Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum coenzyme Q10 (CoQ10: 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34 ,38 -tetracontadecaenyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone, CAS 303-98-0) and cholesterol levels were measured to assess the effect of cholesterol-lowering therapy in patients with non-insulin-dependent diabetes mellitus (NIDDM). Twenty healthy volunteers, 97 NIDDM patients and 2 patients with familial hypercholesterolemia were studied. None had overt heart failure or any other heart disease. Mean serum CoQ10 concentrations were significantly (p < 0.01) lower in diabetic patients with normal serum cholesterol concentrations, either with or without administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) including simvastatin (normal: 0.91 +/- 0.26 (mean +/- SD) mumol 1(-1); diabetic with HMG-CoA RI: 0.63 +/- 0.19; diabetic without HMG-CoA RI: 0.66 +/- 0.21). CoQ10 concentrations were higher (1.37 +/- 0.48, p < 0.001) in diabetic patients with hypercholesterolemia. Simvastatin or low density lipoprotein apheresis decreased serum CoQ10 concentrations along with decreasing serum cholesterol. Oral CoQ10 supplementation in diabetic patients receiving HMG-CoA RI significantly (p < 0.001) increased serum CoQ10 from 0.81 +/- 0.24 to 1.47 +/- 0.44 mumol 1(-1), without affecting cholesterol levels. It significantly (p < 0.03) decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7%. In conclusion, serum CoQ10 levels in NIDDM patients are decreased and may be associated with subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.
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PMID:Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients. 1033 51

Most clinical trials of lipid intervention and coronary artery disease prevention have been conducted in study populations that exclude diabetic individuals. Three trials have conducted post hoc analyses of their diabetic subgroups. One of these was a primary intervention trial with gemfibrozil (Helsinki Heart Study). Although this trial found a reduction in coronary events, the numbers were too small to reach significance. The two other trials (the Scandinavian Simvastatin Survival Study [4S] and Cholesterol and Recurrent Events Trial [CARE]) were secondary intervention trials conducted with hydroxymethylglutaryl-CoA reductase inhibitors, simvastatin, and pravastatin. Both of these trials found a reduction in coronary events. Although these two trials present the strongest evidence in support of the clinical benefits of lipid reduction in diabetes, they must be interpreted with caution. They are post hoc subgroup analyses, they looked at mainly hypercholesterolemic populations, and they are secondary intervention studies. Four studies aimed at testing the "lipid hypothesis" specifically in diabetes are currently under way. Three of these studies (Fenofibrate Intervention and Event Lowering in Diabetes [FIELD], Collaborative Atorvastatin Diabetes Study [CARDS], and Lipids in Diabetes Study [LDS]) are primary prevention trials, with clinical events as the primary end point. FIELD uses micronized fenofibrate, CARDS uses atorvastatin, and LDS uses both micronized fenofibrate and cerivastatin alone or in combination. These trials are in the early stages of starting or recruiting. One study (Diabetes Atherosclerosis Intervention Study [DAIS]) using micronized fenofibrate is nearing completion. It is an angiographic study that combines those with and without preexisting clinical coronary disease.
Diabetes Care 2000 Apr
PMID:Lipid intervention trials in diabetes. 1086 Jan 91

The reverse tetracycline-dependent transactivator system was employed in insulinoma INS-1 cells to achieve controlled inducible expression of hepatocyte nuclear factor-1 alpha (HNF1 alpha)-P291fsinsC, the most common mutation associated with subtype 3 of maturity-onset diabetes of the young (MODY3). Nuclear localized HNF1 alpha-P291fsinsC protein exerts its dominant-negative effects by competing with endogenous HNF1 alpha for the cognate DNA-binding site. HNF1 alpha controls multiple genes implicated in pancreatic beta-cell function and notably in metabolism- secretion coupling. In addition to reduced expression of the genes encoding insulin, glucose transporter-2, L-pyruvate kinase, aldolase B and 3-hydroxy-3-methylglutaryl coenzyme A reductase, induction of HNF1 alpha-P291fsinsC also significantly inhibits expression of mitochondrial 2-oxoglutarate dehydrogenase (OGDH) E1 subunit mRNA and protein. OGDH enzyme activity and [(14)C]pyruvate oxidation were also reduced. In contrast, the mRNA and protein levels of mitochondrial uncoupling protein-2 were dramatically increased by HNF1 alpha-P291fsinsC induction. As predicted from this altered gene expression profile, HNF1 alpha-P291fsinsC also inhibits insulin secretory responses to glucose and leucine, correlated with impaired nutrient-evoked mitochondrial ATP production and mitochondrial membrane hyperpolarization. These unprecedented results suggest the molecular mechanism of HNF1 alpha-P291fsinsC causing beta-cell dysfunction.
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PMID:Molecular targets of a human HNF1 alpha mutation responsible for pancreatic beta-cell dysfunction. 1094 8

The incidence of coronary heart disease (CHD) is greatly increased in overweight diabetic patients. Modification of dietary intake and weight loss improve hypercholesterolaemia. However, cholesterol goal levels are not achieved in several patients under this treatment. The aim of our study was to evaluate the effect of Cerivastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in patients with type 2 diabetes mellitus. A population of 40 diabetic type 2 outpatients were analyzed in a prospective way. The mean+/-SD age was 60.7+/-11.6 years, with a diabetes duration of 8.5+/-6.6 years. All patients were treated with cerivastatin (0.2 mg once a day) for 6 months. Weight HbAlc fasting blood glucose, urine microalbuminuria, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were measured at the beginning of the study and again after 3 and 6 months of treatment with cerivastatin. An improvement in lipid levels was achieved, with a significant decrease in LDL-cholesterol (27.7%), total cholesterol (21.4%), triglycerides levels (10.4%) and a significant increase in HDL-cholesterol levels (8.3%) (P<0.05). Cardiovascular risk ratios such as; total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol improved during treatment, decreasing 11.3% and 30%, respectively (P<0.05). Low incidence of side effects was demonstrated. In summary, cerivastatin improved lipid control in patients with type 2 diabetes, with a low incidence of side effects.
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PMID:Effect of cerivastatin on serum cholesterol levels in patients with type 2 diabetes mellitus. 1103 Oct 77

Cardiovascular disease (CVD) is a major cause of morbidity and mortality among patients with chronic renal insufficiency (CRI). beta-Adrenergic blockers, acetylsalicylic acid (ASA), angiotensin-converting enzyme (ACE) inhibitors, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) all reduce CVD mortality, but little is known about the extent to which these medications are used in patients with CRI. This study, a prospective cross-sectional study of consecutive patients seen by nephrologists in four Canadian centers for follow-up of progressive CRI in 1999, was performed to investigate the prevalence of coronary risk factors and use of cardioprotective medications among patients with CRI. Patients had creatinine clearances of 75 mL/min or less but were not on dialysis therapy. Three hundred four consecutive patients meeting the inclusion criteria were enrolled. Mean age was 60.8 +/- 15.7 years, mean creatinine clearance was 30.3 +/- 18 mL/min, and the case mix of kidney diseases was similar to that in the Canadian Organ Replacement Registry data. One hundred seventeen of 304 patients (38.5%) had a history of previous CVD, and the prevalence of CVD was greater in patients with more severe CRI. Two hundred forty-three patients (79.9%) had a history of hypertension, 132 patients (43.4%) had hyperlipidemia, 114 patients (37.5%) had diabetes mellitus, and 71 patients (27.3%) were smokers. Thirty-five percent of the patients with CVD had blood pressures greater than 140/90 mm Hg; 103 patients (33.9%) were administered beta-blockers; 196 patients (64.5%), ACE inhibitors or angiotensin-receptor blockers; 83 patients (27.3%), ASA; and 56 patients (18.4%), statins. Patients with diabetes were not more likely than those without diabetes to be prescribed cardioprotective medications. CVD is common in the predialysis population, and its prevalence increases with more severe kidney failure. Despite this, the use of cardioprotective medications is relatively low, and many patients had suboptimal blood pressure control. Given the high burden of disease in these patients, beta-blockers and ACE inhibitors should be used to control hypertension and/or for cardioprotection, and the increased use of ASA and statins should be considered.
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PMID:Cardiac risk factors and the use of cardioprotective medications in patients with chronic renal insufficiency. 1122 71

Oxidative stress may be an important factor in the development of diabetic complications. Advanced glycation end-products have drown attention as potential sources of oxidative stress in diabetes. We investigated the protective effects of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on oxidative DNA damage from reactive oxygen species or advanced glycation end-products in vitro, as well as effects of main fluvastatin metabolites and other inhibitors of the same enzyme, pravastatin and simvastatin. Protective effects were assessed in terms of the DNA breakage rate in a single-stranded phage DNA system in vitro. DNA was exposed to either reactive oxygen species or advanced glycation end-products. Fluvastatin and its metabolites showed a strong protective effect comparable to those seen with thiourea and mannitol, though pravastatin and simvastatin did not exert clear protective effects. Furthermore, fluvastatin reduced the mutagenesis by reactive oxygen species or advanced glycation end-products in Salmonella typhimurium test strains. Both pravastatin and simvastatin still lacked protective activity. Fluvastatin and its metabolites protect against oxidative DNA damage and may reduce risk of consequent diabetic complications.
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PMID:Protective effects of fluvastatin against reactive oxygen species induced DNA damage and mutagenesis. 1123 94

The nephrotic syndrome, caused by glomerulonephritis, diabetes mellitus, or amyloidosis, is still a therapeutic challenge. Newer therapeutic approaches may be sought in the fields of immunosuppression, nonspecific supportive measures, heparinoid administration, and removal of a supposed glomerular basement membrane toxic factor. In immunosuppression, the newer drugs now used in organ transplantation (cyclosporine, tacrolimus, and mycophenolate mofetil) can also be used in the treatment of glomerulonephritis. In nonspecific supportive treatment, angiotensin II receptor antagonists are now used in addition to angiotensin-converting enzyme inhibitors. Positive effects of hydroxymethylglutaryl coenzyme A reductase inhibitors on the nephrotic syndrome have not yet been proven. Cyclooxygenase II inhibitors must be tested but probably have too many renal side effects, similar to those of nonsteroidal anti-inflammatory drugs. Heparinoids or glycosaminoglycans serve as polyanions and thus have protective effects on the negative charge of the glomerular basement membrane. They can now be administered as oral medications. The removal of a supposed glomerular basement membrane toxic factor that induces proteinuria has been attempted for 20 yr and now is usually performed using immunoadsorption. Especially in cases of recurrent nephrotic syndrome after renal transplantation for patients with glomerulonephritis, this approach has been successful in decreasing proteinuria, although in most cases its effect is not lasting but must be continuously renewed.
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PMID:New aspects of the treatment of nephrotic syndrome. 1125 Oct 31

The liver plays a central role in lipoprotein metabolism and cholesterol homeostasis. As the physiopathology of lipid disorders in non-insulin-dependent diabetes mellitus (NIDDM) is multifactorial and still imperfectly known, we evaluated its onset on plasma lipid transport and hepatic cholesterol metabolism in Psammomys obesus. This sand rat lapses into hyperinsulinemia and hyperglycemia when transferred from its native food to laboratory rodent diets. Marked hypertriglyceridemia and hypercholesterolemia developed in hyperinsulinemic (Group B) and hyperglycemic/ hyperinsulinemic (Group C), compared with normal P. obesus (Group A). Group B showed significantly (P<0.05) higher plasma VLDL-cholesterol (41.9%) and LDL-cholesterol (47.3%) concentrations, whereas Group C was characterized by an even more marked increase in VLDL-cholesterol (176%, P<0.001) compared with Group A. Lipoprotein composition was also altered, displaying impaired lipid and apolipoprotein moiety distribution in IDL, LDL, HDL(2) and HDL(3) lipoprotein fractions of Groups B and C. The activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, was consistently lower in Group B (P<63.4%, P<0.001) and C (43.9%, P<0.005). In contrast, the direct measurement of microsomal acyl-CoA:cholesterol acyltransferase (ACAT), controlling the acylation of cholesterol, showed an increase averaging 53% in Group B (P<0.01) and 61% in Group C (P<0.005). Similarly, elevated activity (171.1%, P<0.05 and 291.4%, P<0.001, respectively) was related to cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. These alterations were accompanied with abundant deposition of triglycerides and cholesterol in the liver. Changes in circulating lipids and liver parameters were related to glucose and insulin levels, indicating the implication of insulin resistance and diabetes. Therefore, our findings demonstrate various disturbances in plasma lipid profile and lipoprotein composition, as well as in liver cholesterol metabolism during the sequential development of insulin resistance and diabetes in P. obesus rats. Furthermore, the current data point to an undoubtedly important role of the liver in the pathogenesis of metabolic disorders in the progression of nutritionally-induced insulin resistance and diabetes in P. obesus. Finally, current research shows that more marked plasma and hepatic lipid perturbations occur in insulin resistance than in diabetes, which may culminate in the development of atherosclerosis.
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PMID:Circulating lipoproteins and hepatic sterol metabolism in Psammomys obesus prone to obesity, hyperglycemia and hyperinsulinemia. 1142 7

The increased risk of coronary artery disease among patients with diabetes mellitus is attributable, in part, to specific disorders of lipoprotein metabolism that are common in this population. These include disordered metabolism of very-low-density lipoprotein and/or chylomicrons that may be proatherogenic. Elevated postprandial triglycerides, peak postprandial triglyceridemia, and late postprandial triglyceride levels have been associated in clinical trials with both early coronary artery and carotid artery atherosclerosis for persons with normal lipid profiles and those with mild-to-moderate hyperlipidemia, independently of established risk factors. If hyperlipidemia cannot be managed through better glycemic control, diet, and exercise, then hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, fibric acid derivatives, and omega-3 fatty acids are safe and effective lipid-altering agents that can be used to correct these disorders.
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PMID:Postprandial dyslipidemia: an atherogenic disorder common in patients with diabetes mellitus. 1157 20

Chronic renal insufficiency is characterized by specific abnormalities in lipoprotein metabolism, affecting both apolipoprotein A (apo A)- and apo B-containing lipoproteins. To evaluate the effects of fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on renal dyslipoproteinemia, we performed a randomized, double-blind, placebo-controlled, two-way, period cross-over study. Study patients were administered fluvastatin, 40 mg/d, or placebo during 8 weeks in randomized order. Forty-five nonnephrotic patients (28 men, 17 women) without diabetes with moderate to advanced chronic renal insufficiency participated in the study. Their mean age was 56.4 +/- 11.0 years. Glomerular filtration rate ranged from 12 to 44 mL/min/1.73 m2 of body surface area (mean, 27.5 +/- 10.5 mL/min/1.73 m2). Fluvastatin treatment resulted in significant reductions in the primary outcome variables low-density lipoprotein cholesterol (LDL-C; -26%; P < 0.001), apo B (-21%; P < 0.001), and lipoprotein B complex (Lp-Bc) (-14%; P < 0.01). There were statistically significant differences between fluvastatin and placebo treatment for the secondary outcome variables total cholesterol (-19%), triglycerides (TGs; -13%), VLDL-C (-13%), apo E (-13%), and Lp-B (-22%). There was no treatment effect on high-density lipoprotein cholesterol or lipoprotein(a). Fluvastatin treatment was well tolerated, with no serious adverse events during the study. In conclusion, fluvastatin treatment was well tolerated in patients with moderately advanced renal insufficiency and led to a significant reduction in cholesterol-rich, but to a lesser extent in TG-rich, apo B-containing lipoproteins. It remains to be clarified whether these positive changes in lipoprotein profile also will result in attenuation of the atherosclerotic process in these patients, as well as beneficially affect the progression of chronic renal failure.
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PMID:Fluvastatin improves lipid abnormalities in patients with moderate to advanced chronic renal insufficiency. 1177 4


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