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)

The liver plays a central role in lipoprotein metabolism. In particular, very-low density lipoprotein (VLDL) is assembled in the hepatocytes and secreted into the blood circulation. The VLDL is then catabolized to low-density lipoprotein by lipoprotein lipase and hepatic triglyceride lipase. Obese subjects, especially those with visceral fat accumulation, are frequently associated with hyperlipidemia, non-insulin-dependent diabetes mellitus (NIDDM), and hypertension. The mechanism of hyperlipidemia in visceral fat obesity has not yet been elucidated. Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model of NIDDM, characterized by obesity with visceral fat accumulation, hyperlipidemia, and late-onset insulin resistance. To elucidate the mechanism of hyperlipidemia observed in OLETF rats, we focused on the production of VLDL by the liver and investigated hepatic messenger RNA (mRNA) levels of microsomal triglyceride transfer protein (MTP), acyl-coenzyme A synthetase (ACS), and apolipoprotein B (apo B), which play important roles in VLDL synthesis and secretion. In 6-week-old OLETF rats, in which insulin resistance had not been manifested, visceral fat weight was already higher and portal free fatty acid (FFA) and VLDL-triglyceride levels were elevated compared with the control rats. Hepatic ACS activity and mRNA levels, and MTP mRNA levels were also increased in OLETF rats, whereas apo B mRNA levels were similar; these results suggest that the enhanced expression of both ACS and MTP genes associated with visceral fat accumulation before developing insulin resistance may be involved in the pathogenesis of hyperlipidemia in obese animal models with NIDDM.
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PMID:Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation. 946 57

Nonalcoholic steatohepatitis (NASH) is a syndrome frequently associated with obesity, diabetes mellitus, and dyslipidemia. Increased fasting insulinemia and blood glucose levels may trigger a reduced catabolism of lipoproteins rich in triglycerides by lipoprotein lipase (LPL) and an increase in their fasting and postprandial levels. An association between postprandial lipemia and coronary heart disease has been observed, and many studies now support this concept. The most important result of our study is the increase in triglyceride-rich lipoproteins response after a fat load in NASH patients, the increase of incremental area under the postprandial curve, and the duration of the hypertriglyceridemic peaks. The persisting postprandial plasma triglyceride elevation in NASH patients was mostly due to the elevated plasma level of large triglyceride-rich particles. These data are coupled with lower plasma HDL2-cholesterol levels. As for lipoprotein analyses, the number of apolipoprotein B100 (ApoB100) particles is not significantly different between the two groups, and the higher content of triglycerides in NASH very low density lipoproteins (VLDL) increases the triglyceride-to-ApoB ratio and the particle size. A decreased enzymatic activity of LPL or a defective assembly and secretion of VLDL from hepatocytes due to a moderate reduction in microsomal triglyceride transfer protein could be involved in the overloading of VLDL. Moreover, the undetectable levels of ApoB48 in triglyceride-rich lipoproteins fraction A could be related to the synthesis of smaller and denser chylomicrons. NASH patients not only are insulin resistant but also tend to present alterations in fatty meal delivery, suggesting that an increase in fasting plasma insulin and glucose, with insulin resistance, joins with depressed metabolism of triglyceride-rich lipoproteins. An increase in postprandial triglyceride levels with production of large VLDL suggests an atherogenic behavior of lipid metabolism, in accordance with the high prevalence of the metabolic syndrome in NASH patients. This paper suggests that a fat load may be useful in early detection of atherogenic risk in the presence of otherwise normal fasting plasma lipids.
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PMID:Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. 1176 56

An elevated low-density lipoprotein (LDL) cholesterol level is a strong predictor of coronary heart disease (CHD) risk. Over the past seven years, equally strong evidence has accumulated that lowering LDL cholesterol with HMG-CoA reductase inhibitors or statins reduces CHD risk and there is now widespread use of these agents for the primary and secondary prevention of CHD. Treatment issues remain regarding the appropriate degree of LDL cholesterol reduction and whether, in people with very high levels, it would be preferable to achieve the LDL cholesterol goal with a powerful statin alone or combined with an agent that lowers LDL cholesterol by a different mechanism. The main focus in the development of novel agents is the patient with low high-density lipoprotein (HDL) cholesterol, usually associated with hypertriglyceridaemia. Already prevalent as a risk factor for CHD, this abnormality has been linked with insulin resistance, which is likely to increase greatly over the next decade, along with increasing obesity and diabetes. Agents that have potent HDL cholesterol raising capacity include cholesteryl ester transfer protein (CETP) inhibitors, retinoid X receptor (RXR) selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and oestrogen-like compounds. Another area of development involves agents that will lower both cholesterol and triglyceride levels, such as partial inhibitors of microsomal triglyceride transfer protein (MTP) and perhaps squalene synthase inhibitors and agonists of AMP kinase. Future emphasis will be on correcting all lipid abnormalities for the prevention of CHD, not just lowering LDL cholesterol.
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PMID:Novel agents for managing dyslipidaemia. 1177 94

We have previously demonstrated that diabetes is associated with an increase in intestinal microsomal triglyceride transfer protein (MTP) mRNA in both the rat and rabbit models. The present study was designed to investigate the relationship between MTP expression and chylomicron assembly in an insulin resistant non-diabetic animal model. Ten insulin resistant Zucker obese fa/fa rats and ten lean fa/minus sign rats were examined at 8-10 weeks of age. The lymph duct was cannulated and lymph collected for 4 h. Lymph chylomicrons were isolated by ultracentrifugation and their composition determined. RNA was extracted from intestinal mucosa and from the liver. MTP mRNA was measured using the RNase protection assay. Blood sugar in the fatty rats was significantly higher (6.3 +/-1.2 vs. 5.4 +/-0.4 P<0.05) and plasma insulin was almost six times that of the lean rats (P<0.001). Plasma cholesterol and phospholipid but not triglyceride were significantly increased in the obese animals (P<0.01). Obese animals secreted significantly more lymph chylomicron apo B48 (0.05 +/-0.02 vs. 0.02 +/-0.01 mg/h P<0.005), triglyceride (9.7 +/-5.3 vs. 3.8+/-1.9 mg/h P<0.005) and phospholipid (1.5 +/-0.7 vs. 0.4 +/-0.3 mg/h P<0.001). The only difference in the chylomicron particle composition between the two groups was a significant increase in phospholipid (P<0.01). Intestinal MTP mRNA expression was significantly higher in the fatty compared to the lean rats (22.1 +/-9.5 vs. 7.8+/-5.6 amol MTP mRNA/microg total RNA P<0.001) as was hepatic MTP mRNA expression (6.9 +/-3.5 vs. 3.4 +/-1.5 amol MTP mRNA/microg total RNA, P<0.01). Thus in this animal model of insulin resistance, increased MTP, which was associated with increased chylomicron particle number, may play a crucial role in the development of atherosclerosis.
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PMID:Microsomal triglyceride transfer protein: does insulin resistance play a role in the regulation of chylomicron assembly? 1184 58

Secondary hyperlipidemia is a major cardiovascular risk factor in individuals with type 2 diabetes. Increased hepatic production of apolipoprotein B (apoB)-containing lipoproteins contributes to the elevated plasma levels, but the mechanism is poorly understood. Recent results have established that microsomal triglyceride transfer protein (MTP) is rate limiting for the assembly and secretion of apoB-containing lipoproteins. To better understand the mechanism of type 2 diabetes-associated hyperlipidemia, we quantified hepatic MTP mRNA levels, hepatic microsomal triglyceride transfer activity, and in vivo triglyceride secretion from the liver in two diabetic mouse models. Obese diabetic (ob/ob) mice had 45% higher (P = 0.006) hepatic MTP mRNA levels, 54% higher (P < 0.0001) microsomal triglyceride transfer activity, and 70% higher (P < 0.0001) in vivo triglyceride secretion rates compared with ob/+ control mice. In contrast, in lean streptozotocin-treated diabetic mice, hepatic MTP mRNA levels were unchanged, whereas microsomal triglyceride transfer activity and in vivo triglyceride secretion rates were marginally decreased. These studies suggest that obesity-induced type 2 diabetes in mice confers increases in hepatic MTP expression and secretion of triglyceride-rich lipoproteins. High blood glucose and altered hepatic expression of sterol regulatory element binding protein genes play a minor role in this diabetic response.
Diabetes 2002 Apr
PMID:Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. 1191 50

Altered plasma levels of lipids and lipoproteins, obesity, hypertension, and diabetes are major risk factors for atherosclerotic cardiovascular disease. To identify genes that affect these traits and disorders, we looked for association between markers in candidate genes (apolipoprotein AII (apo AII), apolipoprotein AI-CIII-AIV gene cluster (apo AI-CIII-AIV), apolipoprotein E (apo E), cholesteryl ester transfer protein (CETP), cholesterol 7alpha-hydroxylase (CYP7a), hepatic lipase (HL), and microsomal triglyceride transfer protein (MTP)) and known risk factors (triglycerides (Tg), total cholesterol (TC), apolipoprotein AI (apo AI), apolipoprotein AII (apo AII), apolipoprotein B (apo B), body mass index (BMI), blood pressure (BP), leptin, and fasting blood sugar (FBS) levels.) A total of 1,102 individuals from the Pacific island of Kosrae were genotyped for the following markers: Apo AII/MspI, Apo CIII/SstI, Apo AI/XmnI, Apo E/HhaI, CETP/TaqIB, CYP7a/BsaI, HL/DraI, and MTP/HhpI. After testing for population stratification, family-based association analysis was carried out. Novel associations found were: 1) the apo AII/MspI with apo AI and BP levels, 2) the CYP7a/BsaI with apo AI and BMI levels. We also confirmed the following associations: 1) the apo AII/MspI with Tg level; 2) the apo CIII/SstI with Tg, TC, and apo B levels; 3) the Apo E/HhaI E2, E3, and E4 alleles with TC, apo AI, and apo B levels; and 4) the CETP/TaqIB with apo AI level. We further confirmed the connection between the apo AII gene and Tg level by a nonparametric linkage analysis. We therefore conclude that many of these candidate genes may play a significant role in susceptibility to heart disease.
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PMID:Candidate genes involved in cardiovascular risk factors by a family-based association study on the island of Kosrae, Federated States of Micronesia. 1211 31

The current knowledge on lipoprotein secretion from the heart is examined in this article. The ability of cells to secrete apolipoprotein B (apo-B) containing lipoproteins depends on expression of the apo-B and microsomal triglyceride transfer protein (MTP) genes. Initially, it was shown that both genes are expressed in cardiac myocytes of mice and humans. Electron microscopy of human cardiac myocytes revealed lipoproteins in the secretory pathway and metabolic labelling studies demonstrated the secretion of LDL-like lipoproteins from minced heart biopsies. To examine the role of lipoprotein formation in the heart, we tested whether overexpression of a human apo-B transgene in the heart affects cardiac triglyceride accumulation. In wild-type mice, diabetes conferred an increase in heart triglycerides. In apo-B transgenic mice, diabetes did not affect heart triglycerides. Also, apo-B overexpression prevents fasting-induced heart triglyceride accumulation, whereas inhibition of MTP expression increases heart triglycerides in mice. In hypoxic human hearts, MTP mRNA expression was negatively associated with triglyceride contents. These findings suggest that lipoprotein formation rates affect cardiac triglyceride stores. The MTP mRNA levels are approximately 2-fold higher in hypoxic compared with normoxic human myocardium and in diabetic compared with non-diabetic mouse hearts. In both hypoxia and diabetes, the delivery of triglycerides to the heart exceeds their utilization for beta-oxidation. Thus, endogenous lipoprotein secretion rates might be upregulated to remove surplus fat from the heart. Diabetes negatively affected indexes of systolic and diastolic function in wild-type mice. However, the diabetogenic effects on the heart were absent or much less pronounced in apo-B transgenic mice. This suggests that accelerated lipoprotein formation by the heart attenuates development of diabetic cardiomyopathy in mice. In conclusion, current evidence suggests that lipoprotein secretion from the heart plays an integrated role in cardiac lipid homeostasis and that it can affect the biomechanical function of the heart.
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PMID:Lipoprotein production by the heart: a novel pathway of triglyceride export from cardiomyocytes. 1257 Jan 65

Type 2 diabetes in humans is associated with increased de novo lipogenesis (DNL), increased fatty acid (FA) fluxes, decreased FA oxidation, and hepatic steatosis. In this condition, VLDL production is increased and resistant to suppressive effects of insulin. The relationships between hepatic FA metabolism, steatosis, and VLDL production are incompletely understood. We investigated VLDL-triglyceride and -apolipoprotein (apo)-B production in relation to DNL and insulin sensitivity in female ob/ob mice. Hepatic triglyceride (5-fold) and cholesteryl ester (15-fold) contents were increased in ob/ob mice compared with lean controls. Hepatic DNL was increased approximately 10-fold in ob/ob mice, whereas hepatic cholesterol synthesis was not affected. Basal rates of hepatic VLDL-triglyceride and -apoB100 production were similar between the groups. Hyperinsulinemic clamping reduced VLDL-triglyceride and -apoB100 production rates by approximately 60% and approximately 75%, respectively, in lean mice but only by approximately 20% and approximately 20%, respectively, in ob/ob mice. No differences in hepatic expression of genes encoding apoB and microsomal triglyceride transfer protein were found. Hepatic expression and protein phosphorylation of insulin receptor and insulin receptor substrate isoforms were reduced in ob/ob mice. Thus, strongly induced hepatic DNL is not associated with increased VLDL production in ob/ob mice, possibly related to differential hepatic zonation of apoB synthesis (periportal) and lipid accumulation (perivenous) and/or relatively low rates of cholesterogenesis. Insulin is unable to effectively suppress VLDL-triglyceride production in ob/ob mice, presumably because of impaired insulin signaling.
Diabetes 2003 May
PMID:Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin. 1271 36

Genetic variation in the microsomal triglyceride transfer protein (MTP) affects the secretion pattern and plasma concentration of apolipoprotein (aopB)-containing lipoproteins and a common functional -493 G/T polymorphism has been reported to influence plasma lipids levels. Recent data suggest that carriers of the T allele might be more sensitive to detrimental factors such as features of the insulin resistance syndrome. Since type 2 diabetes is associated with obesity and insulin resistance, the present study investigated the effect of this polymorphism on plasma lipids, apoB and LDL subfractions in 281 Chinese type 2 diabetic subjects and 364 non-diabetic controls. The frequency of the rare T allele was 0.162 and 0.126 in subjects with and without diabetes respectively. There were no differences in the effect of the polymorphism on plasma lipids and apoB in the two groups. However, the TT genotype was associated with a higher concentration of small dense LDL-III than the GT or GG variants in the diabetic subjects (P=0.01) whereas no such effect was observed in the controls. In the diabetic patients, age, plasma triglyceride and the MTP genotype were independent determinants of LDL-III concentrations in linear regression analysis (R(2)=10%, P=0.04) whereas in the controls, only plasma triglyceride and age were important determinants (R(2)=15%, P=0.01). In conclusion, the -493 G/T polymorphism only has a minor effect on LDL subfraction pattern in Chinese and the effect is only apparent in the presence of type 2 diabetes.
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PMID:Effect of the microsomal triglyceride transfer protein -493 G/T polymorphism and type 2 diabetes mellitus on LDL subfractions. 1281 11

The regulation of hepatic VLDL secretion mainly depends on apolipoprotein (apo) B synthesis, on microsomal triglyceride transfer protein, insulin and the availability of triglycerides, free fatty acids (FFA) and cholesteryl ester. Four sources of fatty acids are used for lipoprotein synthesis: de-novo lipogenesis, cytoplasmic triglyceride stores, fatty acids derived from lipoproteins taken up directly by the liver and plasma FFA. Quantitatively, de-novo lipogenesis plays a minor role in regulating VLDL synthesis, but evidently it is elevated under conditions of high carbohydrate feeding. Cytoplasmic triglyceride stores appear to essentially contribute to VLDL triglycerides. Plasma FFA enter the hepatocytes and are either oxidized or esterified. The relationship between oxidation and esterification appears to be important in regulating the VLDL synthesis. An enhanced esterification is accompanied by increased VLDL secretion. The addition of oleic acid to hepatocytes has been shown to stimulate production of VLDL triglyceride and apoB. In human beings, an acute experimental elevation of plasma FFA stimulates VLDL production. In healthy men strong positive relations were found between the late increases in large triglyceride-rich lipoproteins and plasma FFA concentrations after 6 h following a mixed meal. In contrast, n-3 fatty acids impair VLDL assembly and secretion. Chronic hyperinsulinemia seems to stimulate VLDL production. On the other hand, the short-term addition of insulin has been shown to inhibit VLDL-triglyceride and apoB production in vitro. There is in vivo evidence that acute hyperinsulinemia suppresses VLDL-apoB and VLDL-triglyceride production in insulin-sensitive humans. Part of this action is due to suppression of plasma FFA. In patients with impaired glucose tolerance (IGT), VLDL production was increased when compared with subjects with normal glucose (NGT). When infusing a lipid emulsion, VLDL production could not be further stimulated in IGT patients in contrast to NGT persons. Hypertriglyceridemia in type 2 diabetes mellitus is usually the consequence of a VLDL overproduction. In type 2 diabetic patients, in contrast to normal men, insulin failed to suppress VLDL1 particle release. In normal men, an elevation of blood glucose led to a decrease in fatty acid oxidation and an increase in hepatic triglyceride secretion. Under these conditions, approximately 30% of total VLDL triglycerides coming out of the liver did not originate from plasma FFA. In conclusion, plasma FFA seem to play an important role in stimulating hepatic VLDL production. Other factors such as chronic hyperinsulinemia or nutrition modify this effect.
Exp Clin Endocrinol Diabetes 2003 Aug
PMID:Influence of plasma free fatty acids on lipoprotein synthesis and diabetic dyslipidemia. 1295 28


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