administered streptozotocin without and with insulin to produce varying degrees of hyperglycemia. Receptor levels were assayed by direct binding of the specific probe [125I-Tyr10]-iodoglucagon; regulatory component activity was assayed by the capacity to reconstitute stimulatory regulation in deficient membranes from cyc- S49 murine lymphoma cells. In rats given 150 mg streptozotocin, glucagon stimulation of adenylyl cyclase as well as basal, sodium fluoride, 5' guanylylimidodiphosphate [GMP-P(NH)P] and Mn-dependent activities were reduced 50%, glucagon receptor levels but not affinity were reduced 67%, and regulatory component activity was decreased 50%. In addition, alpha 1-adrenergic receptors and 5'-nucleotidase were similarly reduced in diabetes. However, specific ouabain-inhibitable Na+, K+, ATPase activity was not altered by streptozotocin treatment. The streptozotocin-induced changes were noted within 24 h and became maximal by 120 h after its administration. All of these decreases were partially reversed by in vivo insulin treatment. DNA, cytochrome c oxidase, glucose-6-phosphatase, and N-acetyl-beta-glucosaminidase content in hepatic plasma membrane preparations were not substantially different in diabetic as compared with control animals. The data demonstrate that glucagon-mediated regulation of cyclic AMP formation is deranged in insulin deficiency owing to a combined decrease in receptors, derangement of the coupling mechanism intervening between receptor and adenylyl cyclase, and possibly, an altered basal effector system. Some of these changes appear to reflect a "desensitization-like" phenomenon which may or may not be attributable to the hyperglucagonemia of diabetes mellitus. There also appears to be a concurrent generalized decrease in several but not all plasma membrane receptor and enzymatic proteins. This may be the result of a number of processes among which is the accelerated proteolysis of uncontrolled diabetes.
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PMID:Glucagon-stimulable adenylyl cyclase in rat liver. The impact of streptozotocin-induced diabetes mellitus. 632 32

We have previously determined the presence of muscarinic receptors and the expression of several G proteins in homogenates and myelin fractions from rat sciatic nerves. In the present study we investigated whether changes in several signal transduction pathways in peripheral nerves might be responsible for some of the biochemical abnormalities (e.g., phosphoinositide metabolism) present in sciatic nerves from streptozotocin-induced diabetic rats. Sciatic nerves from 5 week diabetic rats that were prelabelled with [3H]-myo-inositol displayed a significant increase in the basal release of inositol mono- and bis-phosphate, while carbamylcholine-stimulated release was significantly smaller. Basal- and forskolin-stimulated adenylyl cyclase activity was significantly decreased in sciatic nerve homogenates from diabetic animals. However, we were unable to detect any significant differences in the levels of cAMP in intact nerves or in nerve segments that were incubated in the presence or absence of forskolin. ADP-ribosylation experiments showed that in sciatic nerves from experimentally diabetic rats there was a significant increase in the ADP-ribosylation catalyzed by cholera and pertussis toxins. Measurements of the levels of alpha-subunits of G proteins revealed that the expression of Gq/11 alpha, Gs alpha, and Gi-3 alpha was increased by 30 to 50%. These results indicate that during the course of experimental diabetes, peripheral nerves exhibit an abnormal production of inositol phosphates and cAMP, together with an abnormal expression and/or function of G proteins. One of the consequences of such alterations is the diminished release of inositol phosphates triggered by muscarinic agonists in diabetic sciatic nerves.
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PMID:Signal transduction alterations in peripheral nerves from streptozotocin-induced diabetic rats. 747 83

Inhibition of insulin secretion by galanin is pertussis toxin (PTX) sensitive, suggesting the activation of one or more heterotrimeric (alpha, beta, gamma) G-proteins (Gi/Go). Multiple effectors, including the K+ATP and L-type Ca2+ channels, adenylyl cyclase, and an as yet unidentified system at a site close to exocytosis, are modulated by galanin. Therefore, it is necessary to delineate the particular G-proteins activated by the galanin receptor as a first step to understanding its net cellular response. During specific conditions, cholera toxin (CTX) can ADP-ribosylate the alpha i/alpha o-subunits of the PTX-sensitive substrates but only during receptor/G-protein interaction. Therefore, we used CTX-catalyzed ADP ribosylation to identify galanin receptor-associated G-protein alpha-subunits in RINm5F cells. Galanin enhanced the ADP ribosylation of membrane proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in two bands at 39,000 and 42,000 M(r). This labeling was blocked in membranes prepared from PTX-treated cells, enhanced by Mg2+, and showed a biphasic dependence on exogenous guanine nucleotides. Identification of the CTX ADP-ribosylated G-proteins by immunoprecipitation with selective antisera indicate activation by the galanin receptor of alpha i1 and alpha i3, which have the same mobility on SDS-PAGE (42,000 M(r)), and alpha i2 (39,000 M(r)). These studies provide evidence for the activation of multiple G-proteins by receptors for galanin in RINm5F cells.
Diabetes 1994 Jan
PMID:ADP ribosylation by cholera toxin identifies three G-proteins that are activated by the galanin receptor. Studies with RINm5F cell membranes. 750 45


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