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)

Relatively little is known about the in vivo functions of the alpha subunit of the heterotrimeric G protein Gz (Galphaz). Clues to one potential function recently emerged with the finding that activation of Galphaz inhibits glucose-stimulated insulin secretion in an insulinoma cell line (Kimple, M. E., Nixon, A. B., Kelly, P., Bailey, C. L., Young, K. H., Fields, T. A., and Casey, P. J. (2005) J. Biol. Chem. 280, 31708-31713). To extend this study in vivo, a Galphaz knock-out mouse model was utilized to determine whether Galphaz function plays a role in the inhibition of insulin secretion. No differences were discovered in the gross morphology of the pancreatic islets or in the islet DNA, protein, or insulin content between Galphaz-null and wild-type mice. There was also no difference between the insulin sensitivity of Galphaz-null mice and wild-type controls, as measured by insulin tolerance tests. Galphaz-null mice did, however, display increased plasma insulin concentrations and a corresponding increase in glucose clearance following intraperitoneal and oral glucose challenge as compared with wild-type controls. The increased plasma insulin observed in Galphaz-null mice is most likely a direct result of enhanced insulin secretion, since pancreatic islets isolated from Galphaz-null mice exhibited significantly higher glucose-stimulated insulin secretion than those of wild-type mice. Finally, the increased insulin secretion observed in Galphaz-null islets appears to be due to the relief of a tonic inhibition of adenylyl cyclase, as cAMP production was significantly increased in Galphaz-null islets in the absence of exogenous stimulation. These findings indicate that Galphaz may be a potential new target for therapeutics aimed at ameliorating beta-cell dysfunction in Type 2 diabetes.
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PMID:Galphaz negatively regulates insulin secretion and glucose clearance. 1809 3

The release of fatty acids and glycerol from lipid droplets (LD) of mammalian adipose cells is tightly regulated by a number of counterregulatory signals and negative feedback mechanisms. In humans unrestrained lipolysis contributes to the pathogenesis of obesity and type II diabetes. In order to identify novel targets for the pharmacological interference with lipolysis, the molecular mechanisms of four antilipolytic agents were compared in isolated rat adipocytes. Incubation of the adipocytes with insulin, palmitate, glucose oxidase (for the generation of H2O2) and the antidiabetic sulfonylurea drug, glimepiride, reduced adenylyl cyclase-dependent, but not dibutyryl-cAMP-induced lipolysis as well as the translocation of hormone-sensitive lipase and the LD-associated protein, perilipin-A, to and from LD, respectively. The antilipolytic activity of palmitate, H2O2 and glimepiride rather than that of insulin was dependent on rolipram-sensitive but cilostamide-insensitive phosphodiesterase (PDE) but was not associated with detectable downregulation of total cytosolic cAMP and insulin signaling via phosphatidylinositol-3 kinase and protein kinase B. LD from adipocytes treated with palmitate, H2O2 and glimepiride were capable of converting cAMP to adenosine in vitro, which was hardly observed with those from basal cells. Conversion of cAMP to adenosine was blocked by rolipram and the 5'-nucleotidase inhibitor, AMPCP. Immunoblotting analysis revealed a limited salt-sensitive association with LD of some of the PDE isoforms currently known to be expressed in rat adipocytes. In contrast, the cAMP-to-adenosine converting activity was stripped off the LD by bacterial phosphatidylinositol-specific phospholipase C. These findings emphasize the importance of the compartmentalization of cAMP signaling for the regulation of lipolysis in adipocytes, in general, and of the involvement of LD-associated proteins for cAMP degradation, in particular.
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PMID:Inhibition of lipolysis by palmitate, H2O2 and the sulfonylurea drug, glimepiride, in rat adipocytes depends on cAMP degradation by lipid droplets. 1818 16

In terms of development of evolutionary biomedicine using invertebrate animals as models for study of molecular grounds of various human diseases, for the first time the streptozocin (ST) model of insulin-dependent diabetes in the mollusc Anodonta cygnea has been developed. This model is based on the following authors' data: (1) redetection of insulin-related peptides (IRP) in mollusk tissues: (2) discovery of the adenylyl cyclase signal mechanism (ACSM) of action of insulin and other peptides of the insulin superfamily in tissues of mammals, human, and mollusc. A. cygnea; (3) concept of molecular defects in hormonal signal systems as causes of endocrine diseases. Studies on the ST model have revealed in mollusc smooth muscle on the background of hyperglycemia at the 2nd, 4th, and 8th day after the ST administration a decrease of the ACSM response to activating action of insulin, IGF-1, and relaxin. These functional disturbances were the most pronounced at the 2nd day of development and rather less marked at the 4th and 8th day. Analysis of data on effect of hormonal and non-hormonal (NaF, GIDP, and forskolin) ACSM activators has shown that the causes of impair of signal-transducing function of this mechanism are (1) a hyperglycemia-induced increase of the basal AC activity and as a consequence--a decrease of the enzyme catalytic potentials in response to hormone; (2) a decrease of functions of Gs-protein and of its coupling with AC. Besides, administration of ST produced in the mollusc muscles an attenuation of regulation by insulin of carbohydrate metabolism enzyme (glucose-6-phosphate dehydrogenase, glycogensynthase). The pattern of disturbances in the studied parameters in the mollusc is very similar to that revealed by the authors in rat and human muscle tissues in type 1 diabetes.
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PMID:[Streptozocin model of diabetes mellitus in the mollusc Anodonta cygnea: functional state of the adenylyl cyclase mechanisms of action of peptides of the insulin superfamily and their effect on carbohydrate metabolism enzymes]. 1826 56

We have recently shown that aorta from streptozotocin (STZ)-induced diabetic rats and A10 vascular smooth muscle cells (VSMCs) exposed to high glucose exhibited decreased levels of inhibitory guanine nucleotide regulatory protein (Gi)alpha proteins. In the present studies, we investigated the implication of oxidative stress in the hyperglycemia/diabetes-induced decreased expression of the Gialpha protein and adenylyl cyclase signaling in VSMCs by using antioxidants. The levels of Gialpha proteins were significantly decreased in A10 VSMCs exposed to high glucose and in aortic VSMCs from STZ-diabetic rats compared with control cells and were restored to control levels by antioxidants. In addition, (111)Mn-tetralis(benzoic acid porphyrin) and uric acid, scavengers of peroxynitrite, and NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase but not catalase, also restored the high glucose-induced decreased expression of Gialpha proteins to the control levels in A10 VSMCs. Furthermore, the enhanced production of superoxide anion (O2-) and increased activity of NADPH oxidase in these cells were also restored to control levels by diphenyleneiodonium, an inhibitor of NADPH oxidase. In addition, the diminished inhibition of adenylyl cyclase activity by inhibitory hormones and forskolin-stimulated adenylyl cyclase activity by low concentrations of GTPgammaS as well as the enhanced stimulation of adenylyl cyclase by stimulatory agonists in hyperglycemic cells were restored to control levels by antioxidant treatments. These results suggest that high glucose-induced decreased levels of Gialpha proteins and associated signaling in A10 VSMCs may be attributed to the enhanced oxidative stress due to augmented levels of peroxynitrite and not to H2O2.
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PMID:Role of oxidative stress in high glucose-induced decreased expression of Gialpha proteins and adenylyl cyclase signaling in vascular smooth muscle cells. 1844 Nov 96

We investigated the effects of epinephrine and dopamine on retinal blood vessels in streptozotocin (STZ, 80 mg/kg, i.p.)-treated rats and age-matched control rats to determine whether diabetes mellitus alters the retinal vascular responses to circulating catecholamines. Experiments were performed 6-8 weeks after treatment with STZ or the vehicle. The fundus images were captured with the digital fundus camera system for small animals we developed and diameters of retinal blood vessels contained in the digital images were measured. Epinephrine increased the diameters of retinal blood vessels, but the vasodilator responses were reduced in diabetic rats. Dopamine produced a biphasic retinal vascular response with an initial vasoconstriction followed by a vasodilation. The vasoconstrictor effects of dopamine on retinal arterioles were enhanced in diabetic rats, whereas the difference between the two groups was abolished by treatment with propranolol. The vasodilator effect of isoproterenol, but not of the activator of adenylyl cyclase colforsin, on retinal blood vessels was reduced in diabetic rats. No difference in vasoconstriction of retinal blood vessels to phenylephrine between non-diabetic and diabetic rats was observed. The vasodilator responses of retinal blood vessels to 1,1-dimethyl-4-phenylpiperazinium, a ganglionic nicotinic receptor agonist, were also attenuated in diabetic rats. These results suggest that diabetes mellitus alters the retinal vascular responses to circulating catecholamines and the impairment of vasodilator responses mediated by beta-adrenoceptors contributes to the alteration.
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PMID:Beta-adrenoceptor-mediated vasodilation of retinal blood vessels is reduced in streptozotocin-induced diabetic rats. 1858 80

For the first time we found in myometrium of the women and pregnant women that adenylyl cyclase (AC) stimulating effects of relaxin, insulin and insulin growth factor 1 are realized via six-component AC signaling mechanisms involving the following signaling chain: receptor-tyrosine kinase ==> Gi protein (beta gamma dimmer) ==> phosphatidylinositol 3-kinase ==> protein kinase C (zeta) ==> Gs protein ==> adenylyl cyclase (AC), which are similar to the discovered adenylyl cyclase signaling mechanisms of insulin and relaxin action in vertebrates (rat) and invertebrates (mollusk). The effect of relaxin is more pronounced as compared with other peptides (relaxin > insulin > insulin-like growth factor-1) in myometrium of pregnant women. It is connected with the specific role ofrelaxin as main regulator of reproductive functions. For the first time we revealed the functional defects in distal parts of adenylyl cyclase signaling mechanisms of the insulin superfamily peptides action in the condition type-2 diabetes (the increase of the basal adenylyl cyclase activity and decrease of the peptide-stimulated AX activity in presence of guanilylimidodiphosphate). The defects are localized on the level of Gs protein, adenylyl cyclase and their functional coupling. The data obtained confirm our conception about molecular defects in hormoneregulated adenylyl cyclase system as a key reason of type-2 diabetes.
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PMID:[Adenylyl cyclase signaling mechanisms of the insulin superfamily peptide action and their impairment in myometrium of pregnant women with type 2 diabetes]. 1906 26

The glucagon-like peptide-1 receptor (GLP-1 receptor) mediates important effects on peripheral tissues and the central nervous system. It seems one of the most promising therapeutic targets for treatment of diabetes mellitus type 2. Surprisingly, very little is known about the cellular mechanisms that regulate its function in vivo. One of the approaches to study receptor dynamics, expression, or signaling is using GFP-tagged fluorescent proteins. In this study, we synthesized and characterized N-terminally GFP-tagged GLP-1 (GFP-GLP-1) receptor in CHO cells. We demonstrated that GFP-GLP-1 receptor is weakly expressed in the plasma membranes and is functionally coupled to adenylyl cyclase via heterotrimeric G-proteins, similarly as its wild type.
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PMID:Functional characterization of N-terminally GFP-tagged GLP-1 receptor. 1985 70

Organophosphates are developmental neurotoxicants but recent evidence points to additional adverse effects on metabolism and cardiovascular function. One common mechanism is disrupted cell signaling mediated through cyclic AMP, targeting neurohumoral receptors, G-proteins and adenylyl cyclase (AC) itself. Earlier, we showed that neonatal parathion evokes later upregulation of the hepatic AC pathway in adolescence but that the effect wanes by young adulthood; nevertheless metabolic changes resembling prediabetes persist. Here, we administered parathion to neonatal rats (postnatal days 1-4, 0.1 or 0.2 mg/kg/day), straddling the threshold for cholinesterase inhibition, but we extended the studies to much later, 5 months of age. In addition, we investigated whether metabolic challenge imposed by consuming a high-fat diet for 7 weeks would exacerbate neonatal parathion's effects. Parathion alone increased the expression or function of G(i), thus reducing AC responses to fluoride. Receptors controlling AC activity were also affected: beta-adrenergic receptors (betaARs) in skeletal muscle were increased, whereas those in the heart were decreased, and the latter also showed an elevation of m(2)-muscarinic acetylcholine receptors, which inhibit AC. The high-fat diet also induced changes in AC signaling, enhancing the hepatic AC response to glucagon while impairing the cardiac response to fluoride or forskolin, and suppressing betaARs and m(2)-muscarinic receptors; the only change in the cerebellum was a decrease in betaARs. Although there were no significant interactions between neonatal parathion exposure and a high-fat diet, their convergent effects on the same signaling cascade indicate that early OP exposure, separately or combination with dietary factors, may contribute to the worldwide increase in the incidence of obesity and diabetes.
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PMID:Neonatal parathion exposure and interactions with a high-fat diet in adulthood: Adenylyl cyclase-mediated cell signaling in heart, liver and cerebellum. 2007 26

Diabetes mellitus (DM) of type 1 induces numerous disturbances in reproductive systems of males and females. We have shown earlier that the main cause of the complications in the case of DM is alteration of adenylyl cyclase signaling system (ACSS) sensitivity to hormones. The aim of the present work was identification of disturbances in hormone-regulated ACSS in reproductive tissues of rats with experimental type 1 DM (EDM1) induced by streptozotocin treatment. Testis of the rats with 5-days EDM1 showed significant decrease in the stimulatory effects of human chorionic gonadotropin (hCG) and PACAP-38 on adenyly] cyclase (AC) activity and G protein GTP-binding. Uterus of the rats with EDM1 exhibited decreased effects of relaxin, PACAP-38 and biogenic amines. In the ovaries, we showed the decrease in hCG effects only. Weakening of the inhibitory influence of somatostatin on ACSS activity was found in all studied tissues of rats with EDM1. Uterus displayed also decreased inhibitory effects of serotonin and adrenaline. Thus, regulatory effects of the hormones in ACSS sensitivity in reproductive tissues of the rats with EDM1 were decreased. The effects of hCG and AC inhibiting hormones were decreased to a greater extent. We suppose that the decrease in ACSS sensitivity to hormones in the case of EDM1 is responsible for pathological changes in reproductive systems of diabetic rats under condition of hyperglycemia and insulin deficiency which are typical for type 1 DM.
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PMID:[Functional state of adenylyl cyclase signaling system in reproductive tissues of rats with experimental type 1 diabetes]. 2035 1

Activity of the adenylate cyclase signaling system was evaluated in the testicular tissue of rats with neonatal streptozotocin-induced diabetes (120 and 180 days duration). This state is similar to type 2 diabetes in humans. The regulation of this system by polypeptide hormones and biogenic amines was studied. Sensitivity of the adenylate cyclase signaling system to the regulatory effect of human chorionic gonadotropin and PACAP (pituitary adenylyl cyclase-activating polypeptide) was significantly reduced. The effects of these agents are realized via stimulatory G proteins. Somatostatin, acting through inhibitory G proteins, produced less pronounced effect on the adenylate cyclase signaling system. The increase in the duration of diabetes was accompanied by a decrease in the stimulatory effects of human chorionic gonadotropin and PACAP on adenylate cyclase. Sensitivity of the adenylate cyclase signaling system to biogenic amines remained unchanged (serotonin) or increased under these conditions (epinephrine). Our results indicate that changes in hormonal regulation of the adenylate cyclase signaling system and functional activity of cAMP-dependent signaling cascades are important factors for dysfunction of spermatogenesis and steroidogenesis during insulin-independent diabetes.
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PMID:Changes in hormone sensitivity of the adenylate cyclase signaling system in the testicular tissue of rats with neonatal streptozotocin-induced diabetes. 2039 97


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