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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been proposed that certain cytokines secreted by islet-infiltrating leukocytes may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. In the present study, the impact of various cytokines on replication and long-term insulin secretion by pancreatic beta-cells was investigated. To this end, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture for 1-3 days to interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interferon-alpha (IFN-alpha), and interleukin-6 (IL-6) at different concentrations. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis during the first day of exposure, an effect that vanished after 2 days and was turned into a potent and dose-dependent stimulation by 3 days of exposure. At this latter time point, IL-1 beta also amplified the mitogenicity of growth hormone (GH) and 16.7 mM glucose. In contrast, basal as well as glucose- and GH-stimulated insulin secretion was consistently suppressed by IL-1 beta from days 1-3. IL-1 beta also lowered the islet adenosine 3',5'-cyclic monophosphate (cAMP) content at all time points studied. However, addition of the stimulatory cAMP analogue Sp-diastereomer of adenosine 3',5'-cyclic monophosphothioate or pertussis toxin, which themselves enhanced DNA synthesis and insulin secretion, failed to prevent the inhibitory actions of IL-1 beta on these parameters, making it unlikely that a decrease in cAMP is an important event in transduction of the inhibitory effects of the cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effects of cytokines on long-term mitogenic and secretory responses of fetal rat pancreatic beta-cells. 132 36

The specific activity of Na(+)-K(+)-ATPase in the renal medulla and cortex of 50-day-old streptozotocin (STZ)-induced diabetic mice was increased 58% and 50%, respectively, as compared to controls. Km values of Na+ and K+ for this enzyme were unaltered, while that of ATP was decreased in diabetic mice. The Na(+)-K(+)-ATPase in control medulla and cortex was activated by both cholera and pertussis toxins, while this effect was abolished in diabetics. Since dibutyryl cAMP stimulates cortical Na(+)-K(+)-ATPase activity in control mice, the activation effect of cholera toxin on this enzyme might be due to its interaction with a Gs-protein and the persistent stimulation of adenylate cyclase activity, while the effect of pertussis toxin might be due to its masking of the inhibitory action of a Gi-protein on adenylate cyclase activity. However, the protein kinase C (PKC)-associated Na(+)-K(+)-ATPase might also be quiescent in diabetes, because the stimulating effect of phorbol 12,13-dibutyrate (PDBu) and phorbol 12-myristate 13-acetate (PMA) on this enzyme was abolished in diabetic cortex. In addition, nicardipine and ouabain were found to have differential effects on this enzyme derived from control and diabetic mice.
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PMID:Differentiation of renal Na(+)-K(+)-ATPase in control and streptozotocin-induced diabetic mice by G-protein acting toxins and phorbol esters. 132 74

The effect of diabetes mellitus on beta-adrenergic receptor number (B(max)), receptor-cyclase coupling and adenylate cyclase (AC) activity was determined in cerebral microvessels isolated from control and streptozotocin induced diabetic rats after 5 weeks of induction of diabetes. Scatchard analysis of [125I]iodocyanopindolol (ICYP) binding indicated that the B(max) (fmol/mg) in diabetic rat cerebral microvessels (63.8 +/- 4.8) (mean +/- S.E.M.) was not significantly different from the B(max) in control rats (56.5 +/- 6.9). Isoproterenol competition of [125I]ICYP binding sites indicated that the percentage of beta-receptors expressing high affinity binding was 53.9 +/- 0.45% in control rats and 47.5 +/- 2.3% in diabetic rats. The total isoproterenol-stimulated AC activity (pmol cAMP/mg) in diabetic rats (76.7 +/- 6.1) was significantly lower than that in control rats (118.4 +/- 11.2) (P less than 0.01). However, the net isoproterenol-stimulated AC activity (i.e. total minus GTP-stimulated AC activity) was not altered in diabetes. The net sodium fluoride (NaF) stimulated AC activity in diabetic rats (109.5 +/- 11.4) was significantly lower than the control rats (154.3 +/- 16.3) (P less than 0.05). It is concluded that diabetes mellitus in rats is associated with reduced post receptor activation of adenylate cyclase in cerebral microvessels while the beta-adrenergic receptor density, affinity and receptor-cyclase coupling are not significantly altered.
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PMID:Beta-adrenergic receptor activity of cerebral microvessels in experimental diabetes mellitus. 132 92

Rat parotid responses to sympathetic nerve stimulation in vivo are impaired 2-4 weeks after the induction of streptozotocin diabetes. In this study, the effects of experimental diabetes of similar duration and severity on noradrenaline-stimulated amylase release and cAMP accumulation were examined in vitro. Amylase levels were significantly lower in acinar cells isolated from diabetic animals than in controls, and cellular amylase increased after treatment of the diabetic animals with either thyroxine (T4) or insulin. Diabetes and T4 had no apparent affect on amylase release measured as a percentage of the total. In contrast, giving insulin resulted in a significant reduction in maximal secretion (20.4 +/- 2.4% compared with 43.6 +/- 7.6%). Similar results were observed when amylase release was stimulated with forskolin. Basal cAMP levels were unaffected by diabetes or T4 (7.8 +/- 2.3 pmol/mg protein), but stimulated cAMP levels were significantly greater in diabetic acinar cells than in controls. Insulin reversed the effects of diabetes on cAMP accumulation, whereas T4 had no effect. Thus, diabetes (2-4 weeks) and insulin in vivo appear to have paradoxical effects on parotid amylase release and cAMP accumulation in vitro. Further, the effects of diabetes appear to be unrelated to thyroid status.
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PMID:Effects of streptozotocin diabetes on amylase release and cAMP accumulation in rat parotid acinar cells. 137 85

Crosstalk between intracellular signalling systems is recognized as the principal means by which a cell orchestrates coordinate responses to stimulation by neurotransmitters, hormones or growth factors. The functional consequences of crosstalk are evident at multiple levels within a given signalling cascade, including the regulation of receptor-ligand interactions, guanine nucleotide-binding proteins, enzyme activities, ion channel function and gene expression. Here we focus on the pancreatic beta-cells of the islets of Langerhans to illustrate the important role crosstalk plays in the regulation of glucose-induced insulin secretion. Recent studies indicating a synergistic interaction in beta-cells between the glucose-regulated ATP-dependent signalling system and the hormonally regulated cAMP-dependent signalling system are emphasized. This interaction gives beta-cells the ability to match the ambient concentration of glucose to an appropriate insulin secretory response, a process we refer to as the induction of glucose competence. The glucose competence concept may provide new insights into the etiology and treatment of non-insulin-dependent diabetes mellitus (Type II diabetes).
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PMID:Signal transduction crosstalk in the endocrine system: pancreatic beta-cells and the glucose competence concept. 145 7

Effects of cilostazol (OPC-13013, CAS 73963-72-1), a selective inhibitor of platelet cAMP-phosphodiesterase, on peripheral vascular disease in diabetes mellitus were studied. Cilostazol in a dose of 200 to 300 mg/d was administered to 5 diabetic patients with arteriosclerosis obliterans. Skin temperature of the finger and the toe, which reflects blood flow to the tissue, was selected as an objective index of cilostazol effects and measured by infra-red thermography at a constant temperature of 26 degrees C. Before administration, digital skin temperatures were low in 9 limbs of 5 patients. 200 mg/d of cilostazol significantly (p less than 0.001) increased the digital skin temperatures of 8 limbs, the increase (mean +/- SD) ranging from 29.9 +/- 1.4 degrees C to 33.2 degrees C +/- 1.2 degrees C for the average skin temperatures and from 28.7 +/- 2.1 degrees C to 33.1 +/- 1.5 degrees C for the lowest ones. An increase in the dose to 300 mg/d resulted in further elevation of skin temperatures of the digits. Cilostazol constantly elicited an increase in blood flow to the digits within the range of its therapeutic dose. This effect was observed about 1 month after initiation of administration and persisted while administration was continued. The measurement of digital skin temperatures by infrared thermography provided a noninvasive means to individualize the dosage of cilostazol and to monitor the cilostazol effect and patient complicance during long-term administration. It is concluded that cilostazol exerts a potent and steady vasodilatory effect on peripheral circulation in patients with diabetes mellitus.
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PMID:Effects of the anti-platelet agent cilostazol on peripheral vascular disease in patients with diabetes mellitus. 149 93

Glucagon-like peptide-I(7-37) [GLP-I(7-37)] is an intestinal peptide with potent insulinotropic activities on pancreatic beta-cells in vivo and in vitro. In earlier studies elevated concentrations GLP-I(7-37) inhibited insulin release and cAMP generation in beta-cells. We now show that the GLP-I(7-37) receptor in the glucose-responsive B-cell line HIT-T15 undergoes rapid and reversible homologous desensitization in response to supraphysiological concentrations of GLP-I(7-37). GLP-I(7-37) stimulated insulin release and cAMP generation in a glucose-dependent biphasic manner with a maximum stimulation at 10 nmol/liter. The first-phase insulin secretory response was reduced by 41% at doses of GLP-I(7-37) of 100 nmol/liter and higher. Preperifusion of B-cells with 100 nmol/liter GLP-I(7-37) for 5 or 10 min reduced a subsequent insulin secretory response to 10 nmol/liter GLP-I(7-37) after hormone washout and recovery periods of 10 min (52% and 55% reduction) or 30 min (33% reduction or full recovery). Preperifusion of HIT-T15 cells with 100 nmol/liter glucagon (10 min) or 100 nmol/liter gastric inhibitory peptide (GIP) (10 min) had no effect on the insulin secretory response to 10 nmol/liter GLP-(7-37). Prior exposure of cells to 100 nmol/liter GLP-(7-37) (10 min) did not alter the GIP-induced (10 nmol/liter) insulin release, but 100 nmol/liter GIP (10 min) reduced the insulin secretion during stimulation with 10 nmol/liter GIP by 56%. These data indicate that: 1) the GLP-I(7-37) receptor is subject to rapid and reversible homologous desensitization and, 2) the GLP-I(7-37) receptor on beta-cells is distinct from that of GIP. The recent finding of elevated GLP-I(7-36)amide levels in subjects with noninsulin-dependent diabetes suggest the possibility that a homologous desensitization of the GLP-I(7-37) receptor might contribute to the impaired insulin secretion in this disorder.
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PMID:Homologous desensitization of the insulinotropic glucagon-like peptide-I (7-37) receptor on insulinoma (HIT-T15) cells. 164 53

Hepatic glucose production is stimulated in vitro twice as effectively by pulsatile as by continuous glucagon, given equivalent time-averaged doses. Efficacy studies of pulsatile insulin have yielded conflicting results. In the rat hepatoma cell line H-4-II-E-C3, insulin rapidly (t1/2 15 min) inhibits transcription of the gene and lowers mRNA levels for the gluconeogenic enzyme. PEPCK via a receptor-mediated process. We attached H-4-II-E-C3 cells to Cytodex-3 microcarriers and used a perifusion column system to test whether pulsatile insulin is more or less effective than equivalent time-averaged doses of continuous insulin. PEPCK transcription was induced by inclusion of cAMP analogue 8-(4-chlorophenyl-thio)-cAMP (0.1 mM) and dexamethasone (0.5 microM) in the perifusion medium. Three columns were exposed either to continuous, pulsatile, or no insulin. After 3 h, total nucleic acid was extracted, and mRNA(PEPCK) was measured with a sensitive-solution hybridization assay. Continuous insulin inhibited PEPCK expression in a dose-dependent fashion with EC50 1 x 10(-11) M. Equivalent time-averaged amounts of insulin delivered as pulses achieved significant inhibition but less effectively than continuous insulin. The apparent EC50 for pulsatile insulin increased from 2 x 10(-11) M to 5 x 10(-11) M as the oscillatory period was raised from 5 to 20 min, respectively. These observations suggest that insulin-mediated inhibition of PEPCK gene transcription is diminished by a pulsatile mode of administration in marked contrast to the pulse enhancement demonstrated for glucagon-mediated hepatic glucose production.
Diabetes 1991 Aug
PMID:Insulin pulses less effective than continuous insulin in inhibiting PEPCK mRNA levels stimulated by cAMP and dexamethasone in perifused hepatoma cells. 165 Mar 13

The study was performed to determine whether the regulation of mononuclear leukocyte beta-adrenergic receptors and responses was changed in insulin-dependent diabetes mellitus (IDDM). The concentrations of noradrenaline, the beta-adrenoceptor densities, basal cAMP levels and maximal isoprenaline-induced cAMP responses were the same in the diabetic and healthy subjects. After isoprenaline-promoted receptor internalization and uncoupling, the receptor densities and the responsiveness did not differ. In the control group, a highly significant correlation existed between the number of beta-adrenoceptors and maximal isoprenaline responses, before (r = 0.99, p less than 0.01) and after (r = 0.96, p less than 0.01) receptor internalization and uncoupling. This correlation between receptor densities and responses was not present in the IDDM group, which also showed elevated levels of plasma adrenaline. This study demonstrates that IDDM subjects have an unaltered mechanism of agonist-promoted beta-adrenoceptor internalization, but indicates a partial dysfunction of the beta-adrenoceptor-coupling to adenylate cyclase.
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PMID:Beta-adrenoceptor regulation in insulin-dependent diabetes mellitus. 165 86

The early alterations of G-protein-dependent transductional mechanisms have been characterized in the retina of alloxan-treated diabetic rats. Five weeks after alloxan injection, pertussis toxin radiolabeling of Gi/Go proteins was markedly reduced in the retina of diabetic animals, suggesting either a reduced expression and/or the presence of some structural modification of these G-protein subtypes. The functional activity of Gs proteins, measured as stimulation of membrane adenylate cyclase by dopamine, did not seem to be impaired at this stage of the pathology; basal adenylate cyclase activity was indeed increased in diabetic rats, consistent with the observed reduction of Gi/Go inhibitory proteins. Such functional alterations of the cAMP producing system were causally related to diabetes induction, since they were reversed by treatment of diabetic animals with insulin. These results suggest that G-protein dependent transduction mechanisms are altered in the retina of diabetic animals, and that a defect of Gi/Go proteins could represent an early transductional damage in the development of diabetic retinopathy.
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PMID:Early alterations of Gi/Go protein-dependent transductional processes in the retina of diabetic animals. 165 57


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