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)

Streptozotocin has been widely used to create animal models of diabetes. Structurally, streptozotocin resembles N-acetylglucosamine, with a nitrosourea group corresponding to the acetate present in N-acetylglucosamine. Streptozotocin has recently been shown to inhibit O-GlcNAc-selective N-acetyl-beta-d-glucosaminidase, which removes O-linked N-acetylglucosamine from proteins. Compared to other cells, beta-cells express much more of the enzyme O-GlcNAc transferase, which catalyzes addition of O-linked N-acetylglucosamine to proteins. This suggests why beta-cells might be particularly sensitive to streptozotocin. In this report, we demonstrate that both streptozotocin and glucose stimulate O-glycosylation of a 135 kD beta-cell protein. Only the effect of glucose, however, was blocked by inhibition of fructose-6-phosphate amidotransferase, suggesting that glucose acts through the glucosamine pathway to provide UDP-N-acetylglucosamine for p135 O-glycosylation. The fact that both glucose and streptozotocin stimulate p135 O-glycosylation provides a possible mechanism by which hyperglycemia may cause streptozotocin-like effects in beta-cells and thus contribute to the development of type 2 diabetes.
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PMID:Glucose and streptozotocin stimulate p135 O-glycosylation in pancreatic islets. 1062 69

Thirty-nine hypertensive patients with type 2 diabetes mellitus were followed under long-term treatment (mean, 20.7 months) with manidipine hydrochloride, a Ca antagonist, or delapril hydrochloride, an ACE inhibitor, at nine institutions. Both the treatments showed similar antihypertensive effects, although slight but significantly larger decreases were observed in systolic and mean blood pressures at months 12 and 24 in the patients treated with manidipine (P < 0.02). The urinary albumin excretion index (AEI) tended to increase throughout the study in both treatment groups, but no significant difference in AEI was observed between the two treatment groups at any time point. Overt albuminuria developed in four patients on manidipine but did not appear in any of the patients on delapril. The risk of progression to overt albuminuria was significantly different between manidipine and delapril groups (P = 0.011). No increase in serum creatinine (Cr) was observed with delapril. The average excretion indexes of tubular markers such as beta2-microglobulin, alpha1-microglobulin, and NAG tended to be higher in the patients on manidipine than in those on delapril. Taken in sum, these findings suggest that the ACE inhibitor delapril is more beneficial than the Ca antagonist manidipine in the treatment of diabetic renal diseases via mechanisms other than the blood pressure regulation, partly through their different effects on tubular function. In conclusion, delapril was significantly more effective than manidipine in inhibiting progression to overt albuminuria in hypertensive type 2 diabetes mellitus patients.
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PMID:Delapril versus manidipine in hypertensive therapy to halt the type-2-diabetes-mellitus-associated nephropathy. 1067 Sep 8

The aim of the study was to evaluate the current antihyperglycaemic and antihypertensive treatment schemes as well as the quality of metabolic control and blood pressure in a population with type 2 diabetes, in view of the United Kingdom Prospective Diabetes Study (UKPDS) data. 318 patients were included. 44% were treated with metformin and/or sulfonylurea. 44% received insulin in monotherapy or combined with oral drugs. HbA1c was 8.0 (7.9-9.4)% (median; percentiles 25-75). Chronic neurological and vascular (micro- and macroangiopathy) complications were present in 21-43% of patients and were related to glycaemic control. (Un)treated hypertension was found in 59% of patients. Main treatments were ACE-inhibitors (40%), calcium channel antagonists and diuretics (20%) and/or beta-blockers (18%). Systolic and diastolic blood pressure were 147 +/- 22 and 86 +/- 12 mm/Hg (mean +/- 1 SD). In conclusion, overall glycaemic control of a type 2 diabetic population remains slightly unsatisfactory in view of the UKPDS recommendations. In contrast, blood pressure control was adequate.
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PMID:Glycaemic and blood pressure controls achieved in a cohort of 318 patients with type 2 diabetes. 1068 5

The role of lipoprotein oxidation in promoting atherosclerosis is gaining recognition as its spectrum of effects is being unveiled. Accelerated atherosclerosis is a major cause of morbidity and mortality in diabetic patients. Treatment with ACE inhibitors reduces oxidation of low-density lipoprotein (LDL-ox) in hypertensive subjects, however, their effect on LDL-ox in diabetic patients is yet obscure. To evaluate the effect of the ACE inhibitor enalapril and the calcium channel blocker nifedipine on LDL oxidation in normotensive type 2 diabetic patients. A randomized single blinded cross-over study was conducted on 24 nonobese, metabolically stable, normotensive patients with type 2 diabetes who were randomly allocated to receive either enalapril, 10 mg/day, or nifedipine, 30 mg/day, for 4 weeks followed by a 2-week washout period. They were then crossed over to a 4-week course with the alternate drug. The oxidation of LDL was evaluated by three methods: dialdehyde analysis using the thiobarbituric acid reactive substances assay with and without the addition of CuSO(4) as well as determination of conjugated dienes in the LDL lipid extract. The propensity of the serum to oxidize LDL was reduced by enalapril by 17-28% depending on the laboratory method used (P=0.0001). Treatment with nifedipine resulted in a rise in LDL-ox of 7-11% as compared to baseline (P<0.05). The difference between the effects of enalapril and nifedipine was statistically significant with all three laboratory methods used (P=0.0001). Both drugs were equally effective in reducing systolic and diastolic blood pressure without affecting HbA(1c) levels and lipid profile. The albumin excretion rate was significantly reduced during treatment with enalapril returning to baseline levels during the washout period and the nifedipine treatment course. Our findings suggest that oxidation of LDL is attenuated by ACE inhibition and augmented by some calcium channel blockers. This observation may contribute insight into the underlying mechanism of the therapeutic effects of ACE inhibition in diabetic patients.
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PMID:Oxidation of low-density lipoprotein in normotensive type 2 diabetic patients. Comparative effects of enalapril versus nifedipine: a randomized cross-over over study. 1080 51

Type 2 diabetes mellitus is associated with hypertension. If untreated, hypertension has a major impact on the clinical course of Type 2 diabetes and its vascular complications. In this review, we discuss rationale for the use of ACE inhibitors (ACEI) in hypertensive Type 2 diabetic patients and compare those theoretical assumptions with results of recent major clinical trials. Furthermore, possible directions for future clinical and experimental research are outlined. The RAS and its effector angiotensin II are important players in a number of cardiovascular and renal disorders. Recent evidence suggests that RAS and factors functionally linked to RAS are activated in Type 2 diabetes. Therefore, there is a theoretical basis for the use of ACEI in the treatment of hypertension in diabetic patients. Some recent studies reported superior outcome in patients treated with ACEI-based antihypertensive regimens compared with non-ACEI based treatments in reducing the risk of macrovascular disease (CAPPP, FACET, ABCD) or both micro- and macrovascular complications in Type 2 diabetes (HOPE). However, at least two of the large prospective studies discussed in this review (UKPDS 38, HOT), supported by results from previously published SHEP study, have recently suggested that the degree of reduction of blood pressure, rather than the choice of a particular class of antihypertensive agent, is associated with decreased risk of cardiovascular events. Studies focusing on renal end-points suggest that ACEI have a superior antiproteinuric effect than the other agents. However, whether ACEI are more nephroprotective, as assessed by the rate of decline in renal function, still remains to be elucidated. Despite promising results from recent trials, large numbers of patients progress despite ACEI treatment. Incomplete inhibition of the RAS may underlie this phenomenon. Treatment strategies that could enhance the degree of RAS inhibition represent one possible direction for clinical research in the near future. However, it is unlikely that the course of such a complex syndrome as Type 2 diabetes could be dramatically changed by just one class of antihypertensive agents. This goal is more likely to be achieved by multifactorial intervention, reflecting the complexity of metabolic syndrome. ACEI should be viewed as an important, but not the only, part of this complex approach.
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PMID:Therapeutic potential of ACE inhibitors for the treatment of hypertension in Type 2 diabetes. 1106 Aug 23

The present study was intended to investigate the different components of fatty acid utilization during a 60-min period of moderate-intensity cycling exercise (50% of VO2max) in eight male type 2 diabetic subjects (aged 52.6 +/- 3.1 years, body fat 35.8 +/- 1.3%) and eight male obese control subjects (aged 45.1 +/- 1.4 years, body fat 34.2 +/- 1.3%) matched for age, body composition, and maximal aerobic capacity. To quantitate the different components of fatty acid metabolism, an isotope infusion of [U-13C]-palmitate was used in combination with indirect calorimetry. In separate experiments, the 13C label recovery in expired air was determined during infusion of [1,2-13C]-acetate (acetate recovery factor). There were no differences in energy expenditure or carbohydrate and total fat oxidation between the groups. The rate of appearance (Ra) of free fatty acid (FFA) (P < 0.05) and the exercise-induced increase in Ra of FFA were significantly lower (P < 0.05) in type 2 diabetic subjects compared with control subjects (baseline vs. exercise [40-60 min]; type 2 diabetes 11.9 +/- 0.9 vs. 19.6 +/- 2.2 micromol x kg(-1) fat-free mass [FFM] x min(-1) and control 15.8 +/- 1.8 vs. 28.6 +/- 2.1 micromol x kg(-1) FFM x min(-1)). The oxidation of plasma-derived fatty acids was significantly lower in type 2 diabetic subjects during both conditions (P < 0.05, baseline vs. exercise [40-60 min]; type 2 diabetes 4.2 +/- 0.5 vs. 14.1 +/- 1.9 micromol x kg(-1) FFM x min(-1) and control 6.2 +/- 0.6 vs. 20.4 +/- 1.9 micromol x kg(-1) FFM x min(-1)), whereas the oxidation of triglyceride-derived fatty acids was higher (P < 0.05). It is hypothesized that these impairments in fatty acid utilization may play a role in the etiology of skeletal muscle and hepatic insulin resistance.
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PMID:Impaired oxidation of plasma-derived fatty acids in type 2 diabetic subjects during moderate-intensity exercise. 1111 13

Patients with type 2 diabetes mellitus and hypertension are thought to be at high risk for cardiovascular diseases. Recent guidelines for treatment of hypertension such as the JNC VI and WHO/ISH guidelines, recommend that antihypertensive agents be strated at as low as at 130/85 mmHg and that blood pressure be lowered to less than 130/85 mmHg. Our study was designed to clarify how well and to what extent blood pressure (BP) was controlled in Japanese hypertensive patients with or without type 2 diabetes mellitus. We interviewed two hundred physicians, randomly sellected from among the members of the Japanese Society of Hypertension (JSH) (n=98) and the Japanese Diabetes Society (JDS) (n=102) and obtained information regarding five most recent cases of hypertension with (n=954 in total) and their 2 most recent cases of hypertension without diabetes (n=371 in total). The achieved BP was below 140/90 mmHg in 40.5% of non-diabetic and 38.3% of diabetic hypertensives. The percentage of patients whose BP was less than 130/85 mmHg was 10.8% in nondiabetics and 11.4% in diabetics. The average number of hypotensive agents used was 1.46 in nondiabetics and 1.52 in diabetics. Physicians prescribed more ACE inhibitors and alpha-blockers in diabetics than in nondiabetics, although Ca-antagonists were administered in more than 70% of patients irrespective of whether or not they had diabetes. In contrast, fewer beta-blockers and diuretics were administered to diabetics. These results suggest that although Japanese physicians are considering the effects of hypotensive agents on metabolism and renal function when they treat diabetic hypertensives, the achieved blood pressure in both hypertensives with and those without diabetes is insufficient, with only one of ten patients having a blood pressure less than 130/85 mmHg even among diabetics. Improved blood pressure control will therefore be needed to treat high risk groups such as patients with diabetes mellitus.
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PMID:Blood pressure control in Japanese hypertensives with or without type 2 diabetes mellitus. 1113 Dec 72

Although diabetic nephropathy is a slowly progressing, well studied disease, it is the most common cause of end stage renal disease in industrialized countries. Recently the first randomized controlled long term trials about microvascular complications in patients with type 2 diabetes have been published. Only seven years ago the first hallmark papers about metabolic control and ACE inhibition emerged. This review highlights the current status of prevention and therapy of diabetic nephropathy by metabolic and blood pressure control in type 1 and type 2 diabetic patients, depending on their stage of nephropathy (normo-, micro-, or macroalbuminuria). In patients with type 1 diabetes and normo- or microalbuminuria, strict metabolic control has been shown to slow the progression of nephropathy. In macroalbuminuric patients an aggressive antihypertensive treatment, preferably with an ACE inhibitor, is more important than the metabolic control. ACE inhibitor therapy has also been proven beneficial in microalbuminuric patients, but not yet in normotensive, non-albuminuric type 1 patients. Because of the high prevalence of hypertension in patients with type 2 diabetes, a strict antihypertensive treatment is more important than metabolic control for the prevention of progression of microvascular disease. Since most patients need a combination of antihypertensive medications a recommendation for a single substance class can not be given.
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PMID:[Effect of blood glucose and blood pressure control on progression of diabetic nephropathy]. 1114 4

The main etiology for mortality and a great percent of morbidity in patients with diabetes mellitus is atherosclerosis. A hypothesis for the initial lesion of atherosclerosis is endothelial dysfunction, defined pragmatically as changes in the concentration of the chemical messengers produced by the endothelial cell and/or by blunting of the nitric oxide-dependent vasodilatory response to acetylcholine or hyperemia. Endothelial dysfunction has been documented in patients with diabetes and in individuals with insulin resistance or at high risk for developing type 2 diabetes. Factors associated with endothelial dysfunction in diabetes include activation of protein kinase C, overexpression of growth factors and/or cytokines, and oxidative stress. Several therapeutic interventions have been tested in clinical trials aimed at improving endothelial function in patients with diabetes. Insulin sensitizers may have a beneficial effect in the short term, but the virtual absence of trials with cardiovascular end-points preclude any definitive conclusion. Two trials offer optimism that treatment with ACE inhibitors may have a positive impact on the progression of atherosclerosis. Although widely used, the effect of hypolipidemic agents on endothelial function in diabetes is not clear. The role of antioxidant therapy is controversial. No data have been published regarding the effects of hormonal replacement therapy on endothelial dysfunction in postmenopausal women with type 2 diabetes.
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PMID:Diabetes and endothelial dysfunction: a clinical perspective. 1115 15

Sulfonylureas may stimulate glucose metabolism by protein kinase C (PKC) activation. Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. Association of PKC-betaII and -epsilon with insulin receptors was increased in glimepiride-treated cells. Selective depletion of cellular PKC-betaII and -epsilon by exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) or treatment of cells with PKC-betaII inhibitor G06976 reversed the effect of glimepiride on intracellular insulin-receptor processing. Glimepiride increased the effects of insulin on glucose incorporation into glycogen by enhancing both sensitivity and maximal efficacy of insulin. Exposing cells to TPA or G06976 inhibitor reversed these effects. Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. These data suggest a novel mechanism of action of sulfonylurea, which may have a therapeutic impact on the treatment of type 2 diabetes.
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PMID:The sulfonylurea glimepiride regulates intracellular routing of the insulin-receptor complexes through their interaction with specific protein kinase C isoforms. 1116 Aug 69


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