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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of an aldose-reductase inhibitor, statil, which blocks the conversion of glucose to sorbitol, in rats rendered diabetic with streptozotocin in order to determine whether the anticipated changes in sorbitol content was associated with beneficial lack of changes in renal morphology and function. Groups of diabetic, insulin-treated and untreated rats were fed statil daily for a period of five months; each group was paired with a non-drug-treatment control group. At the conclusion of the study period, statil was not found to affect renal sorbitol concentrations nor did it effect functional or structural changes seen in the kidney. We conclude that further study, using other doses of statil and longer duration over which data is collected, must be undertaken in order to implicate the polyol pathway in the renal complications of diabetes mellitus.
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PMID:Effect of statil on kidney structure, function and polyol accumulation in diabetes mellitus. 826 69

Hypertension and diabetes appear to increase coronary heart disease risk in part by causing an abnormality in lipid metabolism. Most affected are patients with familial dyslipidemic hypertension (FDH) and noninsulin-dependent diabetes mellitus (NIDDM). The lipid disorders most often encountered in these patients are increased levels of triglycerides, very low-density lipoprotein (VLDL) cholesterol, and small, dense low-density lipoprotein (LDL) cholesterol, and low levels of high-density lipoprotein (HDL) cholesterol. These abnormalities appear to result from increased hepatic secretion of VLDL particles due to increased concentrations of free fatty acids and glucose, reduced VLDL clearance due to reduced activity of lipoprotein lipase, and reduced LDL clearance due to glycosylation of ligand proteins. Treatment of the dyslipidemia associated with FDH should follow the guidelines from the National Cholesterol Education Program. Treatment in men and women with NIDDM should be considered when LDL cholesterol levels are 130 mg/dl or above, triglyceride levels are 200 mg/dl or above, or non-HDL cholesterol levels are 160 mg/dl or greater. Aggressive lifestyle changes should be initiated first, including weight loss in obese patients, control of glucose levels in those with NIDDM, avoidance of antihypertensive drugs that may worsen lipid levels in patients with FDH, and eating a diet restricting saturated fat and cholesterol. Addition of lipid-altering drugs should be considered if such changes do not achieve effective lipid control. The agent should be tailored to the patient's lipid profile, in general by using bile acid resins, niacin, or reductase inhibitors to lower LDL cholesterol and gemfibrozil or niacin to lower triglycerides. Niacin should be avoided in patients with NIDDM.
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PMID:Understanding and treating dyslipidemia associated with noninsulin-dependent diabetes mellitus and hypertension. 836 60

Sugar alcohols have been reported to accumulate in retinal pigment epithelium (RPE) of diabetic animals. This finding has raised interest in the role of RPE in diabetes-associated retinal changes such as cystoid macular edema. To confirm the presence of aldose reductase in this tissue, the NADPH-dependent enzyme was purified to an apparent homogeneity from cultured human RPE cells, characterized, and its biochemical properties investigated. The induction of aldose reductase by hypertonic stress was also examined. The purification of aldose reductase was performed by a series of chromatographic steps which include gel filtration, affinity chromatography and chromatofocusing. Final purity achieved was monitored by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The kinetic properties and susceptibility to inhibition of the purified aldose reductase were essentially identical to aldose reductase purified from human placenta and kidney. In addition to aldose reductase, chromatofocusing demonstrated the presence of aldehyde reductase, another NADPH-dependent reductase. However, the amounts of aldehyde reductase present were much smaller than those of aldose reductase and the levels of aldehyde reductase appeared too small to contribute to the polyol production in the RPE cells. Culture of RPE cells in hypertonic medium containing 150 mM sodium chloride (600 mosmol total) increased both reductase activity, monitored with DL-glyceraldehyde as substrate, and immunoblot staining for aldose reductase. Chromatofocusing of RPE cells cultured in hypertonic media resulted in a prominent increase in the peak corresponding to aldose reductase compared to the peak height of cells grown in control medium. No increase in aldehyde reductase from RPE cells cultured in hypertonic medium was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aldose reductase in human retinal pigment epithelial cells. 840 90

The effect of simvastatin (MK-733, Banyu, Tokyo, Japan), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on triglyceride kinetics, was studied in chronically streptozocin-diabetic rats. Diabetic rats, in whom diabetes was induced by a single intravenous injection of streptozotocin (40 mg/kg body weight) 2 months before the experiment, had significantly higher plasma glucose, triglyceride, and cholesterol levels compared with nondiabetic control rats, but triglyceride secretion rate was not increased. Both triglyceride secretion rate and plasma triglyceride level were significantly suppressed under nonfasting conditions in diabetic rats fed a (0.1%) simvastatin-containing diet for 10 days. After an overnight fast, their triglyceride secretion rate was not suppressed by this diet. However, their plasma triglyceride level was significantly (50%) suppressed, suggesting improved triglyceride removal from the circulation. In diabetic rats, the newly secreted triglyceride-rich lipoprotein particles were significantly cholesterol-enriched, but simvastatin had no effect on their lipid composition. These results suggest that the hypertriglyceridemia seen in chronically diabetic rats is mainly due to a triglyceride-removal defect, and that simvastatin reduces plasma triglyceride levels in these rats both by stimulating triglyceride removal and by reducing its entry into the circulation.
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PMID:Effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on triglyceride kinetics in chronically streptozotocin-diabetic rats. 844 48

Hyperlipidemia associated with non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance is characterized by high triglyceride levels; raised levels of total low-density lipoprotein (LDL), which is made up of small, dense, cholesterol-rich particles; low levels of high-density lipoprotein (HDL); and glycosylation of apolipoproteins. Optimal drug therapy for this lipid profile is controversial. To test whether a fibrinic acid derivative (gemfibrozil) or a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (lovastatin) would produce better results in these patients, a crossover study was performed. Gemfibrozil 600 mg twice daily and, after a washout period, lovastatin 20 to 40 mg twice daily were administered to nine patients with NIDDM. Gemfibrozil significantly decreased triglyceride, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) levels, the total cholesterol:HDL ratio, and the IDL plus VLDL;HDL ratio, and significantly increased levels of HDL, HDL2, and HDL3. Lovastatin significantly decreased levels of total cholesterol, calculated LDL, directly measured LDL, IDL, total triglycerides, VLDL, and the ratios of LDL:HDL, total cholesterol:HDL, and directly measured LDL:HDL and significantly increased total HDL and HDL3 levels. Gemfibrozil was significantly more effective than lovastatin in raising total HDL and HDL3 levels and in lowering the IDL plus VLDL:HDL ratio. Lovastatin was significantly more effective than gemfibrozil in lowering total cholesterol, LDL, directly measured LDL, and the LDL:HDL and directly measured LDL:HDL ratios. In the absence of malignant hypertriglyceridemia, an HMG-CoA reductase inhibitor, rather than a fibrinic acid derivative, is indicated for the treatment of patients with dyslipidemia associated with NIDDM and insulin resistance.
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PMID:A comparison of lovastatin, an HMG-CoA reductase inhibitor, with gemfibrozil, a fibrinic acid derivative, in the treatment of patients with diabetic dyslipidemia. 859 42

Are newer types of antihypertensive agents, which are currently more costly to purchase on average, as good or better than diuretics in reducing coronary heart disease incidence and progression? Will lowering LDL cholesterol in moderately hypercholesterolemic older individuals reduce the incidence of cardiovascular disease and total mortality? These important medical practice and public health questions are to be addressed by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind trial in 40,000 high-risk hypertensive patients. ALLHAT is designed to determine whether the combined incidence of fatal coronary heart disease (CHD) and nonfatal myocardial infarction differs between persons randomized to diuretic (chlorthalidone) treatment and each of three alternative treatments--a calcium antagonist (amlodipine), an angiotensin converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). ALLHAT also contains a randomized, open-label, lipid-lowering trial designed to determine whether lowering LDL cholesterol in 20,000 moderately hypercholesterolemic patients (a subset of the 40,000) with a 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, will reduce all-cause mortality compared to a control group receiving "usual care." ALLHAT's main eligibility criteria are: 1) age 55 or older; 2) systolic or diastolic hypertension; and 3) one or more additional risk factors for heart attack (eg, evidence of atherosclerotic disease or type II diabetes). For the lipid-lowering trial, participants must have an LDL cholesterol of 120 to 189 mg/dL (100 to 129 mg/dL for those with known CHD) and a triglyceride level below 350 mg/dL. The mean duration of treatment and follow-up is planned to be 6 years. Further features of the rationale, design, objectives, treatment program, and study organization of ALLHAT are described in this article.
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PMID:Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group. 900 61

Development of atherosclerosis in diabetes patients is thought to be associated with high D-glucose-induced changes in vascular cell proliferation. This study was designed to investigate the intracellular mechanisms of altered proliferation in porcine aortic endothelial and smooth muscle cells under high D-glucose conditions. Two different technical approaches were used for determination of cell proliferation, a cell counting procedure and bromodeoxyuridine incorporation. D-Glucose diminished endothelial cell proliferation (30.3%) and increased smooth muscle cell proliferation (143%) in a dose-dependent manner. Neither D-mannitol, sucrose nor L-glucose mimicked the effect of D-glucose. Inhibition of D-glucose uptake into vascular cells by cytochalasin B prevented the effect of high D-glucose on cell proliferation. The aldose-reductase inhibitors, sorbinil and zopolrestat, little affected high D-glucose-attenuated endothelial cell proliferation, while the enhanced proliferation of smooth muscle cells was prevented by aldose-reductase inhibitors. Elevation of cellular glutathione levels yielded protection of both cell types from high D-glucose-mediated changes in cell proliferation, suggesting that high D-glucose may act via generation of oxidative species. Finally, aminoguanidine was shown to constitute a very potent inhibitor of D-glucose-induced dysfunction in vascular cell proliferation. These data suggest that high D-glucose-induced changes in cell proliferation of endothelial and smooth muscle cells are related to specific D-glucose uptake rather than hyperosmolality. Aldose-reductase seems to be mainly involved in the effect of high D-glucose only on smooth muscle cell proliferation, while in endothelial cells there is (are) other factor(s) in addition to the sorbitol pathway involved in high D-glucose-induced changes in cell proliferation.
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PMID:Intracellular mechanism of high D-glucose-induced modulation of vascular cell proliferation. 878 35

Pretreatment of porcine aortic endothelial cells with high D-glucose results in enhanced endothelium-derived relaxing factor (EDRF) formation (39%) due to increased endothelial Ca2+ release (57%) and Ca2+ entry (97%) to bradykinin. This study was designed to investigate the intracellular mechanisms by which high D-glucose affects endothelial Ca2+/EDRF response. The aldose-reductase inhibitors, sorbinil and zopolrestat, failed to diminish high D-glucose-mediated alterations in Ca2+/EDRF response, suggesting that aldose-reductase does not contribute to high D-glucose-initiated changes in Ca2+/EDRF signaling. Pretreatment of cells with the nonmetabolizing D-glucose analog, 3-O-methylglucopyranose (3-OMG), mimicked the effect of high D-glucose on Ca2+ release (41%) and Ca2+ entry (114%) to bradykinin, associated with elevated EDRF formation (26%). High D-glucose and 3-OMG increased superoxide anion (O2-) formation (133 and 293%, respectively), which was insensitive to inhibitors of cyclooxygenase (5,8,11,14-eicosatetraynoic acid [ETYA], indomethacin), lipoxygenase (ETYA, gossypol, nordihydroguaiaretic acid [NDGA]), cytochrome P450 (NDGA, econazole, miconazole), and nitric oxide (NO) synthase (L-omega N-nitroarginine), while it was diminished by desferal, a metal chelator. The gamma-glutamyl-cysteine-synthase inhibitor, buthioninesulfoximine (BSO), also increased formation of O2- by 365% and mimicked the effect of high D-glucose on Ca2+/EDRF signaling. The effects of high D-glucose, 3-OMG, and BSO were abolished by co-incubation with superoxide dismutase. Like high D-glucose, pretreatment with the O2(-)-generating system, xanthine oxidase/hypoxanthine, elevated bradykinin-stimulated Ca2+ release (+10%), Ca2+ entry (+75%), and EDRF (+73%). We suggest that prolonged exposure to pathologically high D-glucose concentration results in enhanced formation of O2-, possibly due to metal-mediated oxidation of D-glucose within the cells. This overshoot of O2- enhances agonist-stimulated Ca2+/EDRF signaling via a yet unknown mechanism.
Diabetes 1996 Oct
PMID:High D-glucose-induced changes in endothelial Ca2+/EDRF signaling are due to generation of superoxide anions. 882 76

Niacin has been used for many years to treat hyperlipidemia. It has been shown to reduce coronary death and non-fatal myocardial infarction and, in a separate analysis of long-term (15-year) follow-up, all cause mortality. It reduces total cholesterol, low density lipoprotein cholesterol (LDL-C) and triglycerides and increases high density lipoprotein cholesterol (HDL-C). Sustained-release niacin may be associated with more dramatic changes in LDL-C and triglyceride, whereas the short acting preparation causes greater increases in HDL-C. The increase of HDL-C occurs at a lower dose (1500 mg/day) than the reduction of LDL-C (> 1500 mg/day). Niacin also favorably influences other lipid parameters including lipoprotein(a) [Lp(a)], alimentary lipemia, familial defective apolipoprotein B-100 and small dense LDL. Combination of niacin with a bile acid sequestrant or a reductase inhibitor represents a powerful lipid-altering regimen. Whereas the reductase inhibitors and bile acid binding resins primarily affect LDL-C, the combined therapy has a synergistic effect to reduce LDL-C and, in addition, the niacin reduces triglycerides and increases HDL-C. The major drawback in the use of niacin is associated side effects (flushing and palpitations) and toxicity (worsening of diabetes control, exacerbation of peptic ulcer disease, gout, hepatitis). Niacin has a long history of use as a lipid lowering agent and has several attractive features. Unfortunately, the side effect profile of this agent warrants its use only in patients with marked dyslipidemia in whom side effects and potential toxicity are closely monitored.
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PMID:New developments in the use of niacin for treatment of hyperlipidemia: new considerations in the use of an old drug. 885 85

Cataract remains the major cause of blindness worldwide and a common complication of diabetes. Polyol accumulation in the lens is associated with cataract formation. Here we present evidence for a novel pathway for xylitol production in the lens involving glucuronate metabolism. Xylitol can be produced in rat and bovine lens from glucose, via the enzymes myo-inositol-oxygen oxidoreductase, D-glucuronate reductase, L-gulonate NAD(+)-3-oxidoreductase and L-iditol-NAD(+)-5-oxidoreductase, which have been found in the mammalian lens for the first time. Glucuronate reductase has been purified and was inhibited by thiol quenching reagents. UDP-glucuronyl transferase is also present in mammalian lenses; this enzyme may be an anti-toxic defense mechanism in the lens.
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PMID:Accumulation of xylitol in the mammalian lens is related to glucuronate metabolism. 889 89


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