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 intracellular content of cyclic GMP (cGMP) is known to mediate the effects of various vasodilating substances on glomerular mesangial cells. However, little is known about the role of soluble guanylate cyclase (SGC) in these cells in diabetes. We, therefore, investigated the changes in SGC activity as well as the cGMP content in rat mesangial cells (MC) cultured under high glucose or hypertonic conditions. The following results were obtained. 1. Sodium nitroprusside (SNP) (10(-4) M, 10min.) increased cyclic GMP (cGMP) content in MC from 8.17 +/- 0.99 pmol/mg protein to 981.6 +/- 86.3. 2. SNP (10(-4) M) stimulated SGC activity from 38.3 +/- 10.8 pmol cGMP formed/mg protein/10 minutes to 74.4 +/- 5.2. 3. In the coincubation experiment with bovine aortic endothelial cells, bradykinin (10(-6) M, 10min.) increased cGMP content in MC from 6.24 +/- 1.35 to 348.3 +/- 45.3. However, 4. the activity of SGC and SNP-induced increase of cGMP were not influenced by culturing MC in high glucose or hypertonic media. Similarly, the cGMP increase in MC coincubated with BAEC under bradykinin stimulation was not altered by culturing under high glucose or hypertonic conditions. These data suggested that SGC may play an important role in the regulation of cGMP content in MC. However, this enzyme may not be involved in the increase of cGMP content in MC cultured under high glucose condition.
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PMID:[Effect of glucose on soluble guanylate cyclase in cultured rat mesangial cells]. 810 Feb 85

Atrial natriuretic peptide (ANP) infusion increases hematocrit and decreases plasma volume by inducing a transfer of plasma fluid from the vascular to the interstitial compartment. Diabetes mellitus is associated with resistance to the renal actions of ANP. We explored the possibility that the extrarenal responses to ANP may also be altered in the diabetic state by measuring changes in arterial pressure and hematocrit during infusion of ANP (1 microgram.kg-1 x min-1 for 45 min) into anesthetized, acutely nephrectomized rats 2-3 wk after induction of diabetes from intravenous streptozotocin (STZ) injection (60 mg/kg). Blood glucose was significantly elevated in diabetic rats when compared with control and insulin-treated diabetic rats. Arterial pressure during ANP infusion decreased similarly in control; diabetic, and insulin-treated diabetic rats (by 7.6 +/- 1.6, 9.6 +/- 1.9, and 8.2 +/- 2% respectively; all P < 0.002). In control rats, hematocrit increased progressively to a maximum value of 9.5 +/- 0.9% as a result of the infusion, corresponding to a decrease in plasma volume of 16.3 +/- 1.3%. In contrast, the ANP-induced increase in hematocrit was markedly blunted in diabetic rats (1.6 +/- 0.8%; P < 0.0001 vs. ANP infusion in control rats). Reducing the hyperglycemia in diabetic rats by insulin therapy restored the increase in hematocrit in response to ANP (8.5 +/- 1.1%; P < 0.0001 vs. ANP infusion in diabetic rats and P = NS vs. control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate (cGMP) was significantly less in diabetic as compared with control and insulin-treated diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Blunted effect of ANP on hematocrit and plasma volume in streptozotocin-induced diabetes mellitus in rats. 814 19

To test the hypothesis that the function of glomerular mesangial cells is impaired in diabetes, we examined the responsiveness of mesangial cells cultured under high concentrations of glucose to atrial natriuretic peptide (ANP1) and angiotensin II (Ang II). The ANP-induced accumulation of cGMP was enhanced in mesangial cells cultured under high glucose conditions, possibly due to the activation of particulate guanylate cyclase. Ang II action in mesangial cells was evaluated by measuring the ability of Ang II to inhibit ANP-induced cGMP accumulation through both activating phosphodiesterase (initial phase) and inhibiting guanylate cyclase (maintenance phase). The inhibition of both ANP-induced cellular cGMP accumulation and particulate guanylate cyclase activity by Ang II was significantly reduced in mesangial cells cultured under high concentrations of glucose. Moreover, in the cells exposed to high concentrations of glucose, both basal and Ang II-stimulated levels of inositol 1,4,5-trisphosphate (IP3) were significantly reduced. These results indicate that, in high glucose conditions, the actions of ANP and Ang II are modulated differently, resulting in the impairment of contractile responsiveness of mesangial cells.
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PMID:Alteration of mesangial response to ANP and angiotensin II by glucose. 823 Oct 24

Protein kinase C (PKC) is activated in rat renal glomerulus within a week of induction of experimental diabetes. Studies in isolated glomeruli and in cultured endothelial and mesangial cells have demonstrated that high ambient concentrations of glucose activate PKC and thus implicate hyperglycemia per se as a mediator of PKC activation in glomerular cells in diabetes. High glucose concentrations activate PKC by increasing cellular levels of diacylglycerol (DAG), the major endogenous modulator of this signalling system. In contrast to physiological extracellular stimuli of PKC that increase cellular DAG levels by receptor-mediated enhancement of membrane inositol phospholipid hydrolysis, in glomerular cells high concentrations of glucose increase DAG by de novo synthesis from glycolytic intermediates. Activation of PKC by glucose or other agonists increases the permeability of endothelial cells to albumin and stimulates matrix protein synthesis in mesangial cells; it thereby may be involved in the pathogenesis of both the functional and structural alterations of the glomerulus in diabetes. Recent studies in isolated glomeruli from diabetic rats have also implicated activation of PKC in suppression of nitric oxide (NO)-mediated increases in glomerular cGMP generation in response to cholinergic stimuli. In mesangial cells, cGMP suppresses PKC-mediated increases in matrix protein synthesis. Thus, impaired NO-mediated cGMP generation in glomeruli of diabetic individuals may amplify matrix protein synthesis in response to hyperglycemia and other stimuli of PKC. These and other observations suggest that activation of the PKC system by hyperglycemia may represent an important pathway by which glucotoxicity is transduced in susceptible cells in diabetes.
Diabetes 1994 Jan
PMID:Activation of protein kinase C in glomerular cells in diabetes. Mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. 826 6

The effect(s) of L-arginine administration on the renal function of rats with untreated diabetes mellitus was examined. Rats received streptozotocin (N = 11) or vehicle (N = 12): Group 1 (normal rats, N = 6) drank tap water; Group 2 (normal rats, N = 6) drank tap water containing 1% L-arginine; Group 3 (diabetic rats, N = 5) drank tap water; and Group 4 (diabetic rats, N = 6) drank tap water with 1% L-arginine. Rats were fed a standard rat chow diet (22.8% protein, 142% L-arginine) with free access to food and water for 14 wk. Diabetic rats gained less weight, had significantly lower plasma levels of albumin and L-arginine, and had greater values for 24-h urine volumes and urine excretion of glucose, protein, urea, creatinine, nitrate, and nitrite than control rats. Diabetic rats given L-arginine (Group 4) had significantly lower protein and cGMP excretion in the urine than did rats of Group 3. The administration of L-arginine did not affect the plasma levels of glucose or L-arginine in Groups 2 or 4 compared with those of their respective controls. Group 3 had significantly higher values for GFR than did the other three groups of rats, but values for effective RPF, mean arterial pressure, hematocrit, and renal vascular resistance were not significantly different between Groups 3 and 4. There was no significant difference in glomerular morphology among the four groups of rats as determined by light microscopy, and both groups of diabetic rats exhibited the Armanni-Ebstein lesion in their tubules.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:L-arginine administration prevents glomerular hyperfiltration and decreases proteinuria in diabetic rats. 828 12

Cytokines have been implicated as immunological effector molecules that mediate beta cell destruction associated with insulin-dependent diabetes mellitus. In this report we demonstrate that the cytokine combination of human recombinant interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) induces the formation of nitric oxide by human islets. This combination of cytokines stimulates both the formation of the nitric oxide derivative, nitrite, and the accumulation of cGMP by human islets. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine prevents formation of both cGMP and nitrite. IL-1 beta and IFN-gamma are sufficient to induce nitric oxide formation by human islets, whereas TNF-alpha potentiates nitrite production. This combination of cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) also influences insulin secretion by human islets. Pretreatment of human islets with low concentrations of this cytokine combination (IL-1 beta at 15 units/ml, 0.7 nM TNF-alpha, and IFN-gamma at 150 units/ml) appears to slightly stimulate insulin secretion. Higher concentrations (IL-1 beta at 75 units/ml, 3.5 nM TNF-alpha, and IFN-gamma at 750 units/ml) inhibit insulin secretion from human islets, and the inhibitory effect is prevented by NG-monomethyl-L-arginine. This higher concentration of cytokines also induces the formation of an electron paramagnetic resonance-detectable g = 2.04 axial feature by human islets that is characteristic of the formation of an iron-dithio-dinitrosyl complex. The formation of this complex is prevented by NG-monomethyl-L-arginine, thus confirming that this cytokine combination induces the formation of nitric oxide by human islets. These results indicate that nitric oxide mediates the inhibitory effects of cytokines on glucose-stimulated insulin secretion by human islets and suggest that nitric oxide may participate in beta-cell dysfunction associated with insulin-dependent diabetes mellitus.
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PMID:Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. 838 25

Because diabetes is associated with impaired vascular endothelium, we have investigated endothelium-dependent cGMP stimulation in isolated glomeruli and renal vasodilation in normal and diabetes mellitus (DM) rats. Rats treated with streptozotocin (60 mg/kg iv) developed high blood glucose, polyuria, enlarged kidneys, and slow weight gain compared with control animals. Chronic treatment with insulin reversed these changes. In isolated glomeruli, the endothelium-dependent vasodilator, acetylcholine (ACh), stimulated cGMP accumulation concentration dependently; however, the response was significantly attenuated in glomeruli from DM rats when compared with normal rats or DM rats treated with insulin. Sodium nitroprusside-induced cGMP accumulation was also slightly but significantly reduced in glomeruli from DM rats, however, the response to atriopeptin III was unaltered. In rats, intravenous infusion of ACh (1 and 10 micrograms.kg-1.min-1) moderately decreased blood pressure and increased renal blood flow without a significant change in glomerular filtration rate. The renal vasodilatory response to ACh was significantly diminished in DM rats, but not in DM rats treated with insulin. Acute treatment with insulin did not restore the ACh response, although the blood glucose level was normalized. We conclude that there is a reduced renal vasodilatory response observed in DM, and this is due to an impairment of the renal vascular endothelium to produce endothelium-dependent relaxation factor (nitric oxide) and/or a defective soluble guanylate cyclase.
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PMID:Attenuated glomerular cGMP production and renal vasodilation in streptozotocin-induced diabetic rats. 838 64

The short-term effects of elevated glucose on cyclic GMP (cGMP) and eicosanoid production in pig aortic endothelial cell monolayers was determined by incubating cells in 5.5 mM or 44 mM glucose for 6 hours. Bradykinin- or A23187-stimulated cGMP production was significantly reduced in cells incubated in 44 mM glucose compared with 5.5 mM glucose. Stimulation of cGMP levels with exogenously added nitric oxide (NO) was also decreased to a similar extent in cells exposed to 44 mM glucose. These data suggest that NO production stimulated by bradykinin or A23187 was unchanged by elevated glucose. Assayed eicosanoids, including 6-ketoprostaglandin (PG) F1 alpha, PGE2 alpha, and 15(S)-hydroxy-(5Z, 8Z, 11Z, 13E)-eicosatetraenoic acid, stimulated by bradykinin or A23187, were increased in cells exposed to 44 mM glucose. These eicosanoid products formed from exogenously added arachidonic acid did not differ between cells incubated in 5.5 mM or 44 mM glucose. Hyperosmolar concentrations of mannose or sucrose had no effect on cGMP levels but did mimic the effect of elevated glucose on eicosanoid production. These data suggest that hyperglycemia in diabetes may interfere with NO-induced guanylate cyclase activation but not NO production in the endothelium and that increased phospholipase activity, secondary to hyperosmolarity, may account for elevated eicosanoid levels.
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PMID:Effect of elevated glucose on cyclic GMP and eicosanoids produced by porcine aortic endothelium. 838 14

To evaluate the possible contribution of atrial natriuretic peptide (ANP) to the development of glomerular hyperfiltration, we examined the effect of non-peptide competitive antagonist for biological receptors of ANP, HS-142-1, on glomerular filtration rate (GFR) and renal plasma flow (RPF) in diabetic rats. Increased GFR and RPF in diabetic rats were significantly ameliorated by the injection of HS-142-1, while blood pressure remained unchanged. Urinary cyclic GMP excretion was significantly higher in diabetic rats than in control rats and HS-142-1 decreased urinary cGMP excretion significantly. These results indicate that atrial natriuretic peptide contributes to the development of glomerular hyperfiltration and hyperperfusion in diabetes and HS-142-1 might be useful in the treatment of them.
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PMID:Antagonist for atrial natriuretic peptide receptors ameliorates glomerular hyperfiltration in diabetic rats. 839 Feb 51

The influence of diabetes on the function of vascular endothelium was examined with respect to the role of nitric oxide (NO) in the regulation of blood pressure (BP) in vivo, the vascular relaxation, and levels of cAMP and cGMP in the effluent of the perfused mesenteric arterial bed from streptozotocin-induced diabetic rats. An intravenous injection of 100 mg/kg N omega-nitro-L-arginine methylester (L-NAME) caused hypertension in both diabetic rats and controls. However, the degree of hypertension in the diabetic rats was significantly lower than that in the controls. Acetylcholine (ACh)-induced vasorelaxation of the perfused mesenteric arterial bed decreased in diabetic rats. At the same time, the levels of cAMP and cGMP in the effluent of the diabetic rats were also lower than in the controls. These data indicate that NO formation is involved in the regulation of BP in rats, and is decreased in diabetic rats, due to an impairment of the vascular endothelium, including the endothelium of resistance vessels.
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PMID:Changes in endothelium-dependent relaxation and levels of cyclic nucleotides in the perfused mesenteric arterial bed from streptozotocin-induced diabetic rats. 839 May 94


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