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)

The incidence of diabetes, now affecting more than 170 million individuals is growing rapidly. Type 2 diabetes, which accounts for 90% of all diabetes cases, is associated with increased cardiovascular morbidity and mortality. Thiazolidinediones (TZDs), used for the treatment of patients with type 2 diabetes improve insulin sensitivity and endothelial dysfunction and exert beneficial effects on the lipid profile by activating the peroxisome proliferator-activated receptor gamma (PPAR-gamma). Moreover, a large body of evidence indicates that TZDs exhibit antiatherogenic effects independent of their antidiabetic and lipid-lowering properties by modulating inflammatory processes. This review will focus on the role of PPAR-gamma agonists in the vessel wall and summarize their effects on C-reactive protein (CRP), plasminogen activator inhibitor type-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), adiponectin and ATP-binding cassette transporter A1 (ABCA1) and their implications for treatment of advanced stages of atherosclerosis, particularly in a setting of type 2 diabetes.
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PMID:Vascular effects of TZDs: new implications. 1674 Apr 17

Gene expression profiling of islets from pre-diabetic male Zucker diabetic fatty (ZDF) rats showed increased expression of hypoxia-related genes, prompting investigation of the vascular integrity of the islets. The islet microvasculature was increased approximately twofold in young male ZDF rats by both morphometric analysis and quantifying mRNA levels of endothelial markers. ZDF rats at 12 weeks of age showed a significant reduction in the number of endothelial cells, which was prevented by pretreatment with pioglitazone. Light and electron microscopy of normoglycemic 7-week-old ZDF rats showed thickened endothelial cells with loss of endothelial fenestrations. By 12 weeks of age, there was disruption of the endothelium and intra-islet hemorrhage. Islets from 7- and 12-week-old ZDF rats showed an approximate three- and twofold increase in vascular endothelial growth factor (VEGF)-A mRNA and VEGF protein secretion, respectively, compared with lean controls. Thrombospondin-1 mRNA increased in 7- and 12-week-old rats by 2- and 10-fold, respectively, and was reduced by 50% in 12-week-old rats pretreated with pioglitazone. Islets from young male control rats induced migration of endothelial cells in a collagen matrix only after pretreatment with matrix metalloproteinase (MMP)-9. Islets from 7-week-old ZDF rats showed a fivefold increase in migration score compared with wild-type controls, even without MMP-9 treatment. Islets from 15-week-old ZDF rats did not induce migration; rather, they caused a significant rounding up of the duct-derived cells, suggesting a toxic effect. These data suggest that in the ZDF rat model of type 2 diabetes, an inability of the islet to maintain vascular integrity may contribute to beta-cell failure.
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PMID:Islet microvasculature in islet hyperplasia and failure in a model of type 2 diabetes. 1706 32

Recent clinical trials have provided evidence that pioglitazone reduces cardiovascular events in patients with type 2 diabetes. However, the underlying mechanisms are not well understood. Because it has been well established that disruption of atherosclerotic plaques is a key event involved in acute myocardial infarction, we hypothesized that pioglitazone reduces cardiovascular events by stabilizing atherosclerotic lesions. In this study, we used an animal model to test our hypothesis. Low-density lipoprotein receptor-deficient (LDLR-/-) male mice were first fed a high-fat diet for 4 months to induce the formation of aortic atherosclerotic plaques and then treated with pioglitazone for the next 3 months. Analysis of atherosclerotic plaques at the end of the study showed that treatment with pioglitazone at 20 mg/kg/day reduced the progression of atherosclerotic plaques as compared to untreated mice. Furthermore, gene array analysis, quantitative real-time polymerase chain reaction, and immunohistochemical analysis showed that pioglitazone inhibited high-fat diet-induced upregulation of matrix metalloproteinase (MMP) expression. Finally, Sirius red staining showed that atherosclerotic lesions in mice receiving pioglitazone had higher collagen contents than those in untreated mice. This study demonstrated for the first time that administration of pioglitazone in LDLR-/- mice inhibited lesion progression and MMP expression in established atherosclerotic plaques and thus delineated a potential mechanism by which pioglitazone reduces cardiovascular events in patients with type 2 diabetes.
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PMID:Administration of pioglitazone in low-density lipoprotein receptor-deficient mice inhibits lesion progression and matrix metalloproteinase expression in advanced atherosclerotic plaques. 1711 Aug 3

In order to define the role of the ubiquitin-proteasome system in atherosclerotic plaque rupture in patients with type 2 diabetes mellitus (T2DM), we evaluated the amount of this system, of the main inflammatory cells, of the collagen content and some indexes indicative of oxidative stress in the carotid plaques of both diabetic and non-diabetic asymptomatic patients. Plaques were obtained from 31 type 2 diabetic and 27 non-diabetic patients undergoing endoterectomy. Both were examined for macrophages, T-lymphocytes, ubiquitin/proteasome 20S activity, NFkB, IkB-b, nitrotyrosine, matrix metalloproteinase-9 (MMP-9) and collagen. Diabetic plaques had more macrophages,T-lymphocytes, inflammatory cells (HLA-DR), ubiquitin/proteasome, NFkB, nitrotyrosine, MMP-9 and lower collagen content and IkB-b levels, in comparison with non-diabetic plaques. These findings indicate that in diabetic patients, ubiquitin/proteasome overactivity is associated with enhanced inflammatory activity induced by diabetic oxidative stress. This induces the NFkB release into the nucleus which, in turn, is responsible for the expression of inflammatory cytokines causing plaque rupture.
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PMID:Role of the ubiquitin-proteasome system in carotid plaque instability in diabetic patients. 1720 20

Increased extracellular matrix material is a pathological hallmark of diabetic nephropathy. In addition to collagens, a variety of non-collagenous glycoproteins such as fibronectin also accumulate in the kidney of diabetics. The effect of diabetes on degradative pathways, in particular those involving non-collagenous proteins, are relatively unexplored. In this study, we determined the expression of the major matrix metalloproteinase (MMP) responsible for degrading the non-collagenous matrix glycoprotein fibronectin. Furthermore, the modulation of these MMPs by advanced glycation end products (AGE), a key factor in the diabetic milieu, was explored. Exposure of mesangial cells to AGEs led to a significant reduction in MMP-7, but not MMP-3 or -10. MMP-7 expression was normalized by both aminoguanidine, an inhibitor of glycation product formation, or by a neutralizing anti-transforming growth factor-beta (TGF-beta) antibody. In streptozotocin-induced diabetic rats, the diminution in MMP-7 expression and excessive fibronectin accumulation were attenuated by aminoguanidine. Humans with type 2 diabetes and nephropathy displayed similar alterations in MMP-7 to their rodent counterparts. Our findings suggest that diminished expression of the glycoprotein-degrading enzyme, MMP-7, may play a role in fibronectin accumulation in the diabetic kidney in response to AGEs and/or TGF-beta.
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PMID:Advanced glycation end products decrease mesangial cell MMP-7: a role in matrix accumulation in diabetic nephropathy? 1755 58

Type 2 diabetes and dyslipidemia oftentimes present in combination. However, the relative roles of diabetes and diet-induced dyslipidemia in mediating changes in vascular structure, mechanics, and function are poorly understood. Our hypothesis was that addition of a high-fat diet would exacerbate small artery remodeling, compliance, and vascular dysfunction in type 2 diabetes. Vascular remodeling indices [media/lumen (M/L) ratio, collagen abundance and turnover, and matrix metalloproteinase dynamics], mechanical properties (vessel stiffness), and reactivity to pressure and vasoactive factors were measured in third-order mesenteric arteries in control Wistar and type 2 diabetic Goto-Kakizaki (GK) rats fed either a regular or high-fat diet. M/L ratios, total collagen, and myogenic tone were increased in diabetes. Addition of the high-fat diet altered collagen patterns (mature versus new collagen) in favor of matrix accumulation. Addition of a high-fat diet caused increased constriction to endothelin-1 (0.1-100 nM), showed impaired vasorelaxation to both acetylcholine (0.1 nM-1 microM) and sodium nitroprusside (0.1 nM-1 microM), and increased cardiovascular risk factors in diabetes. These results suggest that moderate elevations in blood glucose, as seen in our lean GK model of type 2 diabetes, promote resistance artery remodeling resulting in increased medial thickness, whereas addition of a high-fat diet contributes to diabetic vascular disease predominantly by impairing vascular reactivity in the time frame used for this study. Although differential in their vascular effects, both hyperglycemia and diet-induced dyslipidemia need to be targeted for effective prevention and treatment of diabetic vascular disease.
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PMID:Differential effects of diet-induced dyslipidemia and hyperglycemia on mesenteric resistance artery structure and function in type 2 diabetes. 1894 Nov 21

Medial thickening and vascular hypertrophy of resistance arteries can lead to cardiovascular complications associated with diabetes. While previous studies have established a role of type 1 diabetes in vascular remodeling, we recently extended these observations to type 2 diabetes and reported increased collagen deposition due to alterations in matrix metalloproteinase expression and activity in mesenteric resistance arteries. These studies also showed that remodeling response was mediated by endothelin-1 (ET-1) via activation of ET(A) receptors, whereas blockade of ET(B) receptors exacerbated the remodeling. However, the effectiveness of glycemic control strategies in preventing these vascular changes, including activation of the ET system still remained unclear. Also, very little is known about whether and to what extent reorganization of the extracellular matrix (ECM) affects vascular compliance and vasomotor tone. Accordingly, this study assessed structural remodeling of mesenteric microvessels, vascular compliance, and myogenic tone, as well as the role of matrix metalloproteinases (MMP) in mediating these processes. Spontaneously diabetic, non-obese Goto-Kakizaki (GK) rats, a model for type 2 diabetes, and normoglycemic Wistar rats were used for the studies. A subset of GK rats were administered metformin to achieve euglycemia. Glycemic control normalized the increased media-to-lumen ratios (M/L) and myogenic tone seen in diabetes, as well as normalizing plasma ET-1 levels and mesenteric ET(A) receptor expression. There was increased collagen synthesis in diabetes paralleled by decreased collagenase MMP-13 activity, while glycemic control attenuated the process. These findings and our previous study taken together suggest that hyperglycemia-mediated activation of ET-1 and ET(A) receptors alter vascular structure and mechanics in type 2 diabetes.
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PMID:Glycemic control prevents microvascular remodeling and increased tone in type 2 diabetes: link to endothelin-1. 1917 90

Diabetes mellitus is a leading cause of morbidity and mortality because of its cardiovascular complications. It has been suggested that hyperglycemia, hyperinsulinemia and insulin resistance, glycation of proteins, oxidative stress, inflammation, and many other factors may be related to atherogenesis in diabetes. The metabolic abnormalities associated with diabetes lead to activation of the renin-angiotensin-aldosterone system (RAAS), with a subsequent increase of angiotensin II and aldosterone levels, which might alter the insulin signaling pathway and promote the formation of reactive oxygen species that induce endothelial dysfunction as well as cardiovascular disease and renal disease. Synthesis of angiotensin II is not only catalyzed by angiotensin-converting enzyme, but also by chymase. Recently, angiotensin II produced by chymase was reported to be involved in vascular proliferation and atherosclerosis. Chymase also activates matrix metalloproteinase-9, leading to extracellular matrix degradation, and promotes cardiovascular remodeling. Many studies have shown that angiotensin-II blockade significantly reduces the levels of proinflammatory mediators and suppresses oxidative stress. In clinical trials, RAAS blockade has been found to delay or prevent the onset of type 2 diabetes, and it also prevents cardiovascular and renal events in diabetic patients. Thus, RAAS inhibition represents first-line treatment for hypertensive and diabetic target organ damage, as well as preventing the progression of cardiovascular disease and kidney disease. This review presents the available information about the role of the RAAS in the cardiovascular and renal complications of diabetes.
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PMID:Impact of the renin-angiotensin-aldosterone-system on cardiovascular and renal complications in diabetes mellitus. 1948 96

The aim of the study was to evaluate the long-term effect of rosiglitazone and metformin monotherapy with medical nutrition treatment (MNT) and of MNT alone on arterial stiffness, serum monocyte chemoattractant protein (MCP)-1 and matrix metalloproteinase (MMP)-9 in drug naive patients with type 2 diabetes mellitus. Fifty type 2 diabetic patients were randomized to receive rosiglitazone 4 mg/day (n=19) or metformin 850 mg/day (n=16) with MNT or MNT alone (n=15), for 52 weeks. Arterial stiffness was assessed by using large and small artery elasticity index (SAEI and LAEI, respectively). SAEI, LAEI, serum MCP-1 and MMP-9 levels were measured at baseline and following 52 weeks of treatment. SAEI was improved only in the rosiglitazone group, and the difference was still statistically significant when the three groups were compared (p=0.024). There were no differences in LAEI in inter- and intragroup comparisons at the end of the study. Serum MMP-9 levels were decreased in the metformin (-13.5+/-34.8%, p=0.02) and rosiglitazone (-27.2+/-51.0%, p=0.023) groups compared with baseline values, whereas no significant change was seen in serum MCP-1 levels. These results suggest that rosiglitazone monotherapy has favorable effects on arterial stiffness compared with metformin monotherapy independent of glycemic control.
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PMID:Effect of rosiglitazone, metformin and medical nutrition treatment on arterial stiffness, serum MMP-9 and MCP-1 levels in drug naive type 2 diabetic patients. 1967 6

Circulating matrix metalloproteinase (MMP) levels may correlate with diabetic complications. Whether they are changed in early diabetic cardiomyopathy is not known and was examined in this study. TIMP-1 and collagen degradation products were also measured. Results from subjects with and without diastolic dysfunction were compared with those obtained for patients with varying stages of diabetic renal disease. Patients with type 2 diabetes with or without diastolic dysfunction with varying degrees of renal disease were recruited for this study. Age-matched non-diabetic subjects served as controls. MMPs (-1, -3 and -7) and TIMP-1 were measured by ELISA, MMP-2 and -9 by zymography and collagen degradation products by radioimmunoassay. Differences in the pattern of MMPs/TIMPs and collagen degradation products were observed. The most consistent change was in totalMMP-7, which was increased in those with diastolic dysfunction and those with macroalbuminuria. MMP-7 correlated with cardiac function (p<0.05 vs control, in those with diastolic dysfunction), and renal filtration function (p<0.05 vs control). In summary, we have identified novel relationships between serum MMP-7 and diabetic complications specifically in renal disease and in diastolic dysfunction. How increased circulating MMP-7 is associated with these diabetic microvascular complications and the significance of these findings will require prospective studies.
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PMID:Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction. 2009 49


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