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)

To evaluate the role of nitric oxide synthase (nNOS) in the pathogenesis of diabetic neuropathy, we investigated nociception and nNOS expression in dorsal root ganglion (DRG) of rats with streptozocin-induced diabetes. Paw withdrawal threshold to noxious mechanical stimuli was decreased in both L-NAME-treated and diabetic rats. The number of NADPH-diaphorase positive neurons was significantly decreased in untreated diabetic compared with control rats. Decreased expression of nNOS protein was confirmed by immunoblotting. Insulin treatment completely prevented decreases in withdrawal threshold and nNOS expression. Cyclic GMP content paralleled nNOS expression in experimental animals. These results suggest that decreased nNOS-cGMP system in DRG may play a role in the pathogenesis of diabetic sensory neuropathy.
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PMID:Hyperalgesia and decreased neuronal nitric oxide synthase in diabetic rats. 950 63

Type 3 cyclic nucleotide phosphodiesterase (PDE-3) isoforms exhibit a high affinity ("low K(m)") for cAMP and are specifically inhibited by cGMP and a number of pharmacological agents, which increase myocardial contractility, inhibit platelet aggregation, and increase smooth muscle relaxation. The PDE-3 family consists of at least two isozymes, PDE-3A (cardiac type) and PDE-3B (adipocyte type), with distinct tissue-specific distributions. PDE-3A mRNA is highly expressed in the cardiovascular system, whereas PDE-3B mRNA is primarily expressed in adipocytes and hepatocytes. Toward understanding potential roles of PDE-3 in diabetes mellitus, we have established a specific and sensitive RNase protection assay (RPA) for quantitating PDE-3A and PDE-3B mRNA in rat diabetic models. In fatty Zucker diabetic (ZDF) rats, PDE-3A mRNA, but not PDE-3B mRNA, was expressed in heart, whereas liver and white and brown fat tissues predominantly expressed PDE-3B mRNA. Unexpectedly, PDE-3B mRNA expression was approximately 2.5 times higher than PDE-3A mRNA in aorta from both ZDF and Sprague-Dawley (SD) rats. In contrast, expression levels of PDE-3A mRNA in heart were similar in both species. With this RPA, we were thus able to compare PDE-3A and -3B mRNA levels in different tissues as well as in different rat species.
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PMID:Cyclic nucleotide PDE-3. Quantitation of PDE-3A and -3B mRNAs in rat tissues by RNase protection assay. 963 Dec 38

In animals and humans, inhibition of nitric oxide (NO) production has widespread effects. Reduced activity of the NO:cyclic GMP pathway has been documented in disease states, including hypertension, diabetes and certain types of renal disease. Inhibitors of NO synthesis occur endogenously, and have been implicated in the regulation of the NO pathway in health and disease. Here we review the possible biological roles of endogenous NO synthase inhibitors, with particular reference to renal disease.
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PMID:Endogenous inhibitors of nitric oxide synthesis: how important are they? 963 34

Mesangial cells are smooth muscle-like pericytes that abut and surround the filtration capillaries within the glomerulus. Studies of the fine ultrastructure of the glomerulus show that the mesangial cell and the capillary basement membrane form a biomechanical unit capable of regulating filtration surface area as well as intraglomerular blood volume. Structural and functional studies suggest that mesangial cells regulate filtration rate in both a static and dynamic fashion. Mesangial excitability enables a homeostatic intraglomerular stretch reflex that integrates an increase in filtration pressure with a reduction in capillary surface area. In addition, mesangial tone is regulated by diverse vasoactive hormones. Agonists, such as angiotensin II, contract mesangial cells through a signal transduction pathway that releases intracellular stores of Ca2+, which subsequently activate nonselective cation channels and Cl- channels to depolarize the plasma membrane. The change in membrane potential activates voltage-gated Ca2+ channels, allowing Ca2+ cell entry and further activation of depolarizing conductances. Contraction and entry of cell Ca2+ are inhibited only when Ca2+-activated K+ channels (BK(Ca)) are activated and the membrane is hyperpolarized toward the K+ equilibrium potential. The mesangial BK(Ca) is a weak regulator of contraction in unstimulated cells; however, the gain of the feedback is increased by atrial natriuretic peptide, nitric oxide, and the second messenger cGMP, which activates protein kinase G and decreases both the voltage and Ca2+ activation thresholds of BK(Ca) independent of sensitivity. This enables BK(Ca) to more effectively counter membrane depolarization and voltage-gated Ca2+ influx. After hyperpolarizing the membrane, BK(Ca) rapidly inactivates because of dephosphorylation by protein phosphatase 2A. Regulation of ion channels has been linked casually to hyperfiltration during early stages of diabetes mellitus. Determining the signaling pathways controlling the electrophysiology of glomerular mesangial cells is important for understanding how glomerular filtration rate is regulated in health and disease.
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PMID:Glomerular mesangial cells: electrophysiology and regulation of contraction. 967 92

By closing ATP-sensitive K+ (K+-ATP) channels, glucose promotes depolarization-dependent Ca2+ entry and cytoplasmic free Ca2+ concentration ([Ca2+]i) rise in beta-cells. Ca2+-dependent exocytosis of insulin granules is then potentiated by a K+-ATP channel-independent action of glucose. The underlying mechanisms of this second pathway are still unclear. They were studied by incubating normal mouse islets in the presence of diazoxide to open K+-ATP channels and 30 mmol/l K+ to restore Ca2+ entry. The effect of glucose did not require priming of beta-cells by preincubation in the presence of high glucose and could not be attributed to interaction of the sugar with a "glucoreceptor." There is no evidence that protein kinases A and C are involved in the K+-ATP channel-independent pathway, because inhibitors of the kinases did not alter the effect of glucose. In 3 mmol/l glucose, fatty acids did not influence K+-induced insulin secretion, even in the presence of bromopalmitate, an inhibitor of fatty acid oxidation. Bromopalmitate alone had no effect, but it decreased the potentiation that the fatty acids produce in 20 mmol/l glucose. It is thus unlikely that long-chain acyl CoAs mediate the effect of glucose. The action of glucose was not associated with an increase in arachidonic acid release from the islets and was not mimicked by exogenous arachidonic acid. Phospholipase A2 inhibitors antagonized the effect of glucose, but their action was not reversed by arachidonic acid or palmitate and was associated with a fall in islet ATP. No evidence could be found for the intervention of NO, cGMP, Mg, phosphate, phosphatidylinositol 3-kinase, or pertussis toxin-sensitive G-proteins. Formycin A, an adenosine analog that is converted to formycin A-triphosphate in islets, increased insulin secretion in the absence and presence of glucose. In conclusion, the present and our previous results strongly suggest that among all known potential second messengers, adenine nucleotides are the best candidates as regulators of insulin secretion through the K+-ATP channel-independent pathway.
Diabetes 1998 Nov
PMID:The K+-ATP channel-independent pathway of regulation of insulin secretion by glucose: in search of the underlying mechanism. 979 40

Carbon monoxide (CO) has been suggested as a novel messenger molecule in the brain. We now report on the cellular localization and hormone secretory function of a CO-producing constitutive heme oxygenase (HO-2) in mouse islets. Islet homogenates produced large amounts of CO which were suppressed dose-dependently by the HO inhibitor zincprotoporphyrin-IX (ZnPP-IX). We also show, for the first time, that glucose markedly stimulates the HO activity (CO production) in intact islets. A further potentiation was induced by the HO substrate hemin. Western blot showed that islet tissue expressed HO-2, and confocal microscopy revealed that HO-2 resided in insulin, glucagon, somatostatin, and pancreatic polypeptide cells. ZnPP-IX dose-dependently inhibited, whereas hemin enhanced, both insulin and glucagon secretion from glucose-stimulated islets. Stimulation or inhibition of CO production was accompanied by corresponding changes in islet cGMP levels. Exogenously applied CO stimulated insulin and glucagon release from isolated islets, whereas exogenous nitric oxide (NO) inhibited insulin and stimulated glucagon release. Islets stimulated by glucose or L-arginine displayed a marked increase in their NO-synthase (NOS) activity. Such an increase was suppressed by hemin, conceivably because NOS activity was inhibited by hemin-derived CO. Consequently, hemin enhanced L-arginine-induced insulin secretion. Insulin release stimulated by either hemin-derived CO or exogenous CO was strongly inhibited by the guanylate cyclase inhibitor ODQ, but it was unaffected by ZnPP-IX. Glucagon release induced by CO (but not by hemin) was inhibited by ODQ and partly inhibited by ZnPP-IX. We propose that the islets of Langerhans are equipped with a heme oxygenase-carbon monoxide pathway, which constitutes a novel regulatory system of physiological importance for the stimulation of insulin and glucagon release. This pathway is stimulated by glucose, is at least partly dependent on the cGMP system, and displays interaction with islet NOS activity.
Diabetes 1999 Jan
PMID:Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release: a biochemical, immunohistochemical, and confocal microscopic study. 989 24

Estrogen deficiency, hyperinsulinemia, type II diabetes, atherosclerosis, and a past history of elevated blood pressure may be associated with increased risk of Alzheimer's disease (AD). Common to all of these risk factors is a diminished capacity of vascular endothelium to generate nitric oxide (NO). Vascular NO has the potential to enhance the membrane polarization of cerebral neurons by increasing the open probability of calcium-activated potassium channels; this may protect neurons from the excessive calcium influx, potentiated by beta-amyloid peptides that is thought to mediate neuronal damage in AD. The possibility that NO/cyclic guanosine 3', 5'-phosphate (cGMP) may modulate the synthesis or processing of the amyloid precursor protein, also merits evaluation. Practical measures for promoting vascular NO production may include increased intakes of arginine, potassium, antioxidants, and fish-oil, as well as lifestyle measures that typically lower elevated blood pressure; potential benefits of chromium, glucosamine, and silicon should also be explored. In hypertensives, angiotensin-converting enzyme (ACE) inhibitors and sodium restriction may favorably influence endothelial function. Fish-oil should have the additional benefit of antagonizing the contribution of interleukin-1 to AD pathogenesis. Ancillary anti-excitotoxic measures such as magnesium, taurine, phenytoin, and vasodilators targeting ATP-dependent potassium (KATP) channels, may likewise reduce AD risk. Most of the nutritional measures suggested here would in any case be recommendable for preservation of vascular health.
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PMID:Vascular nitric oxide may lessen Alzheimer's risk. 1005 65

Little is known about the mechanism(s) of endothelial dysfunction in diabetes. In this study, the effect of nonenzymatic glycated LDL, a phenomenon induced by elevated D-glucose levels associated with diabetes, on porcine aortic endothelial cells was investigated. Two fractions of LDL from diabetic patients were separated by affinity column chromatography and are referred to herein as fraction alpha (nonglycated LDL) and fraction beta (glycated LDL). Incubation of endothelial cells for 24 h with total LDL isolated from diabetic subjects (dLDL) increased the release of superoxide anions (*O2-) by fivefold, while no effect of LDL isolated from healthy individuals (nLDL) was found. Fraction beta, but not fraction alpha, evoked the *O2- release. In vitro-glycated LDL mimicked the effect of dLDL/fraction beta on *O2- release that correlated with its degree of glycation (R2 = 0.96). Moreover, nitric oxide (NO) stability (measured with a porphyrinic-based electrode) and NO bioactivity (measured by its ability to elevate cellular cGMP levels) were reduced in cells treated with dLDL by 46 and 41%, respectively. dLDL (but not nLDL or fraction alpha) abolished shear stress-induced L-arginine uptake. The inhibitory effect of dLDL on shear stress-induced L-arginine uptake was mimicked by in vitro-glycated LDL. The efficiency of in vitro-glycated LDL to diminish shear stress-evoked L-arginine uptake correlated with the extent of glycation (R2 = 0.88). Moreover, dLDL, but not nLDL or fraction alpha, reduced shear stress-mediated cGMP formation and NOx production by 47 and 88%, respectively. This effect was also mimicked by in vitro-glycated LDL, correlating with its degree of glycation (R2 = 0.86). Under these experimental conditions, glycated LDL reduced shear stress-induced increase in NO synthesis by inhibition of shear stress-stimulated L-arginine uptake and NO bioactivity due to increased endothelial cell *O2- release. These properties may contribute to the reduced vasodilatory response and the vascular complications in diabetes.
Diabetes 1999 Jun
PMID:Glycated low-density lipoprotein attenuates shear stress-induced nitric oxide synthesis by inhibition of shear stress-activated L-arginine uptake in endothelial cells. 1034 24

The pathogenesis of diabetic neuropathy remains unclear, although several factors have been implicated in its pathogenesis. We have examined possible roles of decreased production of nitric oxide, ion channel dysfunction and decreased capacity of nerve regeneration. STZ-induced diabetic rats showed decreases in nociceptive threshold and NADPH-diaphorase positive neurons, nNOS level and cGMP content of DRG at 12 weeks after induction of diabetes. The rats injected by L-NAME, potent nNOS inhibitor, showed decreased nociceptive threshold, although D-NAME, inactive in nNOS inhibition, did not. These results suggest that decreased NO production might be involved in hyperalgesia in diabetic rats. Both hyperglycemia and decreased Na/K-ATPase activity are thought to be characteristic features of diabetic neuropathy. To investigate the presence of ion channel abnormality in diabetic nerves, a Vaseline-gap voltage clamp technique was applied for a single myelinated fibers under 30 mM high glucose plus 0.1 mM ouabain. Since K current was increased, a Ca activated K channel blocker was applied and this increase was shown to be suppressed. Furthermore, Ca channel blockers all suppressed increased K currents, suggesting that the condition induced an increase of Ca influx, thereby increasing Ca activated K currents through K channels. The data are important in that diabetic condition may induce both Ca influx, leading to nerve degeneration, and increased K current, resulting in decreased nerve conduction. Nerve regeneration has been known to be disturbed in diabetic condition. We have shown a decrease in nerve elongation rate in diabetic rats after crush of sciatic nerve, although this decrease was not ameliorated by ARI. Furthermore, Wallerian degeneration was shown to be delayed in diabetic nerves, leading to delayed nerve regeneration. Hyperphosphorylation of both medium and high molecular weight neurofilaments that might be induced by protein kinases including CDK 5 may be involved in the mechanism.
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PMID:[New trend in pathogenesis of diabetic neuropathy]. 1037 17

Dysfunction of the urinary bladder is a recognised complication of diabetes mellitus (DM) which has been attributed, in part, to a direct effect on bladder smooth muscle tissue. The objective of this study was to investigate the effect of alloxan-induced DM on endogenous modulators of smooth muscle tone such as cyclic AMP (cAMP), cyclic GMP (cGMP) and prostaglandins. Male New Zealand white rabbits were rendered diabetic (hyperosmolar, non-ketotic) with an i.v. injection of alloxan. After 6 months, the urinary bladders and urethrae were excised, cut into segments, incubated with stimulators and the formation of prostaglandins (PG), cAMP and cGMP measured using radioimmunoassays. PGE2 and PGI2 formation was impaired in response to arachidonic acid stimulation, whereas it was increased in response to acetylcholine in DM detrusor, bladder neck and urethra compared to controls. Cyclic AMP and cGMP formation in response to forskolin and sodium nitroprusside, respectively, was significantly reduced in the DM tissues of the lower urinary tract compared to the control. Alterations in the formation of prostaglandins, cAMP and cGMP by the smooth muscle of DM lower urinary tract suggests that these biochemical mediators may have a pathophysiological role in the urinary bladder dysfunction associated with DM.
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PMID:Alterations in the formation of cyclic nucleotides and prostaglandins in the lower urinary tract of the diabetic rabbit. 1065 Nov 36


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