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)

I review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin action is lacking, whether through leptin deficiency or leptin resistance, overnutrition causes disease of nonadipose tissues with generalized steatosis, lipotoxicity, and lipoapoptosis. Examples of such disorders of liporegulation include generalized lipodystrophies, mutations of leptin and leptin receptor genes, and diet-induced obesity. Lipotoxicity of pancreatic beta-cells, myocardium, and skeletal muscle leads, respectively, to type 2 diabetes, cardiomyopathy, and insulin resistance. In humans this constellation of abnormalities is referred to as the metabolic syndrome, a major health problem in the United States. When lipids overaccumulate in nonadipose tissues during overnutrition, fatty acids enter deleterious pathways such as ceramide production, which, through increased nitric oxide formation, causes apoptosis of lipid-laden cells, such as beta-cells and cardiomyocytes. Lipoapoptosis can be prevented by caloric restriction, by thiazolidinedione treatment, and by administration of nitric oxide blockers. There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents.
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PMID:Lipotoxic diseases. 1181 77

Type 2 diabetes mellitus is frequently associated with arterial hypertension. The mechanisms involved in this association are not known in detail, but endothelial dysfunction and a blunted vascular response to endogenous vasodilators are thought to play a role. In the present study we investigated the in vitro activity of vascular and renal soluble guanylyl cyclase in type 2 diabetic Goto-Kakizaki rats aged 5, 15, and 30 weeks, in comparison with age-matched Wistar controls. Blood pressure was monitored by radiotelemetry, and serum glucose and insulin concentrations were measured by standard assays. Goto-Kakizaki rats of all age groups had serum glucose concentrations significantly higher than those of corresponding Wistar controls. Serum insulin was unchanged until 15 weeks of age and was elevated in the 30-week-old diabetic rats. Blood pressure in Goto-Kakizaki rats was significantly higher than that in Wistar controls, and heart rate was significantly lower. Mesenteric arteries of diabetic rats showed a blunted relaxation in response to acetylcholine and sodium nitroprusside. In aortic tissue from Wistar rats an age-dependent increase was found in nitric oxide-stimulated cGMP formation, which was absent in the diabetic animals. Moreover, the maximum activity of soluble guanylyl cyclase was significantly lower in Goto-Kakizaki rats in all age groups studied. In renal tissue no differences were found between diabetic and control rats, except at 30 weeks of age when Goto-Kakizaki rats showed a significant reduction in basal and stimulated guanylyl cyclase activity. In conclusion, the present study shows a persistent reduction in vascular nitric oxide-sensitive guanylyl cyclase in Goto-Kakizaki rats, which occurred shortly after weaning and may contribute to the elevation in blood pressure in this strain of genetically diabetic rats.
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PMID:Dysfunction of soluble guanylyl cyclase in aorta and kidney of Goto-Kakizaki rats: influence of age and diabetic state. 1182 39

Lysophosphatidylcholine (lysoPC), a component of oxidized low-density lipoprotein cholesterol (LDL-C), has been reported to impair nitric oxide production and endothelium-dependent vasorelaxation. The effects of troglitazone (CAS 97322-87-7), which is an antidiabetic agent with antioxidant properties, on serum levels of lysoPC and nitrite/nitrate (NOx) have been studied. Eight patients with Type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM) were studied (age: 61.5 +/- 2.8 years; diabetes duration: 10.2 +/- 1.6 years). They were additionally given troglitazone (200 mg once daily) since their fasting plasma glucose (FPG) and HbA1c levels had been increased in spite of conventional medications. Before and after 12 weeks of treatment with troglitazone their blood pressure, FPG, HbA1c, lipid profiles and NOx were measured. Troglitazone treatment had a slight depressor effect (decreasing the blood pressure from 133 +/- 5/72 +/- 3 to 127 +/- 4/68 +/- 1 mmHg; p < 0.05). FPG and HbA1c were significantly decreased with the therapy (181 +/- 10 to 160 +/- 10 mg/dl; p < 0.05 and 9.1 +/- 0.6 to 8.1 +/- 0.5%; p < 0.05, respectively). In contrast, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and LDL-C were maintained within normal limits throughout the study. Although lysoPC and NOx levels were not altered, a negative correlation between lysoPC and NOx levels was observed. These results suggest that troglitazone is a beneficial agent improving FPG and HbA1c levels in NIDDM patients, while its effects on serum lysoPC and NOx levels, at least for 12 weeks, seem to be minimal.
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PMID:Effect of troglitazone on endothelial function in type 2 diabetic patients. 1183 72

The role of islet constitutive nitric oxide synthase (cNOS) in insulin-releasing mechanisms is controversial. By measuring enzyme activities and protein expression of NOS isoforms [i.e., cNOS and inducible NOS (iNOS)] in islets of Langerhans cells in relation to insulin secretion, we show that glucose dose-dependently stimulates islet activities of both cNOS and iNOS, that cNOS-derived nitric oxide (NO) strongly inhibits glucose-stimulated insulin release, and that short-term hyperglycemia in mice induces islet iNOS activity. Moreover, addition of NO gas or an NO donor inhibited glucose-stimulated insulin release, and different NOS inhibitors effected a potentiation. These effects were evident also in K+-depolarized islets in the presence of the ATP-sensitive K+ channel opener diazoxide. Furthermore, our results emphasize the necessity of measuring islet NOS activity when using NOS inhibitors, because certain concentrations of certain NOS inhibitors might unexpectedly stimulate islet NO production. This is shown by the observation that 0.5 mmol/l of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) stimulated cNOS activity in parallel with an inhibition of the first phase of glucose-stimulated insulin release in perifused rats islets, whereas 5.0 mmol/l of L-NMMA markedly suppressed cNOS activity concomitant with a great potentiation of the insulin secretory response. The data strongly suggest, but do not definitely prove, that glucose indeed has the ability to stimulate both cNOS and iNOS in the islets and that NO might serve as a negative feedback inhibitor of glucose-stimulated insulin release. The results also suggest that hyperglycemia-evoked islet NOS activity might be one of multiple factors involved in the impairment of glucose-stimulated insulin release in type II diabetes mellitus.
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PMID:Role of nitric oxide synthase isoforms in glucose-stimulated insulin release. 1205 99

Obesity is a risk for type II diabetes mellitus and increased vascular resistance. Disturbances of nitric oxide (NO) physiology occur in both obese animals and humans. In obese Zucker rats, we determined whether a protein kinase C-beta II (PKC-beta II) mechanism may lower the resting NO concentration ([NO]) and predispose endothelial NO abnormalities at lower glucose concentrations than occur in lean rats. NO was measured with microelectrodes touching in vivo intestinal arterioles. At rest, the [NO] in obese Zucker rats was 60 nm less than normal or about a 15% decline. After local blockade of PKC-beta II with LY-333531, the [NO] increased approximately 90 nm in obese rats but did not change in lean rats. In lean rats, administration of 300 mg/dl D-glucose for 45 min depressed endothelium-dependent dilation; only 200 mg/dl was required in obese animals. These various observations indicate that resting [NO] is depressed in obese rats by a PKC-beta II mechanism and the hyperglycemic threshold for endothelial NO suppression is reduced to 200 mg/dl D-glucose.
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PMID:Obesity lowers hyperglycemic threshold for impaired in vivo endothelial nitric oxide function. 1206 13

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

In three groups of subjects, those with type 2 diabetes and nephropathy, those with type 1 diabetes without nephropathy, and healthy volunteers subjected to short-term hyperglycemia, we observed a counterintuitive relationship. In all three groups, baseline renal plasma flow (RPF) was positively correlated with the RPF response to blocking the renin-angiotensin system (RAS). This seems paradoxical in that an opposite result would have been expected if angiotensin-dependent renal vasoconstriction was responsible for the renal vasodilator response to RAS blockade. This suggests a link between the renal vasodilator response, mediated by nitric oxide (NO), and the activation of the intrarenal RAS. The complex interrelationships between hyperglycemia, insulin, NO, and the RAS may result in phenotypes that indicate varying risk of diabetic nephropathy and underlying genetic polymorphisms.
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PMID:Renal perfusion and the renal hemodynamic response to blocking the renin system in diabetes: are the forces leading to vasodilation and vasoconstriction linked? 1208 29

Nitric oxide (NO) synthase inhibition reduces leg glucose uptake during cycling without reducing leg blood flow (LBF) in young, healthy individuals. This study sought to determine the role of NO in glucose uptake during exercise in individuals with type 2 diabetes. Nine men with type 2 diabetes and nine control subjects matched for age, sex, peak pulmonary oxygen uptake (VO(2) peak), and weight completed two 25-min bouts of cycling exercise at 60 +/- 2% VO(2) peak, separated by 90 min. N(G)-monomethyl-L-arginine (L-NMMA) (total dose 6 mg/kg) or placebo was administered into the femoral artery for the final 15 min of exercise in a counterbalanced, blinded, crossover design. LBF was measured by thermodilution in the femoral vein, and leg glucose uptake was calculated as the product of LBF and femoral arteriovenous glucose difference. During exercise with placebo, glucose uptake was not different between control subjects and individuals with diabetes; however, LBF was lower and arterial plasma glucose and insulin levels were higher in individuals with diabetes. L-NMMA had no effect on LBF or arterial plasma glucose and insulin concentrations during exercise in both groups. L-NMMA significantly reduced leg glucose uptake in both groups, with a significantly greater reduction (P = 0.04) in the diabetic group (75 +/- 13%, 5 min after L-NMMA) compared with the control group (34 +/- 14%, 5 min after L-NMMA). These data suggest a greater reliance on NO for glucose uptake during exercise in individuals with type 2 diabetes compared with control subjects.
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PMID:Nitric oxide synthase inhibition reduces glucose uptake during exercise in individuals with type 2 diabetes more than in control subjects. 1214 73

A clustering of risk factors, including elevated triglycerides, decreased high-density lipoprotein cholesterol, hyperinsulinemia, and hypertension often are observed in patients who are insulin resistant. Insulin resistance has been found to play a critical role in the development of cardiovascular disease, particularly in patients with type 2 diabetes. Patients with insulin resistance have an increase in small, dense low-density lipoprotein (LDL) cholesterol, which is more atherogenic than large, buoyant LDL cholesterol. In the context of insulin resistance, insulin has reduced effects on the phosphatidylinositol 3 kinase (PI3K) pathway, whereas mitogen-activated protein kinase activity is maintained. The result is an exaggeration of the mitogenic actions of insulin leading to vascular smooth muscle proliferation and elevated plasminogen activator inhibitor (PAI)-1. Notably, nitric oxide-mediated vasodilation also is impaired, further contributing to atherogenicity. In addition, hyperinsulinemia further contributes to cardiovascular risk by promoting thrombosis. Patients who are insulin resistant have decreased fibrinolysis, as indicated by increased levels of PAI-1. Studies have shown that enhancing insulin sensitivity with insulin sensitizers, such as thiazolidinediones, may improve insulin resistance and limit the development of adverse cardiovascular consequences.
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PMID:Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. 1223 Oct 75

Nitric oxide (NO) derived from endothelial cells is profoundly related to the maintenance of physiological vascular tone. Impairment of endothelial NO generation brought about by gene polymorphism is considered the major deterioration factor for progressive renal disease, including diabetic nephropathy. The present study aimed to elucidate the Glu298Asp polymorphism of endothelial NO synthase (eNOS) in patients with end-stage renal disease (ESRD) and its role as a predisposing factor for cardiovascular complications. Glu298Asp in exon 7 of the eNOS gene was determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis, in ESRD patients (n=185) and compared with that of unrelated healthy individuals (n=304). The occurrence of 298Asp was significantly higher in the ESRD group (P=0.0020; odds ratio [OR] 1.65; 95% confidential interval [CI]: 1.21 to 2.25). In this group, 72 patients had type 2 diabetes mellitus (DM). Although 298Asp did not reach a significant level in the non-DM ESRD subgroup, the occurrence of 298Asp was significantly higher in DM-derived ESRD patients (P=0.0010; OR 2.02; 95% CI: 1.37 to 3.07). The functional effect of the Glu298Asp was examined using Chinese hamster ovary (CHO) cells stably overexpressing either 1917G or 1917T. NO-selective electrode measurements and fluorometric nitrite assay revealed a statistically significant difference in NO production or nitrite accumulation between CHO 1917G and 1917T (P<0.01). These data indicated that Glu298Asp is the predisposing factor in ESRD, especially DM-derived ESRD. The functional difference in NO generation depending on eNOS with either glutamate or aspartate at position 298 was also confirmed in vitro.
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PMID:Association of eNOS Glu298Asp polymorphism with end-stage renal disease. 1269 20


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