Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Culture of rat pancreatic islets with interleukin-1 (IL-1) results in up-regulation of the inducible isoform of nitric oxide synthase and overproduction of nitric oxide (NO). This is associated with reversible inhibition of both glucose-induced insulin secretion and islet glucose oxidation, and these effects are prevented by the inducible nitric oxide synthase inhibitor NG-monomethylarginine. IL-1 also induces accumulation of nonesterified arachidonic acid in islets by an NO-dependent mechanism, and one potential explanation for that effect would involve an IL-1-induced enhancement of islet glycolytic flux. We have therefore examined effects of IL-1 on islet glycolytic utilization of glucose and find that culture of islets with IL-1 in medium containing 5.5 mM glucose results in suppression of islet glucose utilization subsequently measured at glucose concentrations between 6 and 18 mM. The IL-1-induced suppression of islet glucose utilization is associated with a decline in islet glucokinase mRNA content, as determined by competitive reverse transcriptase-polymerase chain reaction, and in glucokinase protein synthesis, as determined by immuoprecipitation experiments, and all of these effects are prevented by NG-monomethylarginine. These findings suggest that IL-1 can down-regulate islet glucokinase, which is the primary component of the islet glucose-sensor apparatus, by an NO-dependent mechanism. Because reductions in islet glucokinase levels are known to cause a form of type II diabetes mellitus, these observations raise the possibility that factors which increase islet NO levels might contribute to development of glucose intolerance.
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PMID:Interleukin-1 reduces the glycolytic utilization of glucose by pancreatic islets and reduces glucokinase mRNA content and protein synthesis by a nitric oxide-dependent mechanism. 921 38

Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1beta-induced beta-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into beta-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1beta-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on beta-cell apoptosis. We also demonstrate that IL-1beta-mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1beta-induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1beta-induced apoptosis in pancreatic beta-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1beta-induced apoptotic pathway in pancreatic beta-cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes.
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PMID:Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis. 1127 6

Complications of diabetes have a genetic influence. Since increased inducible nitric oxide synthase (iNOS) gene ( NOS2A) expression can contribute to tissue damage, NOS2A is a worthy candidate for such a role. We therefore tested a 4-bp insertion/deletion (+/-) polymorphism 0.7 kb upstream of NOS2A for association with complications in type 2 diabetes patients, and also performed transient transfection experiments to examine the effect of this variant on promoter activity in kidney cells in culture. We investigated 379 Caucasian type 2 diabetes patients of British/European descent, 93 of whom had microalbuminuria, 26 overt nephropathy, 46 retinopathy, and 73 clinical neuropathy. Genotyping for the variant was carried out by PCR and automated Genescan analysis. Transient transfection studies involved the renal HEK 293 cell line and luciferase reporter gene constructs containing 1.1 kb of 5'-flanking DNA from '+' or '-' allele homozygotes. We found that the '+' allele frequency in patients without microalbuminuria was 12%, but was 23% in those with microalbuminuria ( P=0.0005), and was 26% in those with nephropathy ( P=0.0007), 22% in those with retinopathy ( P=0.037), and 23% in those with neuropathy ( P=0.045). The odds ratios for homozygote +/+ to have microalbuminuria or nephropathy were 2.4 (95% CI 1.4-4.2, P=0.0023) and 5.4 (95% CI 1.8-16, P=0.0009), respectively. Luciferase reporter gene constructs containing 1 kb of NOS2A promoter DNA for each allele were made and sequence analysis confirmed that the +/- variation was the only sequence difference present. Transient transfection of these into HEK 293 cells revealed 25 times higher reporter gene activity for the '+' allele compared with the '-' allele. Gel shift analysis with 30mer oligonucleotides corresponding to each allele showed specific binding to nuclear extracts, being greater for the '+' allele. Thus the '+' allele of the NOS2A promoter variant may confer higher iNOS expression, and could contribute to complications of type 2 diabetes, especially in the approximately 5% of patients homozygous for this variant.
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PMID:Association of a functional inducible nitric oxide synthase promoter variant with complications in type 2 diabetes. 1190 46

This study investigated the time course of NADH oxidase, a source of superoxide in the vascular endothelium, inducible nitric oxide synthase (iNOS), and peroxynitrite (ONOO(-)) in the BBZ/Wor rat, a spontaneous model of noninsulin dependent diabetes (NIDDM). Colloidal gold-labeled immunocytochemical studies of iNOS and nitrotyrosine, a marker for OONO(-), were done on sections of retinas from male BBZ/Wor rats in which NADH oxidase was localized by cerium derived cytochemistry at three time points: pre-diabetes (prior to the onset of hyperglycemia); new onset diabetes (2-6 days after onset of hyperglycemia); and chronic diabetes (4-18 months after onset of hyperglycemia). Control retinas were from age matched non-diabetic BB(DR)/Wor rats. The percentage of blood vessels positive for NADH oxidase increased significantly (P = 0.05) in new onset (64.2 +/- 6.5%) and chronic diabetes (83.2 +/- 11.4%), as compared to pre-diabetes (25.8 +/- 5.6%) and nondiabetic controls (33.6 +/- 15.9%). The percentage of blood vessels positive for iNOS immunoreactivity was significantly higher in new onset diabetic retinas (69.6 +/- 5.88%, P = 0.0001; 8.9 +/- 3.29 colloidal gold particles (cgp) /50 microm(2)) than in chronic diabetic retinas (49.9 +/- 9.75%; 7.9 +/- 5.12 cgp) and both were significantly higher (P = 0.0001) than in prediabetic (3.7 +/- 0.81%; 0.4 +/- 0.56 cgp) and nondiabetic control retinas (8.7 +/- 4.66%; 1.2 +/- 1.40 cgp). In new onset diabetes, levels of nitrotyrosine immunoreactivity (60.8 +/- 16.91 cgp) were significantly higher (P = 0.0001) than those in chronic diabetes (29.5 +/- 4.31 cgp); both were significantly higher (P = 0.0001) than those in prediabetic (8.2 +/- 1.70 cgp) and nondiabetic retinas (9.0 +/- 1.87 cgp). There was no cumulative increase in nitrotyrosine in the chronic diabetic retinas as a function of time. In rats with diabetes there was disruption of the inner blood-retinal barrier. These results suggest that iNOS and ONOO(-) may contribute to retinal damage in diabetes from the onset of hyperglycemia in NIDDM.
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PMID:Time course of NADH oxidase, inducible nitric oxide synthase and peroxynitrite in diabetic retinopathy in the BBZ/WOR rat. 1200 47

Nitric oxide, a signal transduction molecule, when modulated causes various diseases including diabetic retinopathy. In diabetes, allelic polymorphism of the inducible nitric oxide synthase (iNOS) gene is associated with retinopathy in the Northern Irish population. In the present study we investigated the Asian Indian population. One hundred and ninety-nine unrelated Asian Indian patients with 15 or more years of type 2 diabetes were divided into two groups: (a) diabetic retinopathy (DR) and (b) diabetic nonretinopathy (DNR) subjects. In these groups the pentanucleotide microsatellite repeat located 2.5 kb upstream of the transcription start site of the iNOS gene was amplified by polymerase chain reaction and analyzed. Eleven alleles, 175-225 bp, were identified. Allele 210 bp was significantly associated with retinopathy (p = 0.044). Individuals carrying this allele had twice the risk of developing retinopathy compared with those who did not carry this allele [odds ratio (OR) - 2.03; 95% CI 0.96-4.35]. Alleles 200 and 220 bp were also significantly associated with no retinopathy and no serious retinopathy complications, respectively. In the Asian Indian population, allele 210 bp of the iNOS gene is a high-risk allele for developing retinopathy and alleles 200 and 220 bp protect an individual from developing retinopathy or its complications.
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PMID:Inducible nitric oxide synthase gene and diabetic retinopathy in Asian Indian patients. 1208 17

We have developed a method to genotype variable number of tandem repeats (VNTRs) and insertion/deletion polymorphisms using an integrated microfluidic chip-based system. We used this method to analyze a) a highly polymorphic pentanucleotide repeat (CCTTT)(n) locus within the 5'-putative promoter region of the human inducible nitric oxide synthase gene (iNOS5) which is associated with diabetic complications and infectious diseases; b) a bi-allelic 27 bp VNTR region within intron 4 of endothelial nitric oxide gene (eNOS27) which is associated with hypertension in type 2 diabetes patients with coronary heart disease and excess risk of advanced diabetic nephropathy in type 1 diabetes patients and c) an insertion/deletion polymorphism within the gene encoding angiotensin-converting enzyme (ACE/ID) which is associated with cardiovascular pathology and nitric oxide activity, and is in strong linkage disequilibrium with functional variants. Following amplifications, samples were mixed with gel-dye and markers and loaded into commercially available microfluidic chips designed for DNA sizing applications. In the study (N = 230), 95 (41%) of the DNA samples were homozygous and 135 (59%) were heterozygous for the iNOS5 repeats. For eNOS27, 173 (75%) of the genotyped DNA samples were homozygous for the larger 4b allele and the remaining 57 samples (25%) were heterozygous (4b/4a). No DNA samples were homozygous for the shorter 4a allele with four 27 bp repeats. In case of ACE/ID, 47 (20%) of the DNA samples were homozygous for the insertion, 65 (28%) were homozygous for the deletion and the remaining 118 (51%) were heterozygous. The results obtained were verified by analyzing random amplicons using bi-directional sequencing and GeneScan 3.0 analyses with 100% concordance being observed. Using the microfluidic chip-based method, separation and DNA sizing and genotyping are rapidly accomplished. The DNA fragments are resolved clearly and the system allows quantitation. Finally, the microfluidic chip-based method may be used for both large- and small-scale genotyping studies.
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PMID:Microfluidic chip-based method for genotyping microsatellites, VNTRs and insertion/deletion polymorphisms. 1255 58

Increased nitric oxide (NO) synthesis has been proposed to participate in the generation of insulin resistance in adipose and muscle tissues. Therefore, we examined the potential rate-limiting role of tetrahydrobiopterin (BH4) in cytokine-induced NO synthesis, and the effect of peroxisome proliferator activated receptor-gamma (PPARgamma) activation using the insulin-sensitizer rosiglitazone on cytokine-induced BH4 synthesis in 3T3-L1 adipocytes. Our data indicate that modulated availability of the mandatory nitric oxide synthase (NOS) cofactor BH4 affected cytokine-induced NO generation. Semiquantitative linear range reverse transcription polymerase chain reaction (RT-PCR) analysis demonstrated that rosiglitazone not only reduced inducible nitric oxide synthase (iNOS) mRNA transcription, but also guanosine triphosphate cyclohydrolase (GTPCH), the rate-limiting and controlling step of BH4 synthesis. Accordingly, intracellular BH4 concentration was reduced by 45% following rosiglitazone treatment. Furthermore, we observed a transient inhibitory effect of natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PJ2) on cytokine-mediated iNOS and GTPCH induction. Thus, the inhibition of cytokine-induced NO synthesis by rosiglitazone is at least in part attributable to reduced availability of BH4, the synthesis of which might represent a potential new target in the treatment of type 2 diabetes and insulin resistance.
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PMID:Diminished production of nitric oxide synthase cofactor tetrahydrobiopterin by rosiglitazone in adipocytes. 1256 86

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR-gamma receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. The thiazolidinedione rosiglitazone (Avandia) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, that was recently approved by the Food and Drug Administration for treatment of type II diabetes mellitus. In the present study, we have investigated the effects of rosiglitazone in animal models of acute inflammation (carrageenan-induced paw oedema and carrageenan-induced pleurisy). We report here for the first time that rosiglitazone (given at 1, 3 or 10 mg/kg i.p. concomitantly with carrageenan injection in the paw oedema model, or at 3, 10 or 30 mg/kg i.p. 15 min before carrageenan administration in the pleurisy model) exerts potent anti-inflammatory effects (e.g. inhibition of paw oedema, pleural exudate formation, mononuclear cell infiltration and histological injury) in vivo. Furthermore, rosiglitazone reduced: (1) the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase (PARP), (2) the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), intercellular adhesion molecules-1 (ICAM-1) and P-selectin in the lungs of carrageenan-treated rats. In order to elucidate whether the protective effect of rosiglitazone is related to activation of the PPAR-gamma receptor, we also investigated the effect of a PPAR-gamma antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone. BADGE (30 mg/kg i.p.) administered 30 min prior to treatment with rosiglitazone significantly antagonized the effect of the PPAR-gamma agonist and thus abolished the anti-inflammatory effects of rosiglitazone. We propose that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of inflammation.
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PMID:Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. 1470 29

We hypothesized that sepsis during hyperglycemia would activate left ventricular (LV) mitogen activated protein kinase (MAPK) signaling mechanisms and modulate generation of endothelin-1 (ET-1) and nitric oxide (NO) that can contribute to the progression of LV dysfunction. A single injection of streptozotocin (STZ, 60 mg/kg, via tail vein) was used to produce type 2 diabetes in male SD rats. Polymicrobial sepsis and sham-sepsis were induced using single i.p. injection of cecal inoculum and sterile 5% dextrose water, respectively, on the 13th and 27th day following STZ injection. Both 2-week (2-wk) and 4-wk diabetes groups were associated with hyperglycemia and weight loss. LV end diastolic pressure (LVEDP) was significantly increased in 4-wk diabetes but not in 2-wk diabetes group. Plasma concentration of tumor necrosis factor-alpha (TNF-alpha) was significantly increased in 4-wk diabetes+sepsis group as compared to sham, 2-wk diabetes+sepsis and sepsis groups. Elevated plasma and LV ET-1 and NO byproducts (NOx) along with LV preproET-1 and inducible nitric oxide synthase (iNOS) protein expression were observed in 4-wk but not in 2-wk diabetes group. Sepsis further elevated LV iNOS and preproET-1 in 4-wk diabetes group. Up-regulated phosphorylation of LV p38-MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and heat shock protein-27 (Hsp27) was observed in 4-wk diabetes group. Sepsis caused a factorial increase in LV p38-MAPK and Hsp27 phosphorylation and iNOS up-regulation but not ERK1/2 following progression from 2-wk to 4-wk diabetes. The study provides evidence that sepsis up-regulated LV iNOS, p38-MAPK phosphorylation and elevated LVEDP during 4-wk diabetes. We concluded that sepsis contributes in the development of LVEDP dysfunction and alteration in signaling mechanisms depending upon the progression from 2-wk to 4-wk diabetes in the rat.
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PMID:Left ventricular mitogen activated protein kinase signaling following polymicrobial sepsis during streptozotocin-induced hyperglycemia. 1533 69

Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1beta and/or TNF-alpha plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappaB and STAT-1. NF-kappaB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially "glucose hypersensitization" and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1beta, NF-kappaB, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappaB and NO independent. Thus, cytokines and nutrients trigger beta-cell death by fundamentally different mechanisms, namely an NF-kappaB-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappaB-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.
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PMID:Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. 1630 47


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