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)

Effect of tolbutamide on liver fructose-2,6-bisphosphate (F-2,6-P2) was examined in isolated perfused rat liver in situ with a flow-through method. Tolbutamide (1 mM) gradually increased liver F-2,6-P2 level from 7.4 +/- 1.6 to 21.2 +/- 1.6 pmol/mg wet wt for 20 min perfusion. The increase of liver F-2,6-P2 induced by tolbutamide was dose dependent and was significantly observed at 10 min perfusion. The maximum plateau level of F-2,6-P2 induced by 16.7 mM glucose was further increased with 1 mM tolbutamide. Glucagon (10(-11) M) decreased the elevated level induced by 16.7 mM glucose, but this effect was completely inhibited with 2 mM tolbutamide. Cyclic AMP level of the liver throughout the perfusion with tolbutamide did not change. Carboxytolbutamide or gliclazide perfusion did not change significantly the liver F-2,6-P2 level; however, the results suggest that tolbutamide may increase the liver F-2,6-P2 level by affecting the phosphorylation state of fructose-6-phosphate, 2-kinase/fructose-2,6-bisphosphatase through cyclic AMP-dependent protein kinase, resulting in the stimulation of glycolysis and the inhibition of gluconeogenesis in the liver. Thus, the extrapancreatic action and the mechanism of action of different sulfonylureas may differ.
Diabetes 1984 May
PMID:Tolbutamide stimulates fructose-2, 6-bisphosphate formation in perfused rat liver. 654 2

The effects of epinephrine, vasopressin, and A23187 on glycogen synthase and phosphorylase were examined in isolated rat liver parenchymal cells from fed animals. In normal calcium-containing hepatocytes, epinephrine, vasopressin, and A23187 were more potent at inactivating glycogen synthase, previously activated with 30 mM glucose, than at activating phosphorylase. In calcium-depleted hepatocytes (cells washed and incubated with 1 mM EGTA), the effect of epinephrine on both enzyme activities was impaired, while the effects of vasopressin and A23187 were completely abolished. Insulin was more effective at inhibiting the effects of epinephrine in calcium-depleted cells, but it was without effect on vasopressin and A23187 actions. The ability of epinephrine, vasopressin, and A23187 to elicit calcium efflux from cells was not altered by the presence of 30 mM glucose. These findings are consistent with the idea that the alpha-adrenergic inactivation of liver glycogen synthase may be a result of the increased stimulation of a calcium-dependent protein kinase, possibly phosphorylase b kinase.
Diabetes 1980 Aug
PMID:The role of calcium in alpha-adrenergic inactivation of glycogen synthase in rat hepatocytes and its inhibition by insulin. 677 24

The rat insulinoma beta-cell line RINm5F, which shares some homology with pancreatic islets, was used to study nitric oxide synthase induction. Nitric oxide is involved during beta-cell destruction and possibly in propagation of insulin-dependent diabetes mellitus. The cytokine interleukin-1 (IL-1) turned out to be the ultimate inducer, whereas tumour necrosis factor-alpha (TNF) and unexpectedly the phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate; 10 nM) synergistically promoted nitrite accumulation. Besides employing TPA directly, the synergistic effect of TNF could be traced back to protein kinase C activation since protein kinase C inhibitors (IC50 value for staurosporine: 4 nM) potently suppressed nitrite production in the case of IL-1/TNF administration. Further experiments using anti-TNF antibodies aimed to an autocrine loop following IL-1 addition to RINm5F cells, possibly involved in nitrite generation. Moreover, the nitric oxide synthase inductive IL-1 signal was antagonized by lipophilic cAMP analogues. Our results for nitrite accumulation in RINm5F cells point to activating protein kinase C and inhibitory protein kinase A signalling pathways.
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PMID:Modulation of inducible nitric oxide synthase in RINm5F cells. 751 91

(1) Glucagon activates hepatic glutaminase in vivo. Mitochondria from glucagon-injected rats retain an enhanced capacity to catabolize glutamine and this is more sensitive to activation by inorganic phosphate. The glucagon-elicited stimulation of glutaminase is not evident in broken mitochondria. A similar activation of glutaminase occurs in a number of situations which are associated with elevated glucagon levels in vivo, i.e., after a high-protein meal, after injection of bacterial endotoxin and in diabetes mellitus. (2) Studies in isolated hepatocytes revealed that glutaminase could be activated, not only by glucagon, but also by a cell-permeable protein kinase A activator (Sp-cAMPS) and by a cell-permeable protein phosphatase 1 and 2A inhibitor (okadaic acid). However, the activation of glutaminase by glucagon was not inhibited by a cell-permeable protein kinase A inhibitor (Rp-8-Br-cAMPS). We suggest that the signalling pathway, for glutaminase activation by glucagon, is complex and possibly contains redundant elements.
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PMID:Hormonal control of hepatic glutaminase. 757 40

The effect of oral administration of sodium selenite on glucose homoeostasis was studied in male Swiss albino mice 6 weeks after they were made diabetic with streptozotocin. Diabetes caused hyperglycaemia (2.5-fold), a marked decrease (4.5-fold) in liver glycogen, a 4-fold increase in the glucose-6-phosphatase activity and significant decrease in plasma insulin levels and protein kinase activity. Although selenium administration in control animals showed no significant effect on various parameters measured, selenite treatment of diabetic mice restored these parameters to near control values. Thus the results show insulin-like in vivo action of selenium in diabetic mice.
Diabetes Res 1994
PMID:A novel effect of selenium on streptozotocin-induced diabetic mice. 764 87

Disruption in transfer of regulatory signal from insulin and EGF receptors in liver plasma membrane of rats, their 3 generation being kept in the Chernobyl accident 30-km zone has been found. As in case with imbalance in hormone binding and receptor phosphorylation of insulin receptors in experimental diabetes mellitus, an increasing of insulin and EGF binding by appropriate receptors with simultaneous decrease of its protein kinase activity after ligand binding was shown in rats chronically irradiated in the 30-km accident zone.
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PMID:[Protein phosphorylation and activity of insulin and epidermal growth factor receptors in liver plasma membranes of rats kept in the zone of the accident at the Chernobyl nuclear power station]. 774 44

In the insulin-secreting beta-cell line beta TC3, stimulation with 11.2 mmol/l glucose caused a rise in the intracellular free Ca2+ concentration ([Ca2+]i) in only 18% of the tested cells. The number of glucose-responsive cells increased after pretreatment of the cells with glucagon-like peptide I (GLP-I)(7-36)amide and at 10(-11) mol/l; 84% of the cells responded to glucose with a rise in [Ca2+]i. GLP-I(7-36)amide induces a rapid increase in [Ca2+]i only in cells exposed to elevated glucose concentrations (> or = 5.6 mmol/l). The action of GLP-I(7-36)amide and forskolin involved a 10-fold increase in cytoplasmic cAMP concentration and was mediated by activation of protein kinase A. It was not associated with an effect on the membrane potential but required some (small) initial entry of Ca2+ through voltage-dependent L-type Ca2+ channels, which then produced a further increase in [Ca2+]i by mobilization from intracellular stores. The latter effect reflected Ca(2+)-induced Ca2+ release and was blocked by ryanodine. Similar increases in [Ca2+]i were also observed in voltage-clamped cells, although there was neither activation of a background (Ca(2+)-permeable) inward current nor enhancement of the voltage-dependent L-type Ca2+ current. These observations are consistent with GLP-I(7-36) amide inducing glucose sensitivity by promoting mobilization of Ca2+ from intracellular stores. We propose that this novel action of GLP-I(7-36)amide represents an important factor contributing to its insulinotropic action.
Diabetes 1995 Jul
PMID:Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting beta TC3-cells by enhancement of intracellular calcium mobilization. 778 44

We have recently identified a new member of the Ras/GTPase superfamily termed Rad which has unique sequence features and is overexpressed in the skeletal muscle of humans with type II diabetes (Reynet, C., and Kahn, C. R. (1993) Science, 262, 1441-1444). When expressed in bacteria as a glutathione S-transferase fusion protein, Rad bound [alpha-32P]GTP quickly and saturably. Binding was specific for guanine nucleotides and displayed unique magnesium dependence such that both GTP and GDP binding were optimal at relatively high Mg2+ concentrations (1-10 mM). Rad had low intrinsic GTPase activity which was greatly enhanced by a GTPase-activating protein (GAP) activity present in various tissues and cell lines. Several known GAPs had no stimulatory effect toward Rad. Conversion of Ser to Asn at position 66 in Rad (equivalent to position 12 in Ras) resulted in a total loss of GTP binding. Mutation of Pro61 (equivalent to Gly12 in Ras) or Gln109 (equivalent to Gln61 in Ras) had no effect on Rad GTPase activity, whereas creation of a double mutation at these positions resulted in exceptionally high intrinsic GTPase activity. In vitro, Rad was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PK). Phosphopeptide mapping indicated two PKA phosphorylation sites near the COOH terminus. Rad also co-precipitated a serine/threonine kinase activity from extracts of various tissues and cell lines which catalyzed phosphorylation on Rad but was not inhibited by PKA inhibitor. Thus, Rad is a GTP-binding protein and a GTPase which has some structure/function similarities to Ras, but displays unique features. Rad may also be phosphorylated on serine/threonine residues by PKA and other kinases, as well as regulated by its own GAP which is present in many tissues and cell types.
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PMID:Characterization of Rad, a new member of Ras/GTPase superfamily, and its regulation by a unique GTPase-activating protein (GAP)-like activity. 787 54

1. We have previously demonstrated that although rats with streptozotocin-induced diabetes (STZ-D) have decreased behavioral mechanical nociceptive thresholds (hyperalgesia), their C-fiber primary afferent mechanical (von Frey hair) thresholds are not altered. Instead, when stimulated with a standardized sustained suprathreshold mechanical stimulus, C-fibers from STZ-D rats were found to have an increased number of spikes (hyperexcitability). We suggested that this C-fiber hyperexcitability contributes to the behavioral hyperalgesia and that agents that reverse the hyperalgesia may act by decreasing this hyperexcitability. Because protein kinase C activity contributes to C-fiber afferent excitability, we examined the effect of agents that inhibit protein kinases on behavioral mechanical nociceptive thresholds and on the response of C-fiber afferents to sustained mechanical stimulation. 2. The effects of intradermal injection of two protein kinase inhibitors, staurosporine and protein kinase C pseudosubstrate inhibitor peptide [PKC(19-36)], on behavioral mechanical nociceptive thresholds were determined using the Randall-Selitto paw-withdrawal device. These agents increased the mechanical nociceptive threshold of STZ-D rats in a dose-dependent manner but did not alter nociceptive threshold in control rats. 3. The same agents were tested for their effects on single C-fiber mechanical thresholds and excitability in response to suprathreshold (445 g) mechanical stimulation. Intradermal injection of staurosporine or PKC(19-36) significantly reduced the response of C-fibers from STZ-D rats to sustained suprathreshold mechanical stimulation but did not alter the response of C-fibers from control rats to the same stimulation. Neither agent altered mechanical threshold in C-fibers from either STZ-D or control rats. 4. In this study we found that both the mechanical behavioral hyperalgesia and the C-fiber hyperexcitability to mechanical stimuli seen in STZ-D rats are reduced by agents that inhibit protein kinase C. This evidence supports our hypothesis that C-fiber hyperexcitability, in part mediated by PKC activity, contributes to hyperalgesia in this model of diabetic neuropathy.
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PMID:Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat. 798 28

We investigated the dose-dependent effects of prostaglandin E1 (PGE1) analogue, OP1206.alpha CD (OP), on motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and Na(+)-K(+)-ATPase (ATPase) activity in streptozocin-induced diabetic rats. At 10 micrograms/kg/day, OP ameliorated MNCV and NBF, but no ATPase activity, whereas at 30 micrograms/kg/day it increased MNCV and ATPase activity, but not NBF. These results suggested a possible direct metabolic effect of OP, at least at a certain dose, on ATPase activity independent of NBF. Since PGE1 exerts an effect on nerve cAMP content, we conducted an in vitro study to clarify the relationship of cAMP to the modulation of ATPase activity in diabetic nerves. We studied sciatic nerves isolated from 53 rats with streptozocin-induced diabetes that had exhibited hyperglycemia for 6 wk. OP increased the activity of ATPase and the accumulation of cAMP in a dose-dependent manner. Dibutyryl cAMP, a cAMP analogue, and aminophyline, which increases nerve cAMP content, enhanced ATPase activity in a dose-dependent manner. In addition, the increased activity of ATPase in diabetic nerves produced by OP was suppressed by a protein kinase inhibitor, H8. These results suggest that ATPase activity in diabetic nerves might be regulated or modified by cAMP and, possibly, by protein kinase A, a finding that is important for clarifying the pathogenesis of diabetic neuropathy and for developing new approaches to treatment.
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PMID:Metabolic effect of PGE1 analogue 01206.alpha CD on nerve Na(+)-K(+)-ATPase activity of rats with streptozocin-induced diabetes is mediated via cAMP: possible role of cAMP in diabetic neuropathy. 806 85


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