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)

Statins reduce coronary heart disease risk by altering blood lipids and other mechanisms. One of the possible other mechanisms is through an effect on thrombosis. We assessed the effect of simvastatin 80 mg daily versus placebo given in a single blind crossover fashion on platelet size in response to standard ex vivo stimuli, a surrogate for platelet activation, in 12 subjects with type 2 diabetes and mixed dyslipidemia. Exposure to collagen, cold, and heat caused the expected changes in platelet volume. Contrary to our expectations, ex vivo platelet size during collagen and cold exposure increased by 2.6 and 1.7%, respectively (P < 0.05), during simvastatin treatment as opposed to the placebo period. We conclude that some of the effects of high dose simvastatin therapy on platelets may not necessarily be anti-atherogenic.
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PMID:The effect of high dose simvastatin on, platelet size in patients with, type 2 diabetes mellitus. 1692

Leptin is a peptide hormone that is mainly, but not exclusively, produced in adipose tissue and plays a pivotal role in regulating food intake and energy expenditure. Besides its effects on regulation of body weight, appetite and energy expenditure, leptin exhibits influence on the immune system and may contribute to the deterioration of renal function. These direct and indirect renal effects of leptin could partly explain obesity-associated kidney disease and may be also relevant for diabetic nephropathy in type 2 diabetes. Leptin is primarily metabolized in the kidney, presumably by binding to megalin, a multiligand receptor in the proximal tubule, tubular uptake and endocytosis. The kidney expresses abundant concentrations of the small isoform of the leptin receptor (Ob-Ra). In cultured renal rat endothelial cells and mesangial cells obtained from db/db mice, leptin can signal through the Ob-Ra receptor isoform. The peptide stimulates proliferation of glomerular endothelial cells, increases TGF-beta1 synthesis, and collagen type IV production. In contrast, leptin did not influence TGF-beta1 production in mesangial cells, but the peptide stimulates glucose transport in these cells, increased collagen type I synthesis, and lead to an upregulation of surface TGF-beta type II receptors through signal transduction pathways involving phosphatidylinositol-3-kinase. Leptin also stimulates hypertrophy, but not proliferation in cultured rat mesangial cells. Infusion of leptin for 3 weeks into normal rats fosters development of glomerulosclerosis and proteinuria. In addition, transgenic mice with leptin overexpression demonstrated a increase in collagen type IV and fibronectin mRNA in the kidney. Additional previously described direct and indirect effects of leptin on the kidney include natriuretic effects, an increase in sympathetic nervous activity, and stimulation of reactive oxygen species. These findings collectively suggest that the kidney is a target organ for leptin and that this hormone might play an important role in renal pathophysiology.
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PMID:Leptin and renal fibrosis. 1692 41

Patients with diabetes mellitus are known to develop osteopenia and osteoporosis, apparently as a reduction in the process of bone formation. In order to evaluate whether bone-modulating hormones--estradiol, testosterone, and 1,25(OH)(2)D(3)--have different effects on osteoblasts derived from diabetic and from normal non-diabetic rats, we studied the specific effects of these hormones on the differentiation and function of cultured osteoblasts derived from 1-year-old Cohen diabetic rats. (The Cohen diabetic model consists of a diabetic-sensitive strain [CDs; diabetic] and a diabetic-resistant strain [CDr; normal]). The CDs and CDr male and female rats were fed on a regular diet (RD) or a high-sucrose low-copper diet (HSD; diabetogenic). On the HSD diet, only CD rats develop type 2 diabetes, while CDr do not. Bones were removed for primary osteoblast cultures, and osteoblastic responses to the bone-modulation hormones--estradiol, testosterone, and 1,25(OH)(2)D(3)--were studied. In male rats fed RD, primary cultures of osteoblasts without hormone addition to the culture medium showed that alkaline phosphatase (ALP) activity was similar in the Cohen diabetic rats (both CDr and CDs) to that of the original Sabra strain. However, collagen synthesis was reduced in the CDr and CDs compared to the Sabra strain. The addition of the hormones to the culture medium did not change ALP activity or collagen synthesis in the male-derived osteoblasts, but increased mineralization in all strains. In female rats (studied only in CDs and CDr animals) there were no differences between animals fed the RD. HSD increased the basal activity of ALP in the CDr but not in the CDs rats, and decreased the rate of collagen synthesis in both CDr and CDs (diabetic) animals. The addition of the bone-modulation hormones to the culture medium further increased ALP activity in the osteoblasts derived from the CDr animals, while decreasing ALP activity in the CDs. These hormones also decreased collagen synthesis in both strains and increased mineralization in all osteoblasts. In conclusion, the metabolic status (HSD and diabetes) in rats prior to culture affected the phenotype of cultured osteoblasts, decreasing their response to bone-modulation hormones. This decreased response, especially to estradiol, may be a major cause of the osteopenia observed in diabetes.
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PMID:Decreased response of osteoblasts obtained from aged Cohen diabetic sensitive rats to sex steroid hormones and 1,25OH2D3 in culture. 1699 16

The Otsuka Long-Evans Tokushima fatty rat is an animal model of Type 2 diabetes mellitus (DM), which is characterized by diastolic dysfunction associated with decreased sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a). The aim of this study was to examine whether gene transfer of SERCA2a can influence coronary blood flow and cardiomyocyte diameter in this model. DM rats were injected with adenovirus carrying SERCA2a (DM+SERCA) or beta-galactosidase gene (DM+betaGal). Coronary blood flow was measured in cross-circulated excised hearts 3 days after infection. Although in all groups coronary blood flow remained unchanged even if left ventricular (LV) volume or intracoronary Ca(2+) infusion was increased, the DM+SERCA group showed a sustained increase in coronary blood flow compared with the other groups. This result suggests that the sustained high coronary blood flow is a specific response in SERCA2a-overexpressed hearts. Although the LV weight-to-body weight ratio (LV/BW) and cardiomyocyte diameter were higher in the DM and DM+betaGal groups than in the non-DM group, in the DM+SERCA group, these measurements were restored to non-DM size. The percentages of collagen area in the three DM groups was significantly higher than results shown in non-DM rats, and there were no significant differences in collagen area percentage among the three DM groups. These results suggest that a lowered LV/BW by SERCA2a overexpression is due mainly to reduced size of cardiomyocytes without any changes in collagen area percentage. In conclusion, in DM failing hearts, SERCA2a gene transfer can increase coronary blood flow and reduce cardiomyocyte size without reduction in collagen production.
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PMID:Transcoronary gene transfer of SERCA2a increases coronary blood flow and decreases cardiomyocyte size in a type 2 diabetic rat model. 1701 46

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

Scleredema of Buschke or scleredema diabetorum is a skin complication of diabetes with deposits of collagen and aminoglycans in the dermis. This disease characterized by thickening and hardening of the skin, is usually localized in nape, back and shoulder areas. Consequences could be a decrease in motility of the shoulders and an impairment of respiratory function. Other possible complications are sleep apnoea syndrome and monoclonal gammapathy. Type 1 or type 2 diabetes may be associated with scleredema of Buschke in more than 50% of cases. Diabetes-related risk factors are long duration of the disease, presence of microangiopathy, overweight and need of insulin. Various specific treatments proposed in the literature are poorly validated. In most severe cases, radiation therapy may be useful.
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PMID:Scleredema adultorum of Buschke: an under recognized skin complication of diabetes. 1711 Sep 4

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

Both diabetes and advanced age have been implicated in delaying wound repair. However, the contribution of age alone has not been shown clinically to significantly impair the ability to heal. To determine the contribution of age and db/db genotype multiple wound healing parameters were determined in young db/db mice, aged db/db mice, age-matched non-db/db control and wild-type C57BL/6 mice. Biomechanical properties (breaking load and tensile stiffness), epithelialization, and collagen deposition were determined for the four groups of mice 14 days after wounding with suture-closed incisional wounds. While neither hyperglycemia nor age alone caused impairment in biomechanical properties, the combination of age and db/db genotype resulted in a 36% reduction in stiffness and a 42% reduction in breaking load, when compared to young control mice, suggesting poor quality of healing. Statistically significant differences in the volume of granulation tissue deposited within the wound site were also observed, with the aged db/db mice displaying more than any other group, suggesting greater dermal loss from the dermal edges of incisional wounds in aged db/db mice, suggesting that the combination of age and diabetes act synergistically to impair healing in mice with type 2 diabetes. Interestingly, the impairment occurs independently of the prevailing glycemia, supporting the hypothesis that diabetes in synergy with advanced age has downstream effects, leading to further impairment, necessitating initiation of early and aggressive intervention in elderly patients with diabetic foot ulcers.
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PMID:The synergism of age and db/db genotype impairs wound healing. 1727 36

To develop a minipig model of type 2 diabetes that simulates the common manifestations of the metabolic abnormalities and resembles the kidney pathology of type 2 diabetes in the human population, male Chinese Bama minipigs were divided into 2 groups (5 in each) and fed with a control diet (CD) or high-fat/ high-sucrose/ high-cholesterol diet (HFSCD) for 5 months. The biochemical parameters of blood and urine, and the oral glucose tolerance test were monitored after the feeding program. The insulin resistance was estimated by the HOMA-IR index and the glucose elimination constant (K(G)), and beta-cell function by the HOMA-beta index and the acute insulin response (AIR). Glomerulosclerosis index (GSI) was semi-quantitated by the degree of glomerular lesions in kidney sections stained with Masson trichrome. Extracellular matrix deposition in the kidney was examined by the protein expression of type IV collagen, connective tissue growth factor (CTGF) and matrix metalloproteinases 2 (MMP-2) using immunohistochemistry. Feeding HFSCD to minipigs markedly caused hyperglycaemia, hyperinsulinaemia and dyslipidaemia. HOMA-IR was significantly increased while HOMA-beta, AIR and K(G) were obviously decreased in the HFSCD group compared with control group. Microalbuminuria, glucosuria and moderate glomerulosclerosis were exhibited in HFSCD-fed minipigs. The expression of type IV collagen and CTGF was elevated whereas that of MMP-2 was reduced in the kidneys of HFSCD group compared with the CD group. We concluded that feeding HFSCD to Chinese Bama minipigs for 5 months can induce humanoid type 2 diabetes and early-stage diabetic nephropathy, and accelerate extracellular matrix deposition and glomerulosclerosis.
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PMID:Severe insulin resistance and moderate glomerulosclerosis in a minipig model induced by high-fat/ high-sucrose/ high-cholesterol diet. 1728 86


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