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

Intracellular production of nitric oxide (NO) is thought to mediate the pancreatic B-cell-directed cytotoxicity of cytokines in insulin-dependent diabetes mellitus, and recent evidence has indicated that this may involve induction of apoptosis. A primary effect of NO is to activate soluble guanylyl cyclase leading to increased cGMP levels and this effect has been demonstrated in pancreatic B-cells, although no intracellular function has been defined for islet cGMP. Here we demonstrate that the NO donor, GSNO, induces apoptosis in the pancreatic B-cell line HIT-T15 in a dose- and time-dependent manner. This response was significantly attenuated by micromolar concentrations of a specific inhibitor of soluble guanylyl cyclase, ODQ, and both 8-bromo cGMP (100 microM) and dibutyryl cGMP (300 microM) were able to fully relieve this inhibition. In addition, incubation of HIT-T15 cells with each cGMP analogue directly promoted cell death in the absence of ODQ. KT5823, a potent and highly selective inhibitor of cGMP-dependent protein kinase (PKG), abolished the induction of cell death in HIT cells in response to either GSNO or cGMP analogues. This effect was dose-dependent over the concentration range of 10-250 nM. Overall, these data provide evidence that the activation of apoptosis in HIT-T15 cells by NO donors is secondary to a rise in cGMP and suggest that the pathway controlling cell death involves activation of PKG.
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PMID:Evidence for the involvement of cGMP and protein kinase G in nitric oxide-induced apoptosis in the pancreatic B-cell line, HIT-T15. 900 15

1. The properties of L-arginine transport have been characterized and correlated with cGMP production (index of nitric oxide (NO)) in whole gastric glands isolated from non-diabetic and alloxan-diabetic rabbits. 2. In non-diabetic and diabetic glands, transport of L-arginine was stereoselective, Na+ and pH independent and inhibited by other cationic amino acids. L-Arginine transport was slightly inhibited by L-leucine and L-phenylalanine, but unaffected by other neutral amino acids. 3. Diabetes enhanced the Vmax for saturable L-arginine transport from 10.7 +/- 1.0 to 17.7 +/- 0.5 pmol (mg protein)-1 s-1, with negligible changes in K(m). 4. Accumulation of the membrane potential-sensitive probe tetra[3H]phenylphosphonium (TPP+) was increased 2-fold in diabetic compared with non-diabetic gastric glands, suggesting a membrane hyperpolarization. 5. Basal intracellular cGMP levels were elevated 2-fold in diabetic gastric glands, and in non-diabetic glands histamine, vasoactive intestinal peptide, and bradykinin increased cGMP levels. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (100 microM) abolished basal cGMP accumulation. 6. Addition of extracellular L-arginine induced a concentration-dependent increase in cGMP levels in gastric glands isolated from non-diabetic rabbits, but had no effect on elevated cGMP levels in diabetic glands. 7. Insulin induced a rapid (5 min) concentration-dependent increase in cGMP levels in non-diabetic gastric glands, but reduced elevated cGMP levels in diabetic gastric glands. 8. The present study has identified a specific transport system for L-arginine in gastric glands which resembles the classical system y+. Our findings also provide the first direct evidence that diabetes increases the basal activity of system y+ and NO synthase in gastric glands. The differential modulation of L-arginine transport by insulin and L-arginine identified in non-diabetic and diabetic glands, may be of importance in protecting the gastric mucosa from injuries associated with diabetes.
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PMID:Diabetes and insulin-induced stimulation of L-arginine transport and nitric oxide synthesis in rabbit isolated gastric glands. 905 89

Culture of mesangial cells (MCs) in 5.6 vs. 30.0 mmol/l glucose for 3 weeks induced a sustained increase in protein kinase C (PKC) activity, transforming growth factor (TGF)-beta1 mRNA, bioactive TGF-beta, and collagen synthesis. Nitric oxide (NO), generated exogenously by the NO donor S-nitroso-N-acetyl, D,L-penicillamine (SNAP) or endogenously after the exposure of MC to interleukin-1beta (IL-1beta), suppressed bioactive TGF-beta in MCs cultured in 5.6 or 30.0 mmol/l glucose and suppressed or abolished increases in TGF-beta1 mRNA and collagen synthesis induced by high concentrations of glucose or phorbol 12,13-dibutyrate without altering values obtained with normal glucose concentrations. SNAP had a transient suppressive effect on PKC activity, which may explain at least in part some of the actions of SNAP. The selective inhibitor of PKC, bisindolylmaleimide (GFX), mimicked NO action. The ability of SNAP and IL-1beta to suppress TGF-beta and collagen synthesis was not mediated by cGMP, since the cGMP analog, 8-Br-PET-cGMP, did not mimic NO action and an antagonist of cGMP-dependent protein kinase, Rp-8-pCPT-cGMPs, did not prevent the inhibitory actions of SNAP. N-omega-L-arginine methyl ester (NMMA) increased TGF-beta in glomerular capillary endothelial cells (GCECs) and stimulated collagen synthesis by MC in a co-culture with GCECs. Captopril inhibited TGF-beta and collagen synthesis and increased cGMP in co-cultures of GCECs and MCs. These effects of captopril were abolished by NMMA, implying mediation by NO. Thus, endogenous NO produced by GCECs may modulate TGF-beta production by both GCECs and MCs and act to suppress matrix protein synthesis by MCs.
Diabetes 1997 Apr
PMID:Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells. 907 10

The secretory, metabolic, and signaling aspects of glucose/palmitate interaction on beta-cell function have been studied on rat islets. Palmitate potentiated the glucose-induced insulin response of perifused islets at suprathreshold (>3 mmol/l) sugar concentrations. This potentiating effect could be suppressed by 8-bromo-cGMP, which also blocks palmitate metabolism. Palmitate did not modify glucose utilization, but it slightly reduced glucose oxidation and concomitantly increased lactate production. The very low rate of palmitate oxidation (80-fold lower than that of 20 mmol/l glucose) might explain its lack of effect on glycolysis and hence that the glucose/fatty acid cycle is inoperative in islet cells. However, glucose determines the metabolic fate of exogenous palmitate, which is mainly diverted toward lipid synthesis at high sugar concentrations and might then generate lipid messengers for cell signaling. Palmitate did not increase glucose-induced production of inositol-1,4,5-trisphosphate, but it stimulated the translocation of protein kinase C activity from a cytosolic to a particulate fraction at 20 but not at 3 mmol/l glucose. This increased translocation was partially or completely blocked by hydroxycitrate or 8-bromo-cGMP, respectively, which are agents interfering with palmitate metabolism (inhibiting lipid synthesis). The metabolic interaction between glucose and palmitate might generate lipid messengers (diacylglycerol, phosphatidylserine) necessary for the activation of islet protein kinase C, which would in turn result in a potentiation of glucose-induced insulin secretion.
Diabetes 1997 Jul
PMID:Stimulation of islet protein kinase C translocation by palmitate requires metabolism of the fatty acid. 920 Jun 50

Glucose stimulation of pancreatic islets is characterized by an initial decline in intracellular Ca2+ concentration ([Ca2+]i) (phase 0), followed by an increase in peak [Ca2+]i (phase 1). The effect of atrial natriuretic peptide (ANP) and cyclic nucleotides on the glucose-induced phase 0 [Ca2+]i was investigated by Fura-2 fluorescent imaging in single beta-cells from isolated islets of rats maintained at 1.67 mmol/l glucose. ANP (1 nmol/l to 1 micromol/l) inhibited the glucose (8.2 mmol/l)-induced phase 0 [Ca2+], in a concentration-dependent manner. Forskolin, 8-bromo-cyclic AMP (8BrcAMP), and 8-bromo-cyclic guanosine monophosphate (8BrcGMP) also inhibited the glucose-induced phase 0 [Ca2+]i. The Ca2+ channel blocker, D 600, prevented the response to 8BrcAMP but not to ANP or 8BrcGMP on phase 0 [Ca2+]i. Thapsigargin (TG) also inhibited phase 0 [Ca2+]i by 90%. ANP, 8BrcGMP, and TG also reduced the time required for glucose to initiate the phase 1 increase in [Ca2+]i, and each of these agents potentiated the effect of glucose on peak [Ca2+]i. Furthermore, sarco(endo)-plasmic reticulum (Ca[2+] + Mg2+)-ATPase (SERCA) activity in RINm5F insulinoma cells was inhibited by 8BrcGMP and TG, but not 8BrcAMP. Thus, ANP and cGMP modulate [Ca2+]i regulation in pancreatic beta-cells perhaps through mechanisms involving changes in SERCA activity and Ca2+ influx.
Diabetes 1997 Aug
PMID:Atrial natriuretic peptide and cyclic nucleotides affect glucose-induced Ca2+ responses in single pancreatic islet beta-cells: correlation with (Ca[2+] + Mg2+)-ATPase activity. 923 56

Several studies showed a diminished production of the endothelium-derived relaxing factor nitric oxide (NO) in the early stage of atherosclerosis. The inhibition of NO-production seems to be mediated by lipoproteins, especially oxidized low-density lipoproteins (ox-LDL). There is some evidence, that the interactions of lipoproteins and NO are associated with the phospholipid fraction of lipoproteins. Since fatty acids have different atherogenic properties-depending on chain length, degree of saturation and steric configuration-, we investigated the effect of fatty acids on endothelial NO-production. Human umbilical vein endothelial cells were incubated with palmitic acid and stearic acid in different concentrations in culture medium enriched with serum albumin for five hours. After that, NO-production was stimulated by calcium-ionophore A23187. NO-production was determined by a bioassay method using RFL-6 cells followed by radioimmunological determination of cGMP. NO-production stimulated by calcium-ionophore A23187(100%) was decreased by palmitic acid (10, 50, 100 microM) to 79 +/- 12%; 63 +/- 10% and 53 +/- 14%. In contrast, incubation with stearic acid (10, 50 and 100 microM) had no effect on A23187-stimulated NO-production (94 +/- 11%; 93 +/- 11%; 104 +/- 15%). Thus, palmitic acid but not stearic acid dose-dependently inhibited NO-release by endothelial cells. These different actions parallel the differing atherogenic potential of the two fatty acids.
Exp Clin Endocrinol Diabetes 1997
PMID:Palmitic acid but not stearic acid inhibits NO-production in endothelial cells. 928 52

Arginine is a precursor amino acid for the synthesis of nitric oxide by nitric oxide synthase. A defect in arginine supply could regulate nitric oxide-mediated, endothelium-dependent relaxation. In this study, we evaluated the effect of supplementation with L-arginine given in vitro on both functional relaxation and cGMP generation in response to acetylcholine in the streptozotocin-induced diabetic rat aorta. The concentration of arginine in plasma and aortic tissue were both decreased by diabetes. Acute incubation in vitro with L-arginine augmented the impaired relaxation to acetylcholine in diabetic rings although not altering relaxation in control rings. L-Arginine also enhanced relaxation to acetylcholine in diabetic rings incubated in the presence of either indomethacin or tetraethylammonium to inhibit cyclooxygenase activity and potassium channel activity, respectively. Acetylcholine-stimulated cGMP generation (which was blocked by L-nitroarginine) was diminished in diabetic rings compared with control rings. L-Arginine restored cGMP in diabetic rings (with but not without endothelium) to levels similar to control rings. L-Arginine did not alter cGMP generated by nitroglycerin. Incubation with L-arginine had no effect on acetylcholine-stimulated cGMP generation in control rings (with and without endothelium). These data suggest a potential intracellular substrate deficiency in nitric oxide production by diabetic endothelium which can be overcome acutely in vitro by provision of substrate for nitric oxide synthase.
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PMID:Plasma and vascular tissue arginine are decreased in diabetes: acute arginine supplementation restores endothelium-dependent relaxation by augmenting cGMP production. 935 86

Previous studies have shown that nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO), is expressed in skeletal muscle. The aim of the present study was to test the hypothesis that NO can modulate glucose metabolism in slow- and fast-twitch skeletal muscles. Calcium-dependent NOS was detected in skeletal muscle, and the enzyme activity was greater in fast-type extensor digitorum longus (EDL) muscles than in slow-type soleus muscles. Both the neuronal-type (nNOS) and endothelial-type (eNOS) enzymes are expressed in resting skeletal muscles. However, nNOS protein was only detected in EDL muscles, whereas eNOS protein contents were comparable in soleus and EDL muscles. NOS expression in muscle cryosections (diaphorase histochemistry) was located in vascular endothelium and in muscle fibers, and the staining was greater in type IIb than in type I and IIa fibers. The macrophage-type inducible NOS (iNOS) was not detected in resting muscle, but endotoxin treatment induced its expression, concomitant with elevated NO production. iNOS induction was associated with impaired insulin-stimulated glucose uptake in isolated rat muscles. In vitro, NOS blockade with specific inhibitors did not affect basal or insulin-stimulated glucose transport in EDL or soleus muscles. In contrast, the NO donors GEA 5024 and sodium nitroprusside induced dose-dependent inhibition (up to 50%) of maximal insulin-stimulated glucose transport in both muscles with minor effects on basal uptake values. GEA 5024 also blunted insulin-stimulated glucose transport and amino acid uptake in cultured L6 muscle cells without affecting insulin binding to its receptor. On the other hand, the permeable cGMP analogue dibutyryl cGMP did not affect muscle glucose transport. These results strongly suggest that NO modulates insulin action in both slow- and fast-type skeletal muscles. This novel autocrine action of NO in muscle appears to be mediated by cGMP-independent pathways.
Diabetes 1997 Nov
PMID:Expression of nitric oxide synthase in skeletal muscle: a novel role for nitric oxide as a modulator of insulin action. 935 14

1. The obese fa/fa Zucker rat is a genetic model of obesity and insulin resistance which develops a number of metabolic and endocrine features of non-insulin-dependent diabetes, including hypertension, proteinuria and glomerular sclerosis. 2. We have investigated the urinary excretion of the metabolites of thromboxane (thromboxane B2) and prostacyclin (6-keto prostaglandin F1 alpha), and of endothelin and cyclic GMP as markers for changes in the balance of renal haemodynamic factors in the obese Zucker rat. 3. Obese fa/fa Zucker rats were hypertensive compared with their lean counterparts (161 +/- 3 and 138 +/- 3 mmHg respectively, P < 0.01); obese animals were also markedly proteinuric (16.7 +/- 6.7 versus 1.1 +/- 0.1 mg/ml) and albuminuric (8.3 +/- 2.9 versus 0.4 +/- 0.25 mg/ml) and excreted less creatinine than lean animals (all P < 0.01). Urinary excretion of endothelin was greater in obese rats (123 +/- 24 versus 62 +/- 10 pg/15 h, P < 0.05) as was the level of pre-proendothelin mRNA, but excretion of cyclic GMP was depressed (12.5 +/- 1.6 versus 27.2 +/- 3.1 nmol/ 15 h, P < 0.01). Histological examination of kidneys from obese animals showed evidence of focal glomerulosclerosis and cortical tubular damage. 4. These results show that increased urinary endothelin is associated with proteinuria and early stage nephropathy in this animal model of non-insulin-dependent diabetes mellitus. This finding, coupled with a decreased excretion of cyclic GMP, suggests that these increased renal vasoconstrictor/vasodilator forces might contribute to the renal functional changes in non-insulin-dependent diabetes mellitus.
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PMID:Elevated renal endothelin-I clearance and mRNA levels associated with albuminuria and nephropathy in non-insulin-dependent diabetes mellitus: studies in obese fa/fa Zucker rats. 949 94

Nitric oxide (NO) produced by platelet nitric oxide synthase (NOS) inhibits platelet activation by increased cytoplasmic cGMP levels. The aim of this study was to investigate platelet NOS activity in insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), which are characterized by enhanced platelet activation. HbA1c levels, platelet NOS and platelet membrane Na+/K+ ATPase activity were determined in 19 IDDM patients, 21 NIDDM patients and 31 healthy control subjects. NOS activity was measured by a spectrophotometric method based on NO-dependent oxidation of oxyhaemoglobin to met-haemoglobin. Na+/K+ ATPase activity was measured by the method of Kitao and Hattori. Both NOS and Na+/K+ ATPase activity were significantly reduced in diabetic subjects compared with control subjects. NOS showed a significant negative relation with HbA1c levels and a positive relation with Na+/K+ ATPase activity in diabetic patients. It is hypothesized that the decreased NOS activity might play a role in the pathogenesis of diabetic vascular complications.
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PMID:Decreased nitric oxide synthase activity in platelets from IDDM and NIDDM patients. 949 37


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