Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased aggregation of platelets might contribute to the development of vascular complication in diabetes mellitus. In this study release of superoxide anions, intracellular Ca2+ signalling and nitric oxide formation stimulated by the receptor-dependent agonist adenosine 5 '-diphosphate (ADP) and the receptor-independent stimulus thapsigargin, were compared in platelets isolated from patients with Type II (non-insulin-dependent) diabetes mellitus and healthy control subjects. Diabetes augmented intracellular Ca2+ release and Ca2+ entry to ADP by 40 and 44% (control subjects: n = 11; diabetic: n = 6), while the median effective concentration (EC50) of ADP to initiate Ca2+ signalling was similar in both groups. The effect of thapsigargin on Ca2+ concentration was increased by 69% in diabetic patients (control subjects: n = 22; diabetic patients: n = 9). In addition, release of superoxide anions was 70% greater in diabetic patients (control subjects: n = 9; diabetic patients: n = 6). Treatment of platelets from control subjects with the superoxide anion-generating mixture xanthine oxidase and hypoxanthine or buthioninesulphoximine (BSO) mimicked the effect of diabetes on platelet Ca2+ signalling. The antioxidant glutathione normalized enhanced Ca2+ response in the diabetic group (control subjects: n = 5: diabetic patients: n = 6). Basal and thapsigargin-evoked nitric oxide synthase activity was reduced in the diabetic group by 85 and 64%, respectively (control subjects: n = 13; diabetic subjects: n = 13). The nitric oxide-donor 2-(N,N-diethylamino)-diazenolate-2-oxide sodium (DEA/NO) normalized enhanced Ca2+ signalling in platelets preincubated with xanthine oxidase and hypoxanthine (n = 12) and in those from diabetics (control subjects: n = 6; diabetic patients: n = 6). Inhibition of nitric oxide synthase by N-nitro-L-arginine (L-NA) augmented thapsigargin-induced Ca2+ signalling by 51% (n = 8). These data indicate that in diabetes platelet Ca2+ signalling might be enhanced by excessive superoxide production and an attenuated negative direct or indirect feedback control by nitric oxide, due to its reduced production.
 ...
PMID:Alterations in platelet Ca2+ signalling in diabetic patients is due to increased formation of superoxide anions and reduced nitric oxide production. 1006 96

Insulin-mediated changes in blood flow are associated with altered blood flow distribution and increased capillary recruitment in skeletal muscle. Studies in perfused rat hindlimb have shown that muscle metabolism can be regulated by vasoactive agents that control blood flow distribution within the hindlimb. In the present study, the effects of a vasoconstrictive agent that has no direct effect on skeletal muscle metabolism but that alters perfusion distribution in rat hindlimb was investigated in vivo to determine its effects on insulin-mediated vascular action and glucose uptake. We measured the effects of alpha-methylserotonin (alpha-met5HT) on mean arterial blood pressure, heart rate, femoral blood flow, hindlimb vascular resistance, and glucose uptake in control and euglycemic insulin-clamped (10 mU x min(-1) x kg(-1)) anesthetized rats. Blood flow distribution within the hindlimb muscles was assessed by measuring the metabolism of 1-methylxanthine (1-MX), an exogenously added substrate for capillary xanthine oxidase. Alpha-met5HT (20 microg x min(-1) x kg(-1)) infusion alone increased mean arterial blood pressure by 25% and increased hindlimb vascular resistance but caused no change in femoral blood flow. These changes were associated with decreased hindlimb 1-MX metabolism indicating less capillary flow. Insulin infusion caused decreased hindlimb vascular resistance that was associated with increased femoral blood flow and 1-MX metabolism. Treatment with alpha-met5HT infusion commenced before insulin infusion prevented the increase in femoral blood flow and inhibited the stimulation of 1-MX metabolism. Alpha-met5HT infusion had no effect on hindlimb glucose uptake but markedly inhibited the insulin stimulation of glucose uptake (P < 0.05) and was associated with decreased glucose infusion rates to maintain euglycemia (P < 0.05). A significant correlation (P < 0.05) was observed between 1-MX metabolism and hindlimb glucose uptake but not between femoral blood flow and glucose uptake. The results indicate that in vivo, certain types of vasoconstriction in muscle such as elicited by 5HT2 agonists, which prevent normal insulin recruitment of capillary flow, cause impaired muscle glucose uptake. Moreover, if vasoconstriction of this kind results from stress-induced increase in sympathetic outflow, then this may provide a clue as to the link between hypertension and insulin resistance that is often observed in humans.
Diabetes 1999 Mar
PMID:Acute vasoconstriction-induced insulin resistance in rat muscle in vivo. 1007 57

Cytokine-induced damage may contribute to destruction of insulin-secreting beta-cells in islets of Langerhans during autoimmune diabetes. There is considerable controversy (i) whether human and rat islets respond differently to cytokines, (ii) the extent to which cytokine damage is mediated by induction of nitric oxide formation, and (iii) whether the effects of nitric oxide on islets can be distinguished from those of reactive oxygen species or peroxynitrite. We have analyzed rat and human islet responses in parallel, 48 h after exposure to the nitric oxide donor S-nitrosoglutathione, the mixed donor 3-morpholinosydnonimine, hypoxanthine/xanthine oxidase, peroxynitrite, and combined cytokines (interleukin-1beta, tumor necrosis factor-alpha and interferon-gamma). Insulin secretory response to glucose, insulin content, DNA strand breakage, and early-to-late stage apoptosis were recorded in each experiment. Rat islet insulin secretion was reduced by S-nitrosoglutathione or combined cytokines, but unexpectedly increased by peroxynitrite or hypoxanthine/xanthine oxidase. Effects on human islet insulin secretion were small; cytokines and S-nitrosoglutathione decreased insulin content. Both rat and human islets showed significant and similar levels of DNA damage following all treatments. Apoptosis in neonatal rat islets was increased by every treatment, but was at a low rate in adult rat or human islets and only achieved significance with cytokine treatment of human islets. All cytokine responses were blocked by an arginine analogue. We conclude: (i) Reactive oxygen species increased and nitric oxide decreased insulin secretory responsiveness in rat islets. (ii) Species differences lie mainly in responses to cytokines, applied at a lower dose and shorter time than in most studies of human islets. (iii) Cytokine effects were nitric oxide driven; neither reactive oxygen species nor peroxynitrite reproduced cytokine effects. (iv) Rat and human islets showed equal susceptibility to DNA damage. (v) Apoptosis was not the preferred death pathway in adult islets. (vi) We have found no evidence of human donor variation in the pattern of response to these treatments.
 ...
PMID:Insulin secretion, DNA damage, and apoptosis in human and rat islets of Langerhans following exposure to nitric oxide, peroxynitrite, and cytokines. 1034 86

Alterations of vascular smooth muscle function have been implicated in the development of vascular complications and circulatory dysfunction in diabetes. However, little is known about changes in smooth muscle contractility and the intracellular mechanisms contributing to altered responsiveness of blood vessels of diabetic patients. Therefore, smooth muscle and endothelial cell function were assessed in 20 patients with diabetes and compared with 41 age-matched control subjects. In rings from uterine arteries, smooth muscle sensitivity to K+, norepinephrine (NE), and phenylephrine (PE) was enhanced by 1.4-, 2.3-, and 9.7-fold, respectively, and endothelium-dependent relaxation was reduced by 64% in diabetic patients, as compared with control subjects. In addition, in freshly isolated smooth muscle cells from diabetic patients, an increased perinuclear Ca2+ signaling to K+ (30 mmol/l >73%; 60 mmol/l >68%) and NE (300 nmol/l >86%; 10 micromol/l >67%) was found. In contrast, subplasmalemmal Ca2+ response, which favors smooth muscle relaxation caused by activation of Ca2+-activated K+ channels, was reduced by 38% in diabetic patients as compared with control subjects, indicating a significant change in the subcellular Ca2+ distribution in vascular smooth muscle cells in diabetic patients. In contrast to the altered Ca2+ signaling found in freshly isolated cells from diabetic patients, in cultured smooth muscle cells isolated from control subjects and diabetic patients, no difference in the intracellular Ca2+ signaling to stimulation with either K+ or NE was found. Furthermore, production of superoxide anion (*O2-) in intact and endothelium-denuded arteries from diabetic patients was increased by 150 and 136%, respectively. Incubation of freshly isolated smooth muscle cells from control subjects with the *O2- -generating system xanthine oxidase/hypoxanthine mimicked the effect of diabetic patients on subcellular Ca2+ distribution in a superoxide dismutase-sensitive manner. We conclude that in diabetic subjects, smooth muscle reactivity is increased because of changes in subcellular Ca2+ distribution on cell activation. Increased *O2- production may play a crucial role in the alteration of smooth muscle function.
Diabetes 1999 Jun
PMID:Human diabetes is associated with hyperreactivity of vascular smooth muscle cells due to altered subcellular Ca2+ distribution. 1034 23

Reactive oxygen metabolites (ROMs) have been implicated in the pathogenesis of the inflammatory response to ischemia/reperfusion (I/R), which is exacerbated in diabetes. This study revealed an increased (P < 0.01) ROMs production in mesenteric tissue (measured using the oxidant-sensitive fluorochrome dihydrorhodamine 123) after I/R in control and diabetic rats, with larger increments (P <0.0001) observed in the latter group, that was associated with an increased inflammatory response measured by intravital microscopy. Either xanthine oxidase inhibition, superoxide scavenging, ICAM-1 immunoneutralization, or blockade of platelet-activating factor or leukotrienes effectively reduced leukocyte recruitment and ROMs production in control and diabetic rats. Moreover, neutrophils from diabetic rats showed an enhanced production of ROMs in vitro in basal and stimulated conditions. We conclude that the oxidative stress during reperfusion is markedly enhanced in diabetes and this appears to result from increased leukocyte recruitment and a higher capacity of diabetic leukocytes to generate ROMs in response to stimulation.
 ...
PMID:Reperfusion-induced oxidative stress in diabetes: cellular and enzymatic sources. 1041 Sep 90

The protective effect of taurine in model in vitro diabetic cataract and the mechanism of this effect were investigated in isolated rat lenses. Isolated rat lenses were incubated in medium 199 in elevated glucose (55.6 m m) with taurine (5 m m). Taurine concentrations in the lenses were determined by amino acid analysis. Accumulative leakage of the intracellular enzyme lactate dehydrogenase (LDH) was used to estimate damage to the lens, as previously reported. In the clear lenses, prior to vacuole formation, after 1 or 2 days of incubation, the taurine and amino acids in lenses decreased progressively in concentration. In lenses incubated with 5 m m taurine, the level of taurine was increased towards that of control lenses. In taurine-treated lenses LDH leakage was significantly decreased, and lens clarity was maintained, similarly to that found previously for vitamin C and lipoic acid. To test whether taurine has similar antioxidant activity, we tested its ability to decrease luminol luminescence generated by (1) superoxide from hypoxanthine/xanthine oxidase and (2) peroxide from diluted glucose/glucose oxidase. For either superoxide or peroxide, the luminescence was decreased to zero, as a function of increasing taurine concentration, at 30 m m, approximately the physiological concentration of taurine in the lens. Spin trapping confirmed that taurine scavenged superoxide. This is consistent with a role for taurine as an important antioxidant protecting the lens against oxidative insults. Amino acids also had antioxidant activity in this assay, and as a group, when all activities were summed, their loss also contributed significantly to the antioxidant loss. Taken in conjunction with Wolff and Crabbe's observation of increased free radical generation by glucose auto-oxidation in diabetes, this suggests a push-pull mechanism for increased oxidative stress in diabetic cataract, involving both increased free radicals and decreased radical scavenging antioxidants.
 ...
PMID:Modelling cortical cataractogenesis 22: is in vitro reduction of damage in model diabetic rat cataract by taurine due to its antioxidant activity? 1047 37

In a 62-year-old woman with non-insulin-dependent diabetes mellitus and Hashimoto's thyroiditis, hypouricemia was detected by a routine examination. Her plasma uric acid level was markedly low and urinary excretion of uric acid was undetectable. The high plasma and urine levels of xanthine were observed, although those of hypoxanthine were within normal ranges at rest after an overnight fast. After taking diet, plasma concentration and urinary excretion of hypoxanthine were markedly increased together with those of xanthine. The xanthine oxidase activity of duodenal mucosa was below the limits of detection. Allopurinol was metabolized to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide in spite of no activity of xanthine oxidase, suggesting that aldehyde oxidase converted allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide. Based on these findings, she was diagnosed as having a subtype of classical xanthinuria type 1 with the normal plasma concentration of hypoxanthine in fast.
 ...
PMID:A case of classical xanthinuria (type 1) with diabetes mellitus and Hashimoto's thyroiditis. 1048 35

Deletions of mitochondrial DNA (mtDNA) are associated with aging and several chronic diseases. We have reported heterogeneous mutations between base pair 8468 and 13446 in mtDNA, the region known as the "common" deletion, in muscle of older humans with impaired glucose tolerance or diabetes mellitus. To further characterize potential effects of age and glycemia on mtDNA integrity, we studied corpulent JCR:LA-cp rats that are characterized by insulin resistance, hyperinsulinemia, and hyperlipidemia, factors strongly associated with both aging and cardiovascular disease. In addition to skeletal muscle, we isolated vascular smooth muscle cells (VSMC) from aortas of 6-, 12-, and 17-month-old rats and exposed them to 5-, 25-, 62-, and 100-mM glucose or a combination of hypoxanthine (100 microM) and xanthine oxidase (0.025 U/ml) to generate reactive oxygen species in separate cultures. Long- and short-fragment and nested polymerase chain reaction was used to detect mutations in the common deletion region. The data demonstrate that aging and the cp genotype confer susceptibility to mtDNA deletions in vivo and that high glucose concentrations can induce mtDNA mutations in vitro. Accordingly, aging and glucose-related oxidative stress and possibly hyperinsulinemia may contribute to alterations in mitochondrial gene integrity and the cp genotype appears to increase the susceptibility of muscle to the age-related accumulation of mtDNA mutations.
 ...
PMID:Aging and high concentrations of glucose potentiate injury to mitochondrial DNA. 1064 38

The effects of alloxan diabetes and subsequent treatment with insulin on extra-mitochondrial oxygen metabolism in terms of D-amino acid oxidase (DAAO), xanthine oxidase and catalase were examined. The DAAO activity in the liver with D-alanine and D-serine decreased by 33-62% in the diabetic group while the decrease in the kidneys was 61-74%. Insulin treatment resulted in overstimulation of DAAO activity in the liver but not in the kidneys. Tissue glycogen content was lowered in the diabetic animals but was restored by insulin treatment. Tissue glycogen content and DAAO activity showed an inverse relationship. The xanthine oxidase activity in the two tissues decreased from 40-55%; the catalase activity decreased from 34-54%. Insulin treatment was unable to restore the xanthine oxidase and catalase activities in both the tissues.
 ...
PMID:Influence of insulin status on extra-mitochondrial oxygen metabolism in the rat. 1074 86

Both reactive oxygen species (ROS) and endothelin-1 (ET- 1) have been implicated in the pathophysiology of diabetic nephropathy. The interrelationship between them, however, has not been documented in this disease. To determine whether ROS regulates ET-1 production in diabetic kidneys, we examined the in vitro and in vivo effects of ROS donors and scavengers on ET-1 production of diabetic rat glomeruli. For in vitro study, the glomeruli were isolated with a sieving method from streptozotocin-induced diabetic rats and killed at 1 week, 1 month, and 3 months, respectively. Superoxide was measured by a spectrophotometer, and ET-1 was measured by radioimmunoassay. The results demonstrated that the basal production levels of superoxide and ET-1 were higher in diabetic glomeruli than in normal glomeruli in vitro. There was a positive correlation between the production of superoxide and ET-1 in diabetic glomeruli. The basal ET-1 production was markedly attenuated by ROS scavengers including superoxide dismutase, catalase, dimethyl sulfoxide, and deferoxamine in diabetic glomeruli. Exogenous ROS generated by xanthine/xanthine oxidase significantly enhanced ET-1 generation by both diabetic and normal glomeruli. A high glucose concentration (500 mg/dL) in vitro increased ET-1 production by normal glomeruli but not diabetic glomeruli, and insulin partly suppressed ET- 1 production by diabetic glomeruli. The in vivo study demonstrated that when diabetic rats were injected daily with superoxide dismutase or catalase after diabetes was induced, the basal production of ET-1 was markedly attenuated after 1 week and 1 month, respectively. These results indicate that exogenously or endogenously derived ROS can enhance ET-1 production by diabetic rat glomeruli and that ROS scavengers suppress ET- 1 production both in vitro and in vivo. The effects of ROS on ET-1 production of diabetic glomeruli may be partly caused by the effect of hyperglycemia or insulin deficiency.
 ...
PMID:Reactive oxygen species enhances endothelin-1 production of diabetic rat glomeruli in vitro and in vivo. 1077 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>