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)

Cardiovascular disease is significantly increased in patients with metabolic syndrome and type 2 diabetes. Several factors such as chronic hyperglycemia, lipId abnormalities, endothelium dysfunction, inflammation, oxIdative stress, increased thrombosis and decreased fibrinolysis are likely to promote cardiovascular events in these patients. Because of positive effects on glucose homeostasis, lipId metabolism, proteins involved in all stages of atherogenesis, endothelium function, inflammation, thrombosis and fibrinolysis, PPARS alpha (fibrates) and PPARs gamma (glitazones) agonists are good candIdates to reduce cardiovascular disease, more precisely in subjects with metabolic syndrome or type 2 diabetes. PPARS alpha agonists (fibrates) are potent hypolipIdemic agents increasing plasma HDL-cholesterol and reducing free fatty acIds, triglycerIdes, LDL-cholesterol and the number of small dense LDL pArticles. Moreover, they reduce vascular inflammation and thrombosis, promote fibrinolysis and inhibit the production of the vasoconstrictor factor, endothelin-1, by the endothelium. They have been shown, in clinical trials, to reduce cardiovascular disease, more particularly in patients displaying lipId abnormalities typical of metabolic syndrome and type 2 diabetes (high triglycerIdes, low HDL-cholesterol). PPARS gamma agonists (glitazones) have not only beneficial effects on glucose homeostasis, by increasing insulin sensitivity and reducing blood glucose level but also on lipId metabolism by elevating plasma HDL-cholesterol, decreasing free fatty acIds and the number of small dense LDL pArticles, and for pioglitazone by reducing plasma triglycerIdes. Furthermore, they diminish vascular inflammation and vasoconstriction, inhibit monocyte chemotaxis, proliferation and migration of smooth muscle cells, in the vascular wall and decrease the production of adhesion molecules and metalloproteinases. PPARs gamma agonists (glitazones) have been shown to reduce the development of atherosclerotic lesions in rats. The potential clinical benefit of PPARs gamma agonists on the reduction of cardiovascular disease, in type 2 diabetic patients, will be specified by the ongoing intervention studies.
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PMID:Clinical interest of PPARs ligands. 1502 92

We evaluated the influence of chronic hypertriglyceridemia and endothelial dysfunction on myocardial glucose uptake (MGU) in Type 2 diabetic patients without coronary heart disease. Patients were divided into two groups according to fasting triglyceride (TG) levels: 5.4 +/- 1.1 and 1.5 +/- 0.3 mmol/l for high- and normal-TG groups, respectively. Five subjects were assigned to the high-TG group and 11 to the normal-TG group. Age, gender, body mass index, systolic and diastolic blood pressure, glucose, insulin, HbA1c, cholesterol, and HDL cholesterol were similar in the two groups, whereas free fatty acid (FFA) levels were higher in the high-TG group basally and at the end of the clamp. Furthermore, five healthy subjects were subjected to the same protocol and used as the control group. MGU was assessed by using 18F-labeled 2-fluoro-2-deoxy-D-glucose under hyperglycemic-hyperinsulinemic conditions. Basal endothelin-1 and nitric oxide levels were significantly higher in the high-TG group than in the normal-TG and control groups, and cGMP and maximal postischemic vasodilation were significantly decreased in the high-TG group compared with the normal-TG and control groups. However, significant alterations were found in the same parameters in the normal-TG group compared with the control group. By the end of the hyperglycemic clamp, in the high-TG group, MGU was approximately 40 and 65% of that in the normal-TG and control groups. MGU negatively correlated with TG, FFA, and endothelin-1, whereas a positive correlation was found with cGMP and maximal postischemic vasodilation. In conclusion, increased TG and FFA levels are risks, in addition to Type 2 diabetes mellitus, for myocardial insulin resistance, endothelial dysfunction, and alteration of nitric oxide/cGMP levels.
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PMID:Myocardial insulin resistance associated with chronic hypertriglyceridemia and increased FFA levels in Type 2 diabetic patients. 1513 Aug 83

Increased extracellular matrix (ECM) protein deposition and capillary basement membrane (BM) thickening are characteristic features of diabetic retinal microangiopathy. Recent observations in the authors' laboratories suggest that high glucose in endothelial cells as well as diabetes causes up-regulation of total fibronectin (FN), as well as extradomain-B (EDB) containing the spliced variant of FN, oncofetal FN, in the retina. This splice variant is normally absent in mature adult tissues and is believed to be involved in angiogenesis. In this study, the authors have investigated the role of C-peptide in the production of ECM proteins and capillary BM thickening in the retina of diabetic rats. They investigated retinas from poorly controlled diabetic BB/Wor rats with or without C-peptide treatment as well as those from age-matched nondiabetic control rats after 8 months of diabetes. In addition, the authors investigated retinas from BBDRZ/Wor rats, a model of type 2 diabetes. Following a treatment period of 8 months, retinal tissues were harvested for gene expression and histological analyses. In the retinas of diabetic BB/Wor rats, a significant increase of oncofetal FN was demonstrated compared to control rats. C-peptide treatment of BB/Wor rats completely prevented such increase. Furthermore, retinas from BBDRZ/Wor rats, did not exhibit any such alteration in oncofetal FN expression. The authors further examined retinal capillary BM thickening using ultrastructural morphometry. C-peptide treatment was ineffective in preventing the diabetes-induced increase in capillary BM thickness. The authors' previous studies of cultured endothelial cells demonstrated that oncofetal FN synthesis is, at least in part, mediated via transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1). Hence, they examined these two transcripts in the retina of these animals. Diabetes caused significant increase in mRNA expression of ET-1 and TGF-beta, which was not prevented by C-peptide treatment. Hence it appears that C-peptide is effective in preventing diabetes-induced oncofetal FN expression and that these effects are not mediated via ET-1 or TGF-beta. In conclusion, these data suggest that C-peptide is involved in regulating ECM protein composition. Furthermore, normalization of diabetes-induced oncofetal FN up-regulation may suggest importance of C-peptide in advanced alterations in diabetic retinopathy such as angiogenesis.
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PMID:C-peptide and retinal microangiopathy in diabetes. 1519 74

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

Resistin is a newly discovered adipocyte hormone. It is related to resistin-like molecules alpha, beta and gamma in structure and function. Resistin is produced by white and brown adipose tissues but has also has been identified in several other tissues, including the hypothalamus, pituitary and adrenal glands, pancreas, gastrointestinal tract, myocytes, spleen, white blood cells and plasma. The tissue level of resistin is decreased by insulin, cytokines such as tumour necrosis factor alpha, endothelin-1 and increased by growth and gonadal hormones, hyperglycaemia, male gender and some proinflammatory cytokines, such as interleukin-6 and lipopolysaccharide. Resistin antagonizes insulin action, and it is downregulated by rosiglitazone and peroxisome proliferator-activated receptor gamma agonists. Since evidence of a direct link between resistin genotype and human diabetes is still weak, more molecular, physiological and clinical studies are needed to determine the role of resistin in the aetiology of type 2 diabetes.
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PMID:An update on the biology and physiology of resistin. 1552 56

Cardiovascular complications are the central feature of type 2 diabetes mellitus, and insulin resistance is an early clinical manifestation of type 2 diabetes mellitus. Calcium channel blockers are widely used to treat cardiovascular diseases in diabetic patients; however, it remains unknown how endothelin-1 (ET-1) is altered and associated with cardiac lesions at the insulin-resistant early stage of type 2 diabetes mellitus, and, if so, whether calcium channel blockers can reverse such alterations. We examined plasma and cardiac expression of ET-1 in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a spontaneous model of human type 2 diabetes mellitus. At 8 weeks of age, OLETF rats were treated for 12 weeks with a long acting calcium channel blocker, benidipine (3 mg/kg per day p.o.) (BEN, n = 15), or with vehicle (OLETF, n = 15), and age-matched genetic control, male Long-Evans Tokushima Otsuka (LETO) rats were also used (n = 15). Blood pressure was significantly higher in OLETF than LETO rats, and benidipine treatment of OLETF rats for 12 weeks did not reduce their blood pressure significantly. Plasma and cardiac levels of ET-1 were significantly higher in OLETF compared with LETO rats (both P < 0.01), and were reversed after benidipine treatment. Our results suggest that ET-1 plays a pivotal role in the pathogenesis of cardiac complications at the insulin-resistant stage of diabetes mellitus, and that benidipine treatment may have a beneficial effect on these complications.
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PMID:The calcium channel antagonist benidipine reduces plasma and cardiac endothelin-1 levels in type II diabetic rat model. 1583 56

In patients on chronic hemodialysis the prevalence of atherosclerosis is increased and is by far the leading cause of morbidity and mortality. Endothelin-1, an endothelium-derived peptide with vasoconstrictive and mitogenic effects on vascular smooth muscles, is involved in the pathogenesis of atherosclerosis. The aim of the present study was to investigate the time course of plasma endothelin-1 levels during a hemodialysis session and to explore the influence of preexisting type 2 diabetes mellitus. Forty-five clinically stable hemodialysis patients (21 females, 24 males; mean age 62 +/- 12 years) were evaluated. Patients with type 2 diabetes (n= 11) were compared with the group of patients without diabetes (n=34). Relative blood volume (BV) changes (hemoglobinometry) and blood pressure (BP) was measured. Samples were taken before, every hour during, and after hemodialysis. Plasma endothelin-1 levels were measured by enzyme-linked immunoassay (ELISA) and results were corrected according to hemoconcentration. Hemodialysis with an ultrafiltration of 2215 +/- 952 mL was performed. Total BV at the end of hemodialysis was 89.3% +/- 8.3% of the pretreatment volume. Plasma endothelin-1 was enhanced in hemodialysis patients compared to normal subjects and increased from 1.28 +/- 0.47 before to 1.44 +/- 0.54 pg/mL (ref. 0.3-0.9) at the end of hemodialysis (p<0.05). The BV change (r=0.41) and the BP (mean BP: r=0.34) correlated with plasma endothelin-1 at the end of hemodialysis (p<0.05). The levels of endothelin-1 were significantly higher in the group of dialysis patients with type 2 diabetes compared to nondiabetics in all measurements (p<0.05). These findings suggest a potential role of endothelin-1 in the pathogenesis of vascular dysfunction in diabetes mellitus. The dialysis procedure per se, through vasoconstriction due to BV decrease, local endothelial injury (a.v. fistula), or bioincompatibility reactions (foreign surface contact) may additionally alter endothelial cell functions.
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PMID:Endothelin-1 plasma levels in hemodialysis treatment--the influence of type 2 diabetes. 1615 88

The aim of the present study was to evaluate the effect of prolonged inhibition of beta-oxidation on glucose and lipid muscle forearm metabolism and cGMP and endothelin-1 forearm release in patients with type 2 diabetes mellitus and ischemic cardiomyopathy. Fifteen patients were randomly allocated in a double-blind cross-over parallel study with trimetazidine (20 mg tid) or placebo lasting 15 days. At the end of each period, all patients underwent euglycemic hyperinsulinemic clamps with forearm indirect calorimetry and endothelial balance of vasodilator and vasoconstricor factors. Compared with placebo, trimetazidine induced 1) an increase in insulin-induced forearm glucose uptake and glucose oxidation accompanied by a reduction in forearm lipid oxidation and citrate release and 2) a decrease of endothelin-1 release paralleled by a significant increase in forearm cGMP release. Forearm glucose oxidation significantly correlated with cGMP release (r=0.37, P<0.04), whereas forearm lipid oxidation positively correlated with endothelin-1 release (r=0.40, P<0.03). In conclusion, for the first time, we demonstrated that insulin-induced forearm glucose oxidation and forearm cGMP release were increased whereas forearm endothelin-1 release was decreased during trimetazidine treatment. Muscle's metabolic and vascular effects of trimetazidine add new interest in the use of trimetazidine in type 2 diabetic patients with cardiovascular disease.
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PMID:Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy. 1617 56

Although past studies have demonstrated decreased renal matrix metalloproteinase (MMP) activity in type 1 diabetes and in mesangial cells grown under high glucose conditions, renal MMP expression and activity in type 2 diabetes and the regulation of MMPs by profibrotic factors involved in diabetic renal complications such as endothelin-1 (ET-1) remained unknown. The renal expression and activity of MMPs in type 2 diabetic Goto-Kakizaki (GK) rats treated with vehicle or ET(A) receptor selective antagonist ABT-627 for 4 wk were assessed by gelatin zymography, fluorogenic gelatinase assay, and immunoblotting. In addition, expression and phosphorylation of epidermal growth factor receptor (EGFR) and connective tissue growth factor were evaluated by immunoblotting. Renal sections stained with Masson trichrome were used to investigate kidney structure. MMP-2 activity and protein levels were significantly increased in both cortical and medullary regions in the GK rats. Membrane-bound MMP (MT1-MMP), MMP-9, and fibronectin levels were also increased, and ABT-627 treatment did not have an effect on MMP activity and expression. Histological analysis of kidneys did not reveal any structural changes. Phosphorylation of EGFR was significantly increased in the diabetic animals, and ABT-627 treatment prevented this increase, suggesting ET-1-mediated transactivation of EGFR. These results suggest that there is early upregulation of renal MMPs in the absence of any kidney damage. Although the ET(A) receptor subtype is not involved in the early activation of MMPs in type 2 diabetes, ET-1 contributes to transactivation of growth-promoting and profibrotic EGFR.
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PMID:Endothelin antagonism prevents early EGFR transactivation but not increased matrix metalloproteinase activity in diabetes. 1623 74

Macro- and microvascular disease states currently represent the principal causes of morbidity and mortality in patients with type I or type II diabetes mellitus. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in various beds in different animal models of diabetes and in humans with type I or type II diabetes. Several mechanisms leading to endothelial dysfunction have been reported, including changes in substrate avail ability, impaired release of NO, and increased destruction of NO. The principal mediators of diabetes-associated endothelial dysfunction are (a) increases in oxidized low density lipoprotein, endothelin-1, angiotensin II, oxidative stress, and (b) decreases in the actions of insulin or growth factors in endothelial cells. An accumulating body of evidence indicates that abnormal regulation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway may be one of several factors contributing to vascular dysfunction in diabetes. The PI3-K pathway, which activates serine/threonine protein kinase Akt, enhances NO synthase phosphorylation and NO production. Several studies suggest that in diabetes the relative ineffectiveness of insulin and the hyperglycemia act together to reduce activity in the insulin-receptor substrates (IRS)/PI3-K/Akt pathway, resulting in impairments of both IRS/PI3-K/Akt-mediated endothelial function and NO production. This article summarizes the PI3-K/Akt pathway-mediated contraction and relaxation responses induced by various agents in the blood vessels of diabetic animals.
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PMID:The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models. 1655 3


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