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)

Studies were undertaken to examine cholesterogenesis in the intestine of streptozotocin-diabetic rats by measuring incorporation of [2(-14)C] acetate into cholesterol and 3-hydroxy-3-methylgultaryl CoA reductase (HMG-CoA reductase, EC 1.1.1.34) activity. In these diabetic rats, the intestinal mucosal weight and food consumption were markedly high. The incorporation of [2(-14)C] acetate into cholesterol was significantly increased in all diabetic intestinal segments. However, the rates of production of fatty acids and carbon dioxide were not affected. Hepatic HMG-CoA reductase activities were markedly reduced during both the diurnal high and low periods in these diabetic rats, and there was no diurnal variation. In contrast, the specific activities of this enzyme in jejunal crypt cells during both the diurnal high and low periods were significantly higher in these diabetic rats without loss of diurnal variation. Total reductase activity per segment of intestine in jejunal and ileal mucose (villi + crypt cells) was increased in these diabetic rats. Control rats had higher total and specific activity of ileal mucosal (velli + crypt cells) reductase than of jejunal mucosal reducatse during the diurnal high period. The jejunal-ileal gradient in reductase activity and the incorporation of [2(-14)C] acetate into cholesterol did not change significantly with streptozotocin-diabetic rats. The results indicate that in streptozotocin-diabetic rats, hepatic cholesterogenesis decreases but intestinal synthesis increases.
Diabetes 1977 May
PMID:Influence of streptozotocin diabetes on intestinal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in the rat. 14 87

The effect of diabetes control on the activities of hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase), cholesterol acyltransferase (ACAT), and phenol 2-monooxygenase, the major enzymes regulating cholesterol metabolism, was determined in alloxan-induced diabetic rabbits, and the results obtained were correlated with lipid and lipoprotein levels. Although intestinal HMG-CoA reductase activity was significantly increased (P less than 0.001) in poorly controlled compared with moderately controlled diabetic rabbits, there was a significant reduction in the activities of intestinal ACAT (P less than 0.01), hepatic HMG-CoA reductase (P less than 0.05) and ACAT (P less than 0.001), and phenol 2-monooxygenase (P less than 0.01). The poorly controlled animals were hypercholesterolemic (P less than 0.01), and this was reflected in the very-low-density and high-density lipoprotein fractions. Serum cholesterol levels in the nondiabetic and moderately controlled diabetic groups were similar. This increase in intestinal HMG-CoA reductase activity in the poorly controlled diabetic animals occurred in the absence of hyperphagia. Although abnormalities in cellular cholesterol metabolism could be partly responsible for the alterations in serum cholesterol levels in diabetes, the precise mechanisms underlying these enzymatic changes have yet to be elucidated.
Diabetes 1990 May
PMID:Cholesterol metabolism in alloxan-induced diabetic rabbits. 233 20

The expressed and total activities of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase (EC 1.1.1.34) were measured in microsomal fractions prepared from cold-clamped liver samples [Easom & Zammit (1984) Biochem. J. 220, 733-738] from control or insulin-treated diabetic animals. Streptozotocin-induced diabetes resulted in a marked decrease in total activity of HMG-CoA reductase and in the fraction of the enzyme in the active form, but appreciable effects were only observed in the liver of animals in which the blood glucose was above 20 mM. Intravenous infusion of insulin into diabetic rats resulted in a rapid (less than 20 min) and total dephosphorylation of the enzyme in vivo without any change in total activity. Longer-term (4 h) treatment with insulin (injected intraperitoneally) produced a rapid increase in expressed/total HMG-CoA reductase activity ratio to about 90%, followed, after a lag of 2-3 h, by a 5-6-fold increase in total activity. These observations are discussed with respect to the possible role of insulin in generating and maintaining the respective diurnal rhythms in total and in expressed/total HMG-CoA reductase activity ratio observed for normal animals in vivo [Easom & Zammit (1984) Biochem. J. 220, 739-745].
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PMID:Effects of diabetes on the expressed and total activities of 3-hydroxy-3-methylglutaryl-CoA reductase in rat liver in vivo. Reversal by insulin treatment. 390 28

Human low-density lipoprotein (LDL) was glucosylated by incubation in vitro with glucose (20-80 mM) with or without addition of cyanoborohydride. The incorporation of covalently bound glucose was linear over time, and amino acid analysis showed the presence of glucosyllysine residues. The glucosylated LDL (glc LDL) moved more rapidly than normal LDL on agarose electrophoresis. The rate of degradation of 125I-labeled glucosylated LDL (glc LDL) by cultured human fibroblasts was reduced compared with that of native I-LDL, the difference increasing with extent of glucosylation. Effects were seen with blockage of as few as 6-15% of the LDL lysine residues; high-affinity degradation was completely lost when one-third of the lysine residues were blocked. Conjugation of LDL with glucose-6-phosphate also blocked high-affinity uptake and degradation. Whereas native LDL uptake inhibited the activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase and stimulated acyl coenzyme A:cholesterol acyltransferase activity, glc LDL had no effects on these enzymes. The fractional catabolic rate of glc LDL in guinea pigs was reduced. Degradation of glc LDL by mouse peritoneal macrophages was not significantly faster than that of native LDL. Finally, the presence of glc LDL in human plasma was demonstrated. Preliminary data show that 1.3% of lysine residues in normal LDL and 2-5.3% of lysines in diabetic LDL were glucosylated. Since, like other plasma proteins, LDL undergoes glucosylation in diabetes, its turnover and sites of catabolism may differ from normal and this may be relevant to the accelerated atherosclerosis of diabetes.
Diabetes 1982 Apr
PMID:Nonenzymatic glucosylation of low-density lipoprotein alters its biologic activity. 681 75

Rats with streptozotocin-induced diabetes stop growing, develop high cholesterol and triacylglycerol levels in plasma, and have decreased activity of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC 1.1.1.34), in liver and increased activity in small intestine. They also eat more than normal. To determine the contribution of hyperphagia to these changes in lipid metabolism, we restricted intake of chow to the amount eaten ad lib by normal rats. Rats were meal-fed for 8 or 22 days from the time diabetes was induced. This regimen normalized reductase activity in both liver and intestine at mid-dark and mid-light, and all but eliminated high plasma cholesterol and triacylglycerol levels, although plasma insulin remained low and glucose remained high. Activation of hepatic reductase by endogenous phosphatase in vitro was reduced in hyperphagic diabetic rats but was normal in diabetic rats eating a normal amount of food. We conclude that hyperphagia, rather than direct effects of insulin deficiency as is usually assumed, is responsible for perturbations of lipid metabolism in chronically diabetic rats. These results support the proposal that hyperphagia increases the input of dietary and newly synthesized cholesterol from the small intestine, and that this increased input raises plasma cholesterol level and inhibits reductase activity in liver.
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PMID:Preventing hyperphagia normalizes 3-hydroxy-3-methylglutaryl-CoA reductase activity in small intestine and liver of diabetic rats. 695 13

We examined the effect of streptozotocin-induced diabetes on the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC 1.1.1.34), in liver and small intestine of rats. During the acute phase of insulin deficiency (first day), food intake, plasma cholesterol, and reductase specific activity in liver all decreased. By 3 days, food intake, plasma cholesterol, and reductase activity in small intestine were all increasing. After 1 week, total reductase activity in small intestine was 2.5 times normal, whereas activity in liver remained low. Thus diabetes shifted the major site of cholesterol synthesis from the liver to the small intestine. These data support the proposal that hyperphagia by diabetic rats leads to increased input of both dietary and newly synthesized cholesterol by the small intestine into thoracic lymph and thereby contributes significantly to their hypercholesterolemia. The possibility that diabetes affected the F--inhibitable activation of reductase in vitro was also tested. There was no evidence of an effect in small intestine, but activation of reductase in vitro was decreased by 1/3 in liver. These data suggest that, in liver, either the activity of the activator was decreased or the fraction of reductase in the active state was increased after more than 12 hr of insulin deficiency.
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PMID:Total hydroxymethylglutaryl CoA reductase activity in the small intestine and liver of insulin-deficient rats. 704 79

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

In the Brazilian cerrado, a preparation obtained from the fruits of Solanum lycocarpum St.-Hil. (Solanaceae), popularly known as 'fruta-de-lobo' (wolf-fruit), have been widely employed for diabetes management, obesity and to decrease cholesterol levels. The medicinal preparation consists of the green fruits which are ground in aqueous solution and filtered. The white 'gum' deposited is decanted and slowly dried providing a powder which is commercialized in capsules with the name of 'polvilho-de-lobeira'. Through phytochemical analysis of this phytomedicine and the fruit of S. lycocarpum we found polysaccharides as the main component. Some polysaccharides slow gastric emptying and act on the endocrinous system affecting the liberation of gastrointestinal hormones, lowering blood glucose levels. The hypocholesterolemic activity could be due to the increased fecal bile acid excretion as well as to the action of the short-chain fatty acids, coming from fermentation, on the synthesis of delta-aminolevulinate and by the increase of the cholesterol 7-alpha-hydroxylase and 3-hydroxy-3-methylglutaryl CoA reductase synthesis.
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PMID:The use of complex polysaccharides in the management of metabolic diseases: the case of Solanum lycocarpum fruits. 1090 83

We previously have found that advanced glycation end products (AGE), senescent macroproteins formed at an accelerated rate in diabetes, arise in vivo not only from glucose but also from reducing sugars. Furthermore, we recently have shown that glyceraldehyde- and glycolaldehyde-derived AGE (glycer- and glycol-AGE) are mainly involved in loss of pericytes, the earliest histopathological hallmark of diabetic retinopathy. However, the effects of these AGE proteins on angiogenesis, another vascular derangement in diabetic retinopathy, remain to be elucidated. In this study, we investigated whether these AGE proteins elicit changes in cultured endothelial cells that are associated with angiogenesis. When human skin microvascular endothelial cells (EC) were cultured with glycer-AGE or glycol-AGE, growth and tube formation of EC, the key steps of angiogenesis, were significantly stimulated. The AGE-induced growth stimulation was significantly enhanced in AGE receptor (RAGE)-overexpressed EC. Furthermore, AGE increased transcriptional activity of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) and then up-regulated mRNA levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in EC. Cerivastatin, a hydroxymethylglutaryl CoA reductase inhibitor; pyrrolidinedithiocarbamate; or curcumin was found to completely prevent the AGE-induced increase in NF-kB and AP-1 activity, VEGF mRNA up-regulation, and the resultant increase in DNA synthesis in microvascular EC. These results suggest that the AGE-RAGE interaction elicited angiogenesis through the transcriptional activation of the VEGF gene via NF-kB and AP-1 factors. By blocking AGE-RAGE signaling pathways, cerivastatin might be a promising remedy for treating patients with proliferative diabetic retinopathy.
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PMID:Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin. 1236 25

An increased oxidative stress may contribute to the accelerated atherosclerosis in diabetic patients. Here we show that 3-hydroxy-3-methylglutaryl CoA reductase inhibitor (statin) attenuates a high glucose-induced and a diabetes-induced oxidative stress through inhibition of vascular NAD(P)H oxidase. Exposure of cultured aortic endothelial cells and smooth muscle cells to a high glucose level (450 mg/dl) for 3 days significantly increased oxidative stress compared with a normal glucose level (100 mg/dl), as evaluated by the staining with 2',7'-dichlorofluorescein diacetate and electron spin resonance (ESR) measurement. This increase was completely blocked by the treatment with pitavastatin (5 x 10(-7)M) as well as a NAD(P)H oxidase inhibitor (diphenylene iodonium) or a PKC inhibitor (calphostin C) in parallel with the change of small GTPase Rac-1 activity, a cytosolic regulatory component of NAD(P)H oxidase. Next, using streptozotocin-induced diabetic rats, the effect of pitavastatin on oxidative stress was evaluated by in vivo ESR measurements, which is a sensitive, noninvasive method. Administration of pitavastatin (5 mg/kg/day) for 4 days attenuated the increased oxidative stress in diabetic rats to control levels. In conclusion, pitavastatin attenuated a high glucose-induced and a diabetes-induced oxidative stress in vitro and in vivo. Thus, our data may provide a new insight into antioxidative therapy in diabetes.
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PMID:Statin attenuates high glucose-induced and diabetes-induced oxidative stress in vitro and in vivo evaluated by electron spin resonance measurement. 1604 16


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