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

1. Rats were injected with a single dose of 35mg of streptozotocin/kg body wt. They exhibited a diabetes that was characterized by glycosuria, polyuria, polydipsia, hyperphagia, hyperglycaemia, increased concentrations of unesterified fatty acids, glycerol and triacylglycerols in the serum and an increased activity of glucose 6-phosphatase in the liver. 2. After 10 weeks the hepatic activities of the microsomal glycerol phosphate acyltransferase, phosphatidate phosphohydrolase, phosphatidate cytidylyltransferase, diacylglycerol acyltransferase, choline phosphotransferase, CDP-diacylglycerol--inositol phosphatidyltransferase and the soluble phosphatidate phosphohydrolase were measured. 3. The only significant changes were an increase in the activity of the soluble phosphatidate phosphohydrolase and a decrease in that of the CDP-diacylglycerol--inositol phosphatidyltransferase in the diabetic rats. 4. These results are discussed in relation to the control of glycerolipid synthesis.
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PMID:The effect of chronic diabetes, induced by streptozotocin, on the activities of some enzymes of glycerolipid synthesis in rat liver. 20 60

Myocardial triacylglycerol hydrolysis is subject to product inhibition. After hydrolysis of endogenous triacylglycerols, the main proportion of the liberated fatty acids is re-esterified to triacylglycerol, indicating the importance of fatty acid re-esterification in the regulation of myocardial triacylglycerol homoeostasis. Therefore, we characterized phosphatidate phosphohydrolase (PAP) and diacylglycerol acyltransferase (DGAT) activities, enzymes catalysing the final steps in the re-esterification of fatty acids to triacylglycerols in the isolated rat heart. The PAP activity was mainly recovered in the microsomal and soluble cell fractions, with an apparent Km of 0.14 mM for both the microsomal and the soluble enzyme. PAP was stimulated by Mg2+ and oleic acid. Oleic acid, like a high concentration of KCl, stimulated the translocation of PAP activity from the soluble to the particulate (microsomal) fraction. Myocardial DGAT had an apparent Km of 3.8 microM and was predominantly recovered in the particulate (microsomal) fraction. Both enzyme activities were significantly increased after acute streptozotocin-induced diabetes, PAP from 15.6 +/- 1.1 to 28.1 +/- 3.6 m-units/g wet wt. (P less than 0.01) and DGAT from 2.23 +/- 0.11 to 3.01 +/- 0.11 m-units/g wet wt. (P less than 0.01). In contrast with diabetes, low-flow ischaemia during 30 min did not affect PAP and DGAT activity in rat hearts. Perfusion with glucagon (0.1 microM) during 30 min did not affect total PAP activity, but changed the subcellular distribution. More PAP activity was recovered in the particulate fraction. DGAT activity was lowered by glucagon treatment from 0.37 +/- 0.03 to 0.23 +/- 0.02 m-unit/mg of microsomal protein (P less than 0.05). The role of PAP and DGAT activity and PAP distribution in the myocardial glucose/fatty acid cycle is discussed.
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PMID:Properties of phosphatidate phosphohydrolase and diacylglycerol acyltransferase activities in the isolated rat heart. Effect of glucagon, ischaemia and diabetes. 216 15

1. Adipocytes were isolated from the interscapular brown fat and the epididymal white fat of normal, streptozotocin-diabetic and hypothyroid rats. 2. Measurements were made of the maximum rate of triacylglycerol synthesis by monitoring the incorporation of [U-14C]glucose into acylglycerol glycerol in the presence of palmitate (1 mM) and insulin (4 nM) and of the activities of the following triacylglycerol-synthesizing enzymes: fatty acyl-CoA synthetase (FAS), mitochondrial and microsomal forms of glycerolphosphate acyltransferase (GPAT), dihydroxyacetonephosphate acyltransferase (DHAPAT), monoacylglycerol phosphate acyltransferase (MGPAT), Mg2+-dependent phosphatidate phosphohydrolase (PPH) and diacylglycerol acyltransferase (DGAT). 3. FAS activity in brown adipocytes was predominantly localized in the mitochondrial fraction, whereas a microsomal localization of this enzyme predominated in white adipocytes. Subcellular distributions of the other enzyme activities in brown adipocytes were similar to those shown previously with white adipocytes [Saggerson, Carpenter, Cheng & Sooranna (1980) Biochem. J. 190, 183-189]. 4. Relative to cell DNA, brown adipocytes had lower activities of triacylglycerol-synthesizing enzymes and showed lower rates of metabolic flux into acylglycerols than did white adipocytes isolated from the same animals. 5. Diabetes decreased both metabolic flux into acylglycerols and the activities of triacylglycerol-synthesizing enzymes in white adipocytes. By contrast, although diabetes decreased metabolic flux into brown-adipocyte acylglycerols by 80%, there were no decreases in the activities of triacylglycerol-synthesizing enzymes, and the activity of PPH was significantly increased. 6. Hypothyroidism increased metabolic flux into acylglycerols in both cell types, and increased activities of all triacylglycerol-synthesizing enzymes in brown adipocytes. By contrast, in white adipocytes, although hypothyroidism increased the activities of FAS, microsomal GPAT and DGAT, this condition decreased the activities of mitochondrial GPAT and PPH. 7. It was calculated that the maximum capabilities for fatty acid oxidation and esterification are approximately equal in brown adipocytes. In white adipocytes esterification is predominant by approx. 100-fold. 8. Diabetes almost abolished incorporation of [U-14C]glucose into fatty acids in both adipocyte types. Hypothyroidism increased fatty acid synthesis in white and brown adipocytes by 50% and 1000% respectively.
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PMID:Comparison of triacylglycerol synthesis in rat brown and white adipocytes. Effects of hypothyroidism and streptozotocin-diabetes on enzyme activities and metabolic fluxes. 335 27

Prolonged exposure of isolated islets to supraphysiologic concentrations of palmitate decreases insulin gene expression in the presence of elevated glucose levels. This study was designed to determine whether or not this phenomenon is associated with a glucose-dependent increase in esterification of fatty acids into neutral lipids. Gene expression of sn-glycerol-3-phosphate acyltransferase (GPAT), diacylglycerol acyltransferase (DGAT), and hormone-sensitive lipase (HSL), three key enzymes of lipid metabolism, was detected in isolated rat islets. Their levels of expression were not affected after a 72-h exposure to elevated glucose and palmitate. To determine the effects of glucose on palmitate-induced neutral lipid synthesis, isolated rat islets were cultured for 72 h with trace amounts of [14C]palmitate with or without 0.5 mmol/l unlabeled palmitate, at 2.8 or 16.7 mmol/l glucose. Glucose increased incorporation of [14C]palmitate into complex lipids. Addition of exogenous palmitate directed lipid metabolism toward neutral lipid synthesis. As a result, neutral lipid mass was increased upon prolonged incubation with elevated palmitate only in the presence of high glucose. The ability of palmitate to increase neutral lipid synthesis in the presence of high glucose was concentration-dependent in HIT cells and was inversely correlated to insulin mRNA levels. 2-Bromopalmitate, an inhibitor of fatty acid mitochondrial beta-oxidation, reproduced the inhibitory effect of palmitate on insulin mRNA levels. In contrast, palmitate methyl ester, which is not metabolized, and the medium-chain fatty acid octanoate, which is readily oxidized, did not affect insulin gene expression, suggesting that fatty-acid inhibition of insulin gene expression requires activation of the esterification pathway. These results demonstrate that inhibition of insulin gene expression upon prolonged exposure of islets to palmitate is associated with a glucose-dependent increase in esterification of fatty acids into neutral lipids.
Diabetes 2001 Feb
PMID:Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. 1127 42

Hepatic triacylglycerol secretion is elevated in insulin-resistant states. Microsomal diacylglycerol acyltransferase (DGAT) catalyzes the final reaction in the synthesis of triacylglycerol (TAG). We have previously described two DGAT activities in rat liver microsomes, one overt (cytosol-facing) and one latent (endoplasmic reticulum lumen-facing) (Owen MR, Corstorphine CG, Zammit VA: Overt and latent activities of diacylglycerol acytransferase in rat liver microsomes: possible roles in very-low-density lipoprotein triacylglycerol secretion. Biochem J 323:17-21, 1977). It was suggested that they are involved in the synthesis of TAG for the cytosolic droplet and VLDL lipidation, respectively. In the present study, we measured the overt and latent DGAT activities in rats fed diets containing one of two hypolipidemic drugs: fenofibrate (a peroxisome proliferator-activated receptor alpha [PPARalpha] agonist) and simvastatin (a 3-hydroxy-3-methylglutaryl [HMG]-CoA reductase inhibitor). We found that the activities of the two DGATs could be varied independently by these treatments. Fenofibrate raised overt DGAT activity but lowered that of latent DGAT. In contrast, simvastatin markedly lowered overt DGAT activity without affecting that of latent DGAT. The increase in overt DGAT activity induced by fenofibrate could not be mimicked by feeding a diet enriched in n-3 polyunsaturated fatty acids (PUFA), which lowered overt DGAT activity but did not affect latent DGAT, suggesting that n-3 PUFA act through a mechanism independent of PPARalpha activation. The fibrate-induced increase in overt DGAT activity and the inhibition of latent DGAT may provide a mechanism through which acyl moieties are retained within the liver for oxidation through the pathways concomitantly upregulated by PPARalpha activation.
Diabetes 2002 Jun
PMID:Differential effects of fenofibrate or simvastatin treatment of rats on hepatic microsomal overt and latent diacylglycerol acyltransferase activities. 1203 56

Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two DGAT enzymes known to catalyze the final step in mammalian triglyceride synthesis. Mice deficient in DGAT1 are resistant to obesity and have enhanced insulin sensitivity. To understand better the relationship between triglyceride synthesis and energy and glucose metabolism, we generated transgenic (aP2-Dgat1) mice in which expression of murine DGAT1 in the white adipose tissue (WAT) was twofold higher than normal. aP2-Dgat1 mice that were fed a regular diet had larger adipocytes and greater total fat pad weight than wild-type (WT) mice. In response to a high-fat diet, aP2-Dgat1 mice became more obese ( approximately 20% greater body weight after 15 weeks) than WT mice. However, the increase in adiposity in aP2-Dgat1 mice was not associated with impaired glucose disposal, as demonstrated by glucose and insulin tolerance tests. Correlating with this finding, triglyceride deposition in the liver and skeletal muscle, two major target tissues of insulin, was similar in aP2-Dgat1 and WT mice. Thus, DGAT1 overexpression in murine WAT provides a model in which obesity does not impair glucose disposal. Our findings support the lipotoxicity hypothesis that the deposition of triglycerides in insulin-sensitive tissues other than adipocytes causes insulin resistance.
Diabetes 2002 Nov
PMID:Dissociation of obesity and impaired glucose disposal in mice overexpressing acyl coenzyme a:diacylglycerol acyltransferase 1 in white adipose tissue. 1240 9

Although postprandial hypertriglyceridemia is a major contributing factor in the development of atherosclerosis, little information is available on the effect of insulin resistance and diabetes on intestinal fat transport. The aim of the present study was to examine intracellular events that govern lipid transport and apolipoprotein (apo) B-48-containing lipoprotein assembly in the small intestine of Psammomys obesus, a model of nutritionally induced insulin resistance and type 2 diabetes. Animals with normoglycemia/hyperinsulinemia and hyperglycemia/hyperinsulinemia exhibited high levels of triglycerides (TGs) in the plasma and intestine and postprandial plasma chylomicrons and apo B-48 compared with normoglycemic/normoinsulinemic animals. In vitro studies, using cultured jejunal explants incubated with either [14C]oleic acid or [35S]methionine, revealed their higher efficiency in de novo TG synthesis, apo B-48 biogenesis, and TG-rich lipoprotein assembly. Accordingly, enhanced monoacylglycerol and diacylglycerol acyltransferase activity was also discernible and concomitant with an increased content of L-fatty acid binding protein and in vivo chylomicron production rates. However, both the I-fatty acid binding protein amount and the apo B-48 proteasomal degradative pathway were decreased. Overall, our findings show that the development of an insulin-resistant/diabetic state in Psammomys obesus triggers the whole intra-enterocyte machinery, leading to lipoprotein assembly and favoring the intestinal oversecretion of apo B-48-lipoproteins, which may contribute to characteristic hypertriglyceridemia.
Diabetes 2003 Oct
PMID:Cellular aspects of intestinal lipoprotein assembly in Psammomys obesus: a model of insulin resistance and type 2 diabetes. 1451 38

Obesity is currently an exceptionally common problem in humans. The last several years have produced a significant number of breakthroughs in obesity related areas of investigation. Triglycerides are considered the main form of storage of excess calories in fat. A key enzyme in the synthesis of triglycerides is acylCoA: diacylglycerol acyltransferase (DGAT). Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. These effects suggest that inhibition of DGAT in vivo may be a novel therapeutic target not only for obesity but also for diabetes.
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PMID:DGAT: novel therapeutic target for obesity and type 2 diabetes mellitus. 1468 57

Mice that lack acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in mammalian triglyceride synthesis, have decreased adiposity and increased insulin sensitivity. Here we show that insulin-stimulated glucose transport is increased in the skeletal muscle and white adipose tissue (WAT) of chow-fed DGAT1-deficient mice. This increase in glucose transport correlated with enhanced insulin-stimulated activities of phosphatidylinositol 3-kinase, protein kinase B (or Akt), and protein kinase Clambda (PKC-lambda), three key molecules in the insulin-signaling pathway, and was associated with decreased levels of serine-phosphorylated insulin receptor substrate 1 (IRS-1), a molecule implicated in insulin resistance. Similar findings in insulin signaling were also observed in DGAT1-deficient mice fed a high-fat diet. Interestingly, the increased PKC-lambda activity and decreased serine phosphorylation of IRS-1 were observed in chow-fed wild-type mice transplanted with DGAT1-deficient WAT, consistent with our previous finding that transplantation of DGAT1-deficient WAT enhances glucose disposal in wild-type recipient mice. Our findings demonstrate that DGAT1 deficiency enhances insulin signaling in the skeletal muscle and WAT, in part through altered expression of adipocyte-derived factors that modulate insulin signaling in peripheral tissues.
Diabetes 2004 Jun
PMID:Role of adipocyte-derived factors in enhancing insulin signaling in skeletal muscle and white adipose tissue of mice lacking Acyl CoA:diacylglycerol acyltransferase 1. 1516 47

Insulin resistance is often associated with obesity. We tested whether augmentation of triglyceride synthesis in adipose tissue by transgenic overexpression of the diacylglycerol aclytransferase-1 (Dgat1) gene causes obesity and/or alters insulin sensitivity. Male FVB mice expressing the aP2-Dgat1 had threefold more Dgat1 mRNA and twofold greater DGAT activity levels in adipose tissue. After 30 weeks of age, these mice had hyperglycemia, hyperinsulinemia, and glucose intolerance on a high-fat diet but were not more obese than wild-type littermates. Compared with control littermates, Dgat1 transgenic mice were both insulin and leptin resistant and had markedly elevated plasma free fatty acid levels. Adipocytes from Dgat1 transgenic mice displayed increased basal and isoproterenol-stimulated lipolysis rates and decreased gene expression for fatty acid uptake. Muscle triglyceride content was unaffected, but liver mass and triglyceride content were increased by 20 and 300%, respectively. Hepatic insulin signaling was suppressed, as evidenced by decreased phosphorylation of insulin receptor-beta (Tyr(1,131)/Tyr(1,146)) and protein kinase B (Ser473). Gene expression data suggest that the gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, were upregulated. Thus, adipose overexpression of Dgat1 gene in FVB mice leads to diet-inducible insulin resistance, which is secondary to redistribution of fat from adipose tissue to the liver in the absence of obesity.
Diabetes 2005 Dec
PMID:Whole-body insulin resistance in the absence of obesity in FVB mice with overexpression of Dgat1 in adipose tissue. 1630 52


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