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)

A microemulsion formulation of cyclosporin (Neoral) has been developed to overcome the problems of poor and variable absorption of cyclosporin. Neoral is a potent immunosuppressive agent that is highly bound in the plasma. It has been proposed that low-density lipoprotein (LDL) delivers cyclosporin (CsA) to T-lymphocytes via the LDL receptor pathway, where it produces its therapeutic effects. Herein, we report a case of minimal change nephrotic syndrome with type 2 diabetes mellitus treated by Neoral and fluvastatin. A 65-year-old male with a 10-year history of type 2 diabetes mellitus suddenly developed nephrotic syndrome. The potential causative drugs, such as NSAIDs and antibiotics, had not been administered. The laboratory findings were as follows: proteinuria 23 g/day, serum albumin 1.9 g/dl, total cholesterol 629 mg/dl, LDL-Cho 1,930 mg/dl. Renal biopsy was normal on light microscopy, and immunofluorescence demonstrated no staining. Due to the risk of deterioration of diabetes by administering prednisolone, he was given Neoral at 2.0 mg/kg/day. He was also given fluvastatin (40 mg/day) for hyperlipidemia after the renal biopsy. At four weeks after the start of Neoral and fluvastatin, his nephrosis continued, but his LDL-Cho and total cholesterol decreased. At six weeks after treatment, proteinuria gradually reduced. At eight weeks after treatment, the proteinuria had disappeared. Nephrotic syndrome is often associated with abnormal lipid metabolism, and many patients with nephrotic syndrome show high levels of LDL-Cho. It has been reported recently that LDL apheresis is effective against nephrotic syndrome. However, in the present case, it can be speculated that the improvement of hyperlipidemia by fluvastatin probably augmented the effect of Neoral, presumably through the increased cellular uptake of Neoral. This suggests that fluvastatin may be considered as the treatment of choice for the disturbed lipoprotein profile in patients with nephrotic syndrome.
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PMID:[Complete remission of minimal change nephrotic syndrome with type 2 diabetes mellitus treated by microemulsion formulation of cyclosporin and fluvastatin]. 1197 50

Overexpression of the renin-angiotensin system is important in the pathogenesis of macroangiopathy (MA). Patients with diabetes with end-stage renal failure have elevated serum angiotensin-converting enzyme (ACE) activity compared with their nonuremic counterparts. Because their major cause of death is MA, the significance of serum ACE activity on outcome of this group of patients is studied. We performed a prospective cohort study of 49 patients with type 2 diabetes on continuous ambulatory peritoneal dialysis (CAPD) therapy. Baseline serum ACE activity was determined by a modified spectrophotometric method and followed up at a median of 34 months. The prevalence of MA (defined as ischemic heart disease, sudden cardiac arrest, stroke, or peripheral vascular disease) and all-cause mortality rates were studied. Risk for MA is associated with serum ACE activity (median with MA, 69.0 U/L [range, 46.0 to 100.1 U/L] versus without MA, 57.2 U/L [range, 36.3 to 81.0 U/L]; P = 0.02). At the end of follow-up, 48% of patients (24 of 49 patients) died, 70% of MA. The group that died had increased baseline serum ACE activity (nonsurvivors, 65.0 U/L [range, 33.5 to 100.0 U/L] versus survivors, 49.4 U/L [range, 36.4 to 86.5 U/L]; P < 0.05) and MA rates (nonsurvivors, 77% versus survivors, 36%; P < 0.01). Cox regression analysis performed with age, sex, mean blood pressure, body mass index, metabolic control, Kt/V, residual renal function, serum albumin level, and ACE activity showed that baseline serum ACE activity (P = 0.033) is an independent predictor for mortality in patients with type 2 diabetes on CAPD therapy. Among patients with type 2 diabetes on CAPD therapy, serum ACE activity is associated with risk for MA and is an independent predictor for mortality. Whether ACE inhibition will have a beneficial effect on the outcome of these patients needs further investigation.
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PMID:Prognostic role of serum ACE activity on outcome of type 2 diabetic patients on chronic ambulatory peritoneal dialysis. 1197 50

This study describes the occurrence of 3-hydroxy-5-hydroperoxy-2-methyl-5,6-dihydropyran-4-one (HMDP) in plasma obtained from normal subjects and patients with type 2 diabetes. We have shown previously that HMDP is a novel hydrophilic hydroperoxide formed in the in vitro Maillard reaction that could be analyzed using ultrasensitive chemiluminescence detection-high-performance liquid chromatography (CL-HPLC). The HMDP concentration was 273+/-227 nmol/l in normal subjects and 656+/-535 nmol/l in patients with diabetes. The HMDP concentration was proportional to the plasma glucose concentration level (r=0.640; P<0.01) but not with the glycated hemoglobin level. To investigate the in vivo effects of HMDP, a range of concentrations of the compound was incubated for different time periods with human serum albumin and lipoproteins. HMDP was found to induce denaturation of these macromolecules by modifying lysine residues and causing cross-linking and polymerization of proteins. In the presence of metal ions such as iron and copper, HMDP induced peroxidative degradation of lipoprotein lipids as measured by an elevation in thiobarbituric acid reactive substances (TBARS) concentration. These results suggested that HMDP is produced as a consequence of both hyperglycemia and increased oxidative stress, and may have the potential to contribute to the pathogenesis of arterial complications in diabetes mellitus.
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PMID:The occurrence of a novel hydrophilic hydroperoxide, 3-hydroxy-5-hydroperoxy-2-methyl-5,6-dihydropyran-4-one, as a reactive glycation product in human plasma. 1238 41

Accumulating evidence suggests that the pathophysiology of diabetes is analogous to chronic inflammatory states. Circulating levels of inflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNFalpha) are increased in both type 1 and type 2 diabetes. TNFalpha plays an important role in the pathogenesis of insulin resistance in type 2 diabetes. However, the reason for this increase remains unclear. Levels of the dicarbonyl methylglyoxal (MGO) are elevated in diabetic plasma and MGO-modified bovine serum albumin (MGO-BSA) can trigger cellular uptake of TNF. Therefore we tested the hypothesis that MGO-modified proteins may cause TNFalpha secretion in macrophage-like RAW 264.7 cells. Treatment of cells with MGO-BSA induced TNFalpha release in a dose-dependent manner. MGO-modified ribonuclease A and chicken egg ovalbumin had similar effects. Cotreatment of cells with antioxidant reagent N-acetylcysteine (NAC) inhibited MGO-BSA-induced TNFalpha secretion. MGO-BSA stimulated the simultaneous activation of p44/42 and p38 mitogen-activated protein kinase. PD98059, a selective MEK inhibitor, inhibited MGO-BSA-induced TNFalpha release as well as ERK phosphorylation. Pretreatment of cells with NAC also resulted in inhibition of MGO-BSA-induced ERK phosphorylation. MGO-BSA induced dose-dependent NFkappaB activation as shown by electrophoresis mobility shift assay. The MGO-BSA-induced NFkappaB activation was prevented in the presence of PD98059, NAC, and parthenolide, a selective inhibitor of NFkappaB. Furthermore, the NFkappaB inhibitor parthenolide suppressed MGO-BSA-induced TNFalpha secretion. Confocal microscopy using dichlorofluorescein to demonstrate intracellular reactive oxygen species (ROS) showed that MGO-BSA produced more ROS compared with native BSA. MGO-BSA could also stimulate protein kinase C (PKC) translocation to the cell membrane, considered a key signaling pathway in diabetes. However, there was no evidence that PKC was involved in TNFalpha release based on inhibition by calphostin C and staurosporine. Our findings suggest that the presence of chronically elevated levels of MGO-modified bovine serum albumin may contribute to elevated levels of TNFalpha in diabetes.
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PMID:Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. 1250 94

A time-delayed fluorescence immunoassay was developed for the determination of serum levels of methylglyoxal (MG)-derived hydroimidazolone using a monoclonal antiserum raised against Nalpha-acetyl-Ndelta-(5-hydro-5-methyl)-4-imidazolone, Europium-labeled anti-mouse IgG antiserum as indicator, and MG modified bovine serum albumin (BSA) as standard. Serum levels of hydroimidazolone were measured in 45 patients with type 2 diabetes aged 59.4 +/- 6.1 (mean +/- SD) years and with duration of diabetes of 7.3 +/- 3.1 years, and in 19 nondiabetic controls aged 56.3 +/- 4.3 years. The serum levels of hydroimidazolone were significantly higher in patients compared to controls: median, 3.0 (5-95 percentile, 1.6 to 5.4) U/mg protein versus 1.9 (1.2 to 2.8) U/mg protein (P =.0005). Significant positive correlations were observed between the serum levels of hydroimidazolone and serum levels of advanced glycation end products (AGEs), measured with a polyclonal anti-AGE antibody: r = 0.59 for patients (P <.0001), and r = 0.65 for controls (P =.002). Similarly, significant correlations were also found between serum levels of hydroimidazolone and N(epsilon)-(carboxymethyl)-lysine (CML): r = 0.36 in patients and r = 0.55 for controls (both P =.02). Serum hydroimidazolone levels did not correlate with fasting plasma glucose or hemoglobin A(1c) (HbA(1c)) levels. The observed differences between patients with diabetes and nondiabetic controls seem to be comparable to differences measured for other AGE compounds.
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PMID:Increased serum levels of the specific AGE-compound methylglyoxal-derived hydroimidazolone in patients with type 2 diabetes. 1260 26

Serum homocysteine (sHcy) has been found to be elevated in patients with type 2 diabetes mellitus, as well as in other clinical conditions associated with insulin resistance and/or vascular diseases. The aims of this study were to measure the relationship between sHcy with biohumoral markers of insulin resistance in pregnant women affected with gestational diabetes mellitus (GDM). We studied 2 groups of pregnant women categorized, after a 100-g, 3-hour oral glucose tolerance test (OGTT) as nondiabetic (n = 78) or affected with GDM (n = 15), by measuring sHcy, serum folate, albumin, vitamin B(12), uric acid, and lipids. In both groups, peripheral insulin sensitivity was measured by using the OGTT-derived index of Matsuda and DeFronzo (ISI(OGTT)). Serum homocysteine was significantly higher in the group with GDM compared with nondiabetic women (5.88 +/- 2.26 micromol/L v 4.45 +/- 1.52 micromol/L; P =.003); was inversely related to serum folate (r = -.48; P =.0001), and was significantly related to serum albumin (r =.27; P =.009), 2-hour plasma glucose (r =.25; P =.01), as well as to serum uric acid (r =.23; P =.03). No relationship was observed between sHcy and serum vitamin B(12), serum triglycerides, total, or high-density lipoprotein (HDL) cholesterol, mean blood pressure and ISI(OGTT). Vitamin B(12) was correlated with ISI(OGTT) (r =.36; P =.0005) and inversely with mean blood pressure (r = -.24; P =.02). GDM remained significantly associated with higher sHcy concentrations also after adjusting for age, serum folate, albumin, uric acid, ISI(OGTT), and vitamin B(12) (P =.006). In conclusion, we found that sHcy is significantly increased in women with GDM, independently of other confounding variables, is significantly related to 2-hour OGTT plasma glucose, and seems unrelated to insulin resistance in these subjects.
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PMID:Serum homocysteine levels are increased in women with gestational diabetes mellitus. 1280 97

Diabetes Mellitus (DM), a state of chronic hyperglycaemia, is a common disease affecting over 124 million individuals worldwide. In this study, erythrocyte glutathione levels, lipid peroxidation, superoxide dismutase, catalase, and glutathione peroxidase and some extracellular antioxidant protein levels of patients with type II diabetes mellitus and healthy controls were investigated. Thirty-eight patients (21 males; with age of mean +/- SD, 53.1+/-9.7 years) and 18 clinically healthy subjects (10 males; with age of mean +/- SD, 49.3+/-15.2 years) were included in the study. Levels of erythrocyte lipid peroxidation, serum ceruloplasmin and glucose levels, HbA1C levels, and erythrocyte catalase activity were significantly increased, whereas serum albumin and transferrin levels, erythrocyte glutathione levels, and glutathione peroxidase activity were significantly decreased compared to those of controls. There was no significant difference in superoxide dismutase activity compared to controls. The results suggest that the antioxidant deficiency and excessive peroxide-mediated damage may appear in non-insulin dependent diabetes mellitus.
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PMID:Antioxidant status and lipid peroxidation in type II diabetes mellitus. 1291 Apr 84

Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic beta-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing beta-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate beta-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted.
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PMID:Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. 1452 86

Individuals with type 2 diabetes and nephropathy represent a particularly high-risk group for both adverse cardiac as well as renal events. Using the Irbesartan in Diabetic Nephropathy Trial (IDNT) cohort, our objective was to determine baseline characteristics of individuals with type 2 diabetic nephropathy and hypertension predictive for cardiac events. IDNT identified 1715 individuals with type 2 diabetic nephropathy and hypertension having serum creatinine of 1.0 to 3.0 mg/dL and urinary albumin excretion rates > or = 900 mg/day. A cardiovascular (CV) composite was used consisting of CV death, nonfatal MI, hospitalization for heart failure, stroke, amputation, and coronary and peripheral revascularization. Using multivariable Cox regression analysis, 41 baseline characteristics determined a priori were analyzed for their potential relationship to risk of experiencing a CV event. Of the 1715 individuals, 518 (30.2%) had at least one of the CV composite end points. Older age, male gender, longer duration of diabetes, history of cardiovascular disease, history of CHF, high urinary albumin:creatinine ratio, and low serum albumin were strong predictors for CV events; of these, prior history of CVD (RR 2.00, 95% CI 1.63-2.45; P < 0.0001) and high urinary albumin:creatinine ratio (RR 1.29 per natural log unit, 95% CI 1.13-1.48; P = 0.0002) at baseline were highly predictive for cardiovascular events. In conclusion, among individuals with hypertension and diabetic nephropathy, both the degree of albuminuria and lower serum albumin levels provide additional prognostic information concerning cardiovascular risk, in addition to traditional coronary risk factors.
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PMID:Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for albuminuria. 1548 18

Thirty-three patients with type 2 diabetes mellitus (16 men, 17 women) were divided into 3 groups based on urinary excretion of albumin (U-Alb)--group A: U-Alb < 30 mg/d; group B: 30 mg/d < or = U-Alb < or = 300 mg/d; and group C: 300 mg/d < U-Alb. Serum creatinine levels were lower than 2.0 mg/dL in all the subjects. There was no difference in age, sex, therapy, body weight, body mass index (BMI), lean body mass (LBM), or hemoglobin A(1c) (HbA(1c)) levels among the 3 groups. Resting metabolic rate (RMR) (kJ/h/m(2)) and adjusted RMR for lean body mass (kJ/h/m(2)) were significantly increased in group C compared with groups A and B. Hb concentrations, serum albumin levels, and creatinine clearance were much lower in group C than in groups A and B (P < .001). There were no difference in serum urea nitrogen, total cholesterol, cholinesterase and free thyroxine, or plasma insulin-like growth factor I (IGF-I) levels among the 3 groups. Linear regression analysis revealed an inverse correlation between RMR and serum albumin levels, correlation between RMR and U-Alb, and inverse correlation between RMR and Hb concentrations, respectively, in these patients. In conclusion, RMR in diabetic patients correlated directly with U-Alb and inversely with serum albumin and Hb concentration. These findings suggest that RMR is related with urinary albumin loss and anemia in patients with type 2 diabetes mellitus accompanied by diabetic nephropathy.
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PMID:Increased resting metabolic rate in patients with type 2 diabetes mellitus accompanied by advanced diabetic nephropathy. 1553 91


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