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 vascular endothelium achieved a critical place in the understanding of vascular physiology and pathophysiology, after the discovery of the production of prostacyclin by endothelial cells, followed by the recognition that substances like acetylcholine, assumed to be direct vasodilators, could only trigger dilation in the presence of an intact endothelium. The endothelium-derived relaxing factor (EDRF) behaves as an endogenous nitrovasodilator and causes vasodilatation through stimulation of guanylyl cyclase and cellular accumulation of cyclic GMP. Subsequently, it was demonstrated that the EDRF is nitric oxide (NO), produced through the metabolism of the aminoacid L-arginine by the nitric oxide synthases (NOS). Three isoforms of this enzyme were discovered and cloned: a constitutive neuronal isoform (nNOS); an inducible isoform (iNOS), ubiquitous in cells stimulated by certain cytokines; and an endothelial isoform (eNOS). The importance of the different isoforms is well demonstrated in animal models; more recently, human studies unveiled the importance of these enzymes. The endothelium produces other vasodilators besides NO and prostacyclin; furthermore, it produces several vasoconstrictors. There is a delicate balance between these factors, which can be disturbed: several well known cardiovascular aggressors, like arterial hypertension, diabetes, smoking, dyslipidemia or renal insufficiency, can alter several invasive or non-invasive tests of endothelial function. The fact that an intervention on these factors may reverse endothelial dysfunction as measured by these tests, raises hope that they may be surrogate markers of global cardiovascular risk. If correlation of these tests with clinical outcomes proves to be robust, they may become extensively used in clinical practise.
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PMID:[Vascular endothelium: the history of a recent revolution in angiology]. 1607 83

The inability of insulin to stimulate glucose metabolism in skeletal muscle fibres is a classic characteristic of type 2 diabetes. Using the non-obese Goto-Kakizaki rat as an established animal model of this type of diabetes, sucrose gradient centrifugation studies were performed and confirmed the abnormal subcellular location of the glucose transporter GLUT4. In addition, this analysis revealed an unexpected drastic reduction in the surface membrane marker beta-dystroglycan, a dystrophin-associated glycoprotein. Based on this finding, a comprehensive immunoblotting survey was conducted which showed a dramatic decrease in the Dp427 isoform of dystrophin and the alpha/beta-dystroglycan subcomplex, but not in laminin, sarcoglycans, dystrobrevin, and excitation-contraction-relaxation cycle elements. Thus, the backbone of the trans-sarcolemmal linkage between the extracellular matrix and the actin membrane cytoskeleton might be structurally impaired in diabetic fibres. Immunohistochemical studies revealed that the reduction in the dystrophin-dystroglycan complex does not induce obvious signs of muscle pathology, and is neither universal in all fibres, nor fibre-type specific. Most importantly, the expression of alpha-syntrophin and the syntrophin-associated neuronal isoform of nitric oxide synthase, nNOS, was demonstrated to be severely reduced in diabetic fibres. The loss of the dystrophin-dystroglycan complex and the syntrophin-nNOS complex in selected fibres suggests a weakening of the sarcolemma, abnormal signalling and probably a decreased cytoprotective mechanism in diabetes. Impaired anchoring of the cortical actin cytoskeleton via dystrophin might interfere with the proper recruitment of the glucose transporter to the surface membrane, following stimulation by insulin or muscle contraction. This may, at least partially, be responsible for the insulin resistance in diabetic skeletal muscles.
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PMID:Expression of the skeletal muscle dystrophin-dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto-Kakizaki rat. 1632 84

It has been demonstrated that subpopulations of myenteric neurons are differentially susceptible to the development of neuropathy in diabetes. Within the myenteric plexus are neurons that contain neuronal nitric oxide synthase (nNOS). However, these are not a homogeneous population. Some of the nNOS-containing neurons also contain heme oxygenase 2 (HO2). Therefore, the aim of this study was to compare the effects of diabetes on HO2- and nNOS-containing neurons within the myenteric plexus of the rat ileum. Diabetes was induced in male Wistar rats (350-400 g) by a single i.p. injection of buffered streptozotocin (65 mg/kg). After 12 weeks, immunostaining of wholemount preparations of ileum revealed that diabetes induced a significant shift (P < 0.001, chi-squared test for trend) towards increased neuronal cell body size in nNOS-immunoreactive neurons while HO2-immunoreactive neurons remained unaffected. Double-labeling studies revealed that approximately 50% of nNOS-containing neurons also contained HO2 and that the diabetes-induced change in size was confined to nNOS-immunoreactive neurons that did not contain HO2 (P < 0.01). No change in the size distribution occurred in neurons in which nNOS and HO2 were colocalized. Differences in the response of these two subpopulations of nNOS-containing neurons to diabetes could occur because they supply different targets within the gastrointestinal tract or indicate that the antioxidant, HO2, protects those nNOS-containing neurons in which it is colocalized, against oxidative stress that occurs in diabetes.
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PMID:Diabetes only affects nitric oxide synthase-containing myenteric neurons that do not contain heme oxygenase 2. 1637 69

Time-dependent potentiation (TDP) of insulin release is normally absent in mice. However, we recently demonstrated that TDP occurs in mouse islets under conditions of forced decrease of intracellular pH (pH(i)) associated with elevated NADPH+H(+) (NADPH) levels. Hence, TDP in mouse islets may be kept suppressed by neuronal nitric oxide (NO) synthase (nNOS), an NADPH-utilizing enzyme with alkaline pH optimum. To determine the role of nNOS in the suppression of TDP in mouse islets, glucose-induced TDP was monitored in mouse islets in which nNOS activity had been genetically removed or chemically inhibited and compared with the TDP response in wild-type mouse islets with and without forced intracellular acidification. Genetic deletion of nNOS was provided by an nNOS knockout (NOS-KO) mouse model, B6-129S4-Nos1(tm1Plh)/J. To explore how nNOS inhibits TDP, we compared pH(i) and NADPH levels in wild-type and NOS-KO islets and monitored TDP with various components of the nNOS reaction added. Glucose normally does not produce TDP in wild-type mouse islets except under forced intracellular acidification. Remarkably, glucose produced strong TDP in NOS-KO islets and in wild-type islets treated with nNOS inhibitors. TDP in NOS-KO islets was not inhibited by the addition of NO, and NOS-KO islets exhibited a lower pH(i) than wild-type islets. The addition of arginine to wild-type islets also enabled glucose to induce TDP. Our results show that nNOS activity contributes to the absence of TDP in mouse islets putatively through depletion of intracellular arginine.
Diabetes 2006 Apr
PMID:Mechanisms of time-dependent potentiation of insulin release: involvement of nitric oxide synthase. 1656 25

Macula densa cells have an important role in the regulation of glomerular blood flow and glomerular filtration by its regulation of afferent arteriolar vascular tone. Nitric oxide derived from neuronal nitric oxide synthase (nNOS) in macula densa can dilate afferent arterioles. Macula densa nNOS is important for renin secretion, and its expression is regulated by dietary salt, renal angiotensin II, intracellular pH, and other factors. In salt-sensitive hypertension, nNOS is suppressed, whereas in SHR or in the early phase of diabetes, nNOS is increased in macula densa along with NADPH oxidase, which limits NO bioavailability. Renal damage induced by hypertension, diabetes, and hyperlipidemia could be prevented by enhancement of nNOS in macula densa with ACEI, dipyridamole, alpha(1)-receptor blocker, a low-salt diet, or sodium bicarbonate. Sodium bicarbonate is a safe and clinically available enhancer of nNOS in macula densa that increases glomerular blood flow and prevents the reduction of GFR in radiocontrast nephropathy and chronic renal failure. In conclusion, the enhancement of nNOS in the macula densa can be a promising strategy to prevent reduction of renal function.
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PMID:Role of macula densa neuronal nitric oxide synthase in renal diseases. 1657 7

Renal cortical cyclooxygenase-2 (COX-2) is restricted to the macula densa and adjacent cortical thick ascending limbs (MD/cTALH). Renal cortical COX-2 increases in response to diabetes and renal ablation, both of which are characterized by hyperfiltration and reduced NaCl delivery to the MD due to increased proximal NaCl reabsorption. High-protein intake also induces hyperfiltration and decreases NaCl delivery to the MD due to increased NaCl reabsorption proximally. We investigated whether high protein induces cortical COX-2 and whether cortical COX-2 contributes to high protein-induced hyperfiltration and increased intrarenal renin biosynthesis. Cortical COX-2 increased after protein loading but decreased after protein restriction. COX-2 inhibition attenuated high protein-induced hyperfiltration but had no effect on high protein-induced intrarenal renin elevation. Therefore, induction of cortical COX-2 contributed to high protein-induced hyperfiltration but not intrarenal renin elevation. In the kidney cortex, neuronal nitric oxide synthase (nNOS) is also localized to the MD, and interactions between intrarenal nNOS and COX-2 systems have been proposed. Cortical COX-2 elevation seen in salt restriction was blocked by nNOS inhibiton. Cortical nNOS expression also increased after protein loading, and inhibition of nNOS activity completely reversed high protein-induced cortical COX-2 elevation and hyperfiltration. These results indicate that NO is a mediator of high protein-induced cortical COX-2 elevation and suggest that both intrarenal nNOS and COX-2 systems appear to regulate afferent arteriolar tone and subsequent hyperfiltration seen in high-protein intake.
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PMID:Role of renal cortical cyclooxygenase-2 expression in hyperfiltration in rats with high-protein intake. 1659 6

Diabetes mellitus results in a loss of neuronal nitric oxide synthase (nNOS) expression in the myenteric plexus but the underlying mechanisms remain unknown. We hypothesized that this may be mediated by advanced glycation end-products (AGEs), a class of modified protein adducts formed by non-enzymatic glycation that interact with the receptor for AGE (RAGE) and which are important in the pathogenesis of other diabetic complications. Whole mount preparations of longitudinal muscles with adherent myenteric plexus (LM-MPs) from the duodenum of adult male rats were exposed to glycated bovines serum albumin (AGE-BSA) or BSA for 24 h. Western blotting, immunohistochemistry and real-time reverse transcriptase polymerase chain reaction (RT-PCR) for mRNA showed a significant reduction in nNOS expression in LM-MPs after exposure to AGE-BSA. NO release, as measured by the Griess reaction, was also significantly reduced by AGE-BSA. A neutralizing antibody against RAGE attenuated the reduction of nNOS protein caused by AGE-BSA. Immunohistochemistry revealed co-localization of RAGE expression with Hu, a marker for neuronal cells but not for S-100, a glial marker. Advanced glycation end-products reduce nNOS expression in the rat myenteric neurones acting via the receptor RAGE. Our results suggest novel pathways for disruption of the nitrergic phenotype in diabetes.
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PMID:Suppression of nNOS expression in rat enteric neurones by the receptor for advanced glycation end-products. 1662 67

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.
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PMID:Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats. 1684 11

The aim of this study was to investigate the ability of aminoguanidine (AG) to prevent diabetes-induced changes in nitric oxide synthase- (nNOS), vasoactive intestinal polypeptide- (VIP) and noradrenaline- (NA) containing nerves of the rat ileum using immunohistochemical and biochemical techniques. Diabetes was induced in adult male Wistar rats by a single intraperitoneal injection of streptozotocin (65 mg/kg). AG was administered in the drinking water to control (1.8 g/l) and diabetic (0.9 g/l) rats over a period of 8 weeks. Diabetes caused a significant increase in the thickness of nNOS-containing nerve fibres (p<0.001) in the circular muscle, in nNOS activity (p<0.05) and in the size distribution of nNOS-containing myenteric neurons (p<0.001). The thickness of VIP-containing nerve fibres was significantly greater (p<0.01) and there was a significant increase in varicosity size (p<0.01) and proportion of VIP-positive myenteric neurons (p<0.01) in diabetes. NA levels were significantly reduced (p<0.01) and the size of varicosities containing tyrosine hydroxylase (TH) was significantly increased (p<0.001) in diabetes. AG treatment completely or partially prevented the diabetes-induced increase in nNOS activity, in VIP-containing varicosity size, and in fibre width of both VIP- and nNOS-containing fibres in the circular muscle but had no effect on the diabetes-induced increase in nNOS-containing neuronal size or proportion of VIP-containing myenteric neurons. In contrast to VIP, AG treatment had no effect on the increase in TH-containing varicosity size in diabetes and also failed to prevent the decrease in NA levels induced by diabetes. These results indicate that AG treatment for neuropathy is not equally effective for all autonomic nerves supplying the ileum and that diabetes-induced changes in NA-containing nerves are particularly difficult to treat.
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PMID:Effect of aminoguanidine treatment on diabetes-induced changes in the myenteric plexus of rat ileum. 1698 13

We previously showed that pancreatic beta-cells express neuronal nitric oxide synthase (nNOS) that controls insulin secretion through two catalytic activities: nitric oxide (NO) production and cytochrome c reductase activity. We now provide evidence that the endogenous protein inhibitor of nNOS (PIN) is expressed in rat pancreatic islets and INS-1 cells. Double-immunofluorescence studies showed a colocalization of PIN with both nNOS and myosin Va in insulin-secreting beta-cells. Electron microscopy studies confirmed that PIN is mainly associated with insulin secretory granules and colocated with nNOS in the latter. In addition, PIN overexpression in INS-1 cells enhanced glucose-induced insulin secretion, which is only partly reversed by addition of an NO donor, sodium nitroprusside (SNP), and unaffected by the inhibitor of cytochrome c reductase activity, miconazole. In contrast, the pharmacological inhibitor of nNOS, Nomega-nitro-l-arginine methyl ester, amplified glucose-induced insulin secretion, an effect insensitive to SNP but completely normalized by the addition of miconazole. Thus, PIN insulinotropic effect could be related to its colocalization with the actin-based molecular motor myosin Va and as such be implicated in the physiological regulation of glucose-induced insulin secretion at the level of the exocytotic machinery.
Diabetes 2006 Dec
PMID:Protein inhibitor of neuronal nitric oxide synthase (PIN) is a new regulator of glucose-induced insulin secretion. 1713 Apr 71


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