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)

Hydrolysis by endothelial lipases of triacylglycerol-rich lipoproteins of diabetic origin were compared to lipoproteins of non-diabetic origin. The plasma lipoprotein fraction of density < 1.006 g/ml, including chylomicrons and VLDL, were incubated in vitro with post-heparin plasma (PHP) lipases. The lipoproteins of diabetic origin were hydrolysed at a significantly slower rate than lipoproteins from normal rats by the lipoprotein lipase component of PHP. However, if rats were fasted for 16 h prior to lipoprotein recovery, no differences in rates of VLDL hydrolysis were observed. Slower hydrolysis of lipoproteins of diabetic origin reflected a decrease in the apolipoprotein CII/CIII ratio and other changes in the apolipoprotein profile. To assess whether diabetic rats were less able to clear triacylglycerol independent of changes in the nature of the lipoproteins, we monitored the clearance of chylomicron-like lipid emulsions in hepatectomized rats. In vivo, emulsion triacylglycerol hydrolysis was not slowed due to diabetes. However, control and diabetic rats, which had been fasted for 16 h, cleared triacylglycerol at about twice the rate of fed rats. Triacylglycerol secretion rates in diabetic and control rats were similar, whether fed or fasted. We conclude that in streptozocin diabetic rats, hypertriglyceridemia was not due to overproduction of chylomicron- or VLDL-triacylglycerol, nor to decreased endothelial lipase activities. Rather, in fed diabetic rats, the triacylglycerol-rich lipoproteins are poorer substrates for lipoprotein lipase. This may lead to slower formation of remnants which would exacerbate slow remnant removal. VLDL of diabetic origin were hydrolysed as efficiently as VLDL from control donors, suggesting that in the fed state the lipolytic defect may be specific for chylomicrons.
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PMID:Hypertriglyceridemia is exacerbated by slow lipolysis of triacylglycerol-rich lipoproteins in fed but not fasted streptozotocin diabetic rats. 142 Feb 85

Diabetes mellitus is associated with a reduction of lipoprotein lipase (LPL) activity and development of hypertriglyceridemia. In the current experiments the mechanisms involved in the regulation of LPL have been examined in control rats, streptozocin-induced diabetic rats, and diabetic rats treated chronically or with a single injection of insulin. Diabetes decreased adipose tissue LPL activity partially by decreasing immunoreactive LPL protein and the steady-state levels of LPL mRNA, but primarily by reducing the catalytic activity of LPL. Both chronic and acute insulin increased adipose tissue LPL activity by correcting the defect in the catalytic activity of LPL and increasing immunoreactive LPL protein; however, only chronic insulin restored LPL mRNA levels to normal. In the heart, LPL activity tended to be elevated with diabetes in parallel to an increase in immunoreactive LPL protein even though levels of LPL mRNA declined. Both chronic and acute insulin normalized LPL activity and immunoreactive LPL protein, while only chronic insulin corrected the levels of LPL mRNA. No changes in the catalytic activity of LPL in heart were detected among the groups. Thus, diabetes and insulin treatment regulate LPL expression pretranslationally, translationally, and post-translationally, with tissue-specific differences apparent in the mechanisms involved.
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PMID:Regulation of lipoprotein lipase in the diabetic rat. 143 Jan 98

An increased risk of developing premature atherosclerosis is associated with stress, diabetes, obesity, and hypertension. These conditions are associated with insulin resistance, hyperglycemia, hypertriglyceridemia and hypercholesterolemia. An alternative way of interpreting insulin resistance is to consider that metabolism in this condition would be regulated to a greater extent by stress hormones and in particular by cortisol. Glucocorticoids and fatty acids (which are produced in response to stress) antagonise the actions of insulin in promoting glucose uptake and protein synthesis, in decreasing gluconeogenesis and protein catabolism, and promoting the clearance of intermediate density lipoprotein and low density lipoprotein from the circulation by the liver. They also promote the secretion of very low density lipoprotein thus producing hypertriglyceridemia and hypercholesterolemia. By contrast to this antagonism, cortisol can also facilitate the action of insulin in stimulating the storage of energy via glycogen and fatty acid synthesis and through lipoprotein lipase in adipose tissue. These effects are significant in relation to obesity and to weight gain. An increased control of metabolism by cortisol therefore produces changes in metabolism that are potentially atherogenic and it is associated with insulin resistance and the other risk factors for atherosclerosis. Benfluorex treatment improves insulin sensitivity and has antihyperglycemic and hypolipidemic effects in human beings and in experimental animals. These effects can be observed independently of weight loss, but lowering food intake also produces a metabolic benefit. Long-term treatment with benfluorex can also decrease stress responses in terms of glucocorticoid release and the stimulation of lipolysis probably by its serotoninergic control of the hypothalamic-pituitary-adrenal axis. Such an action provides for an integrated treatment of the obese-diabetic-hyperlipidemic syndrome. Benfluorex produces overall changes in metabolism that tend to normalise the major risk factors associated with premature atherosclerosis. This provides a potential advantage over other therapies for atherosclerosis which may ameliorate a symptom (e.g., hyperlipidemia) without treating the underlying metabolic disturbance that predisposes to atherogenesis.
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PMID:[Mode of action of benfluorex. Recent data]. 143 2

In this study, some important metabolic responses to exercise will be discussed, and aspects of particular interest for patients with diabetes mellitus will be emphasized. Alterations in the metabolic responses to exercise induced by physical endurance training and consequences of training for metabolism of plasma lipids and lipoproteins will be discussed. Glucoregulation during exercise is not perfect in normal subjects and is less so in patients with diabetes mellitus. For instance, during intense exercise, large increases in the plasma glucose concentration occur and a state of insulin resistance exists for a few hours after intense exercise. Even so, increased sensitivity to insulin is found the day after intense exercise and also shortly after more moderate intensity exercise, both in healthy subjects and in patients with diabetes mellitus. Increased sensitivity to insulin is also found after endurance training, whereas insulin sensitivity is decreased after inactivity. Exercise training increases the ability of muscle to take up and oxidize free fatty acids during exercise and also increases the activity of the enzyme lipoprotein lipase in muscle. The activity of lipoprotein lipase in muscle correlates with muscle insulin sensitivity. This might explain why insulin resistance is often associated with hypercholesterolemia, hypertriglyceridemia, and low high-density lipoprotein cholesterol.
Diabetes Care 1992 Nov
PMID:Metabolic responses to exercise. Effects of endurance training and implications for diabetes. 146 13

Data from several different studies are reviewed suggesting that a subset of hypertension is associated with metabolic abnormalities involving lipids, insulin, and often obesity, all aggregating strongly in families. Persons with 'familial dyslipidaemic hypertension (FDH)' have an especially high risk of early coronary disease. The clinical and biochemical features of FDH are compared with Reaven's Syndrome X, familial combined hyperlipidaemia, dense LDL subfractions, diabetes, impaired glucose tolerance, central and general obesity, pre-diabetes, pre-hypertension, and heterozygous lipoprotein lipase deficiency. Some contribution from major gene effects is suggested in specific subsets reported in several different genetic studies reviewed in this report. It seems likely that multiple metabolic abnormalities are genetically heterogeneous. The data also suggest significant contributions from environmental factors such as diet and physical activity.
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PMID:Familial dyslipidaemic hypertension and other multiple metabolic syndromes. 148 41

The objective of this investigation was to test the hypothesis that the diabetes-induced reduction in lipoprotein lipase activity in cardiac myocytes may be due to hypertriglyceridemia. Administration of 4-aminopyrazolopyrimidine (50 mg/kg) to control rats for 24 h reduced plasma triacylglycerol levels and increased the heparin-induced release of lipoprotein lipase into the incubation medium of cardiac myocytes. The acute (3-5 days) induction of diabetes by streptozotocin (100 mg/kg) produced hypertriglyceridemia and reduced heparin-releasable lipoprotein lipase activity in cardiac myocytes. Treatment of diabetic rats with 4-aminopyrazolopyrimidine resulted in a fall in plasma triacylglycerol content and increased heparin-releasable lipoprotein lipase activity. Administration of Triton WR-1339 also resulted in hypertriglyceridemia, but the heparin-induced release of lipoprotein lipase from control cardiac myocytes was not reduced in the absence of lipolysis of triacylglycerol-rich lipoproteins. Treatment with Triton WR-1339 did, however, increase the heparin-induced release of lipoprotein lipase from diabetic cardiac myocytes. Preparation of cardiac myocytes with 0.9 mM oleic acid resulted in a decrease in both total cellular and heparin-releasable lipoprotein lipase activities. These results suggest that the diabetes-induced reduction in heart lipoprotein lipase activity may, at least in part, be due to an inhibitory effect of free fatty acids, derived either from lipoprotein degradation or from adipose tissue lipolysis, on lipoprotein lipase activity in (and (or) release from) cardiac myocytes.
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PMID:Regulation of lipoprotein lipase activity in cardiac myocytes from control and diabetic rat hearts by plasma lipids. 149 94

Because the accumulation of lipid in macrophages is a characteristic feature of atherosclerosis, the mechanisms by which this lipid accumulation occurs have been intensively studied. This paper reviews the receptor- and non-receptor-mediated pathways that promote lipid accumulation in macrophages. Particular emphasis is placed on the contributions of two secretory products of macrophages, lipoprotein lipase and apolipoprotein E, to both receptor- and non-receptor-mediated uptake of triglyceride-rich lipoproteins by macrophages. The hormonal, lipid, and immunological factors that regulate the secretion of LpL and apoE by macrophages are discussed, as are how changes in the secretion of apoE and LpL that can modulate the uptake of triglyceride-rich lipoproteins by macrophages might influence the atherosclerotic process in people with diabetes.
Diabetes 1992 Oct
PMID:Role of lipoprotein lipase and apolipoprotein E secretion by macrophages in modulating lipoprotein uptake. Possible role in acceleration of atherosclerosis in diabetes. 152 41

Plasma lipid levels are elevated in people with diabetes, and a direct relationship can be demonstrated between indices of diabetic control and plasma lipid levels. Many observations suggest that diabetes may be associated with enhanced cytokine production, raising the possibility that some of the metabolic abnormalities associated with diabetes may be due to or exacerbated by cytokine overproduction. Tumor necrosis factor induces a rapid increase in serum triglyceride levels caused by an increase in VLDL of normal composition. Although in vitro studies showed that TNF decreases adipose tissue lipoprotein lipase activity, recent studies with intact animals demonstrated that TNF increases serum triglyceride levels by stimulating hepatic lipid secretion, not by affecting clearance. The increase in hepatic VLDL triglyceride secretion induced by TNF is due to both the stimulation of hepatic de novo fatty acid synthesis and an increase in lipolysis. Other cytokines including IL-1, IL-6, and alpha-interferon increase hepatic de novo fatty acid synthesis. Similarly, cytokines such as IL-1 and alpha-, beta-, and gamma-interferon also increase lipolysis. Thus, a variety of cytokines acting at different receptors can affect multiple processes that can alter lipid metabolism and increase serum lipid levels. These cytokine-induced increases in serum lipoprotein levels may be a beneficial response for the host. Studies show that lipoproteins, including VLDL, bind endotoxin and can protect against the toxic effects of endotoxin. Moreover, lipoproteins bind a variety of viruses, reducing their infectivity. Lipoproteins also bind urate crystals, which reduces the inflammatory response induced by these crystals.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Oct
PMID:Role of cytokines in inducing hyperlipidemia. 152 45

The thiazolidinediones are a class of novel antidiabetic compounds that enhance the response of target tissues to insulin. Pioglitazone, a thiazolidinedione analog, lowers blood glucose and insulin levels in rodent models of non-insulin-dependent diabetes mellitus. We have studied the effect of pioglitazone on 3T3-L1 cells, a cell line that undergoes differentiation from a preadipocyte fibroblastic morphology to that of an adipocyte. Pioglitazone treatment of preadipocytes enhanced the insulin- or insulin-like growth factor-1 (IGF-I)-regulated differentiation (monitored by the rate of lipogenesis or triglyceride accumulation), whereas treatment of the cells in the absence of insulin or IGF-I resulted in no apparent change in the cellular phenotype. Pioglitazone caused both a leftward shift and enhanced maximum response for the IGF-I-regulated differentiation of the cells, consistent with the idea that the drug enhances the sensitivity of cells to polypeptide hormones. A series of pioglitazone analogs were tested in this system, and variations in activity relative to that of the parent compound were observed. A study of the time required for the drug to exert an effect on differentiation revealed that an increased rate of lipogenesis occurred 16-24 hr after drug treatment in appropriately staged cells. An increased rate of glucose transport and increased activity of lipogenic enzymes were noted in a time frame that correlated with the change in lipogenesis. Analysis of mRNA abundance for Glut-4, lipoprotein lipase, and glucose-6-phosphate dehydrogenase showed that pioglitazone enhanced the insulin induction of these mRNA species. Thus, pioglitazone, in combination with insulin or IGF-I, appears to be exerting effects on the cellular phenotype by eliciting changes in the expression of genes that regulate metabolic pathways leading to the acquisition of the differentiated phenotype.
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PMID:Enhancement of adipocyte differentiation by an insulin-sensitizing agent. 153 16

Patients with diabetes commonly manifest hypertriglyceridemia along with decreased adipose tissue lipoprotein lipase (LPL) activity, and improved diabetes control tends to reverse these abnormalities. To better understand the mechanism of regulation of LPL in diabetes, 11 diabetic patients (3 type I, 8 type II) were brought under improved glycemic control, and adipose tissue LPL gene expression was assessed by performing paired fat biopsies. Six of the 11 patients attained improved control with insulin, with a decrease in glycohemoglobin (glyc Hgb) from 13.8 +/- 0.9 to 10.4 +/- 0.6%; 5 patients attained improved control with glyburide (glyc Hgb fell from 14.2 +/- 2.4 to 8.8 +/- 0.6%), and together they demonstrated a lowering of serum triglycerides and total cholesterol. No changes were observed in HDL cholesterol. Improved diabetes control resulted in a significant increase in LPL activity in both the heparin-releasable (HR) and extractable (EXT) fractions of adipose tissue, as well as in LPL immunoreactive mass. The change in LPL activity with improved control was variable, and showed a positive correlation with the HDL levels prior to treatment (r = 0.74, P less than 0.02). When adipose tissue was pulse-labeled with [35S]methionine, there was an increase in isotope incorporation into LPL after treatment, indicating an increase in LPL synthetic rate. However, improved diabetes control resulted in no significant change in LPL mRNA levels. Thus, improved glycemic control resulted in an increase in LPL activity which correlated with each patient's basal high density lipoprotein. This increase in LPL activity was accompanied by an increase in LPL immunoreactive mass, and an increase in LPL synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of improved diabetes control on the expression of lipoprotein lipase in human adipose tissue. 155 36


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