Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-insulin-dependent diabetes mellitus (NIDDM) is frequently associated with macroangiopathies and coronary heart diseases. Lipoprotein lipase (LPL), an enzyme known to undergo significant functional alterations in diabetic state, is also a potential atherogenic protein. Since, to the best of our knowledge, there are no data concerning LPL secreted by macrophages of NIDDM patients we conducted a study to assess the expression and activity of LPL secreted by monocyte-derived macrophages from NIDDM patients with cardiovascular complications versus cardiovascular patients without diabetes (controls). Isolated cells from NIDDM patients, after 7 days in culture in the presence of 20% autologous serum, readily exhibit a foam cell phenotype, in contrast to the cells from controls. Macrophages were mainly loaded with triglycerides, whose cellular amount was well correlated to triglyceridemia of NIDDM subjects. Concomitantly, macrophages from NIDDM patients displayed a approximately six-fold decrease of mRNA expression and a approximately two-fold reduction of the activity of secreted LPL, as compared to control cells. These data suggest that in complicated diabetic state, macrophage loading leading to foam cell formation is accelerated, at least in part, due to a diminished expression and activity of LPL. These observations add and extend the data that may explain the occurrence of accelerated atherogenesis and of the atherosclerotic complications associated with diabetes.
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PMID:Diabetic state induces lipid loading and altered expression and secretion of lipoprotein lipase in human monocyte-derived macrophages. 1105 15

Lipoprotein lipase (LPL) plays a central role in triglyceride metabolism, and the LPL gene T495G HindIII polymorphism has been associated with variations in lipid levels and heart disease in Caucasians with the more common H+ allele being associated with adverse lipid profiles and increased risk of CHD. We investigated this polymorphism in 785 Chinese subjects with varying components of the metabolic syndrome, including 61.4% with early-onset type 2 diabetes (age at diagnosis < or = 40 years), and 167 healthy control subjects using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) method. The allele and genotype frequencies were similar in the patients and control subjects. When grouped above or below standard cutoffs for triglyceride levels, the H+ allele was more frequent in hypertriglyceridemic than that in normotriglyceridemic subjects in the total population (81.5% v 76.1%) and early-onset type 2 diabetics (84.4% v 77.4%, both P <.05). Moreover, H+H+ carriers had significantly higher plasma triglyceride and lower high-density lipoprotein (HDL)-cholesterol levels when compared to subjects with the H- allele in the total population, and in patients with early-onset diabetics (both P <.05). In the total population and the early-onset diabetic patients, this relationship was confined to males when gender was considered. We conclude that the H+ allele of the LPL gene HindIII polymorphism is associated with higher plasma triglyceride and lower HDL-cholesterol levels in Chinese patients with early-onset diabetes.
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PMID:The lipoprotein lipase gene HindIII polymorphism is associated with lipid levels in early-onset type 2 diabetic patients. 1264 73

Elevated plasma triglyceride and nonesterified fatty acid concentrations may cause insulin resistance. Lipoprotein lipase (LPL) is a rate-determining enzyme in lipid metabolism. To investigate the role of the LPL gene in Chinese patients with hypertriglyceridemic type 2 diabetes, 277 patients with type 2 diabetes and 241 healthy control subjects were recruited and screened for sequence changes in the LPL gene by PCR, SSCP, restriction analysis and direct DNA sequencing. Ten mutations were identified: four missense mutations, Ala71Thr, Val181Ile, Gly188Glu and Glu242Lys; one nonsense mutation Ser447Ter; and five silent mutations. Ser447Ter was found in both patients and controls with no significant difference in frequency. The four missense mutations were located in the highly conserved exon 3, 5, and 6 regions and in highly conserved amino acid sites. They led to reduced LPL mass and enzyme activities in both post-heparin plasma and in vitro expression. The modeled structures displayed major differences between the mutant and wildtype molecules. These results indicated that the four missense mutations lead to LPL deficiency and subsequent hypertriglyceridemia. Based on our study and published data, a putative pathogenic pathway was suggested: LPL enzyme deficiency causes elevated plasma triglyceride level and subsequent insulin resistance; both increased free fatty acids and insulin resistance promote gluconeogenesis and hyperglycaemia, a vicious circle leading to type 2 diabetes.
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PMID:Pathogenic mutations of the lipoprotein lipase gene in Chinese patients with hypertriglyceridemic type 2 diabetes. 1265 75

Insulin resistance and type 2 diabetes mellitus are generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. Several enzymes including lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), as well as cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), participate in HDL metabolism and remodelling. Lipoprotein lipase hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. Hepatic lipase reduces HDL particle size by hydrolysing its triglycerides and phospholipids. A decreased postheparin plasma LPL/HL ratio is a determinant of low HDL2 cholesterol in insulin resistance. The esterification of free cholesterol by LCAT increases HDL particle size. Plasma cholesterol esterification is unaltered or increased in type 2 diabetes mellitus, probably depending on the extent of triglyceride elevation. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins, and is involved in decreasing HDL size. An increased plasma cholesteryl ester transfer is frequently observed in insulin-resistant conditions, and is considered to be a determinant of low HDL cholesterol. Phospholipid transfer protein generates small pre beta-HDL particles that are initial acceptors of cell-derived cholesterol. Its activity in plasma is elevated in insulin resistance and type 2 diabetes mellitus in association with high plasma triglycerides and obesity. In insulin resistance, the ability of plasma to promote cellular cholesterol efflux may be maintained consequent to increases in PLTP activity and pre beta-HDL. However, cellular cholesterol efflux to diabetic plasma is probably impaired. Besides, cellular abnormalities that are in part related to impaired actions of ATP binding cassette transporter 1 and scavenger receptor class B type I are likely to result in diminished cellular cholesterol efflux in the diabetic state. Whether hepatic metabolism of HDL-derived cholesterol and subsequent hepatobiliary transport is altered in insulin resistance and type 2 diabetes mellitus is unknown. Specific CETP inhibitors have been developed that exert major HDL cholesterol-raising effects in humans and retard atherosclerosis in animals. As an increased CETP-mediated cholesteryl ester transfer represents a plausible metabolic intermediate between high triglycerides and low HDL cholesterol, studies are warranted to evaluate the effects of these agents in insulin resistance- and diabetes-associated dyslipidaemia.
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PMID:Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. 1463 88

Lipoprotein lipase (LPL) is one of the enzymes regulated by insulin and its plasma activity reflects insulin sensitivity. Although intravenous heparin injection is required to measure LPL activity, we can detect LPL mass in preheparin serum (Pr-LPL mass) by immunoassay. In this study, we examined whether Pr-LPL mass reflects insulin sensitivity. We measured Pr-LPL mass, insulin sensitivity (Si), and acute insulin release in response to a glucose bolus (AIRg) in subjects with normal glucose tolerance (NGT; n = 23), impaired glucose tolerance (IGT; n = 10), and Type II diabetes mellitus (DM; n = 48). Si and AIRg were determined by minimal model analysis. We also compared Pr-LPL mass with the homeostasis model assessment of insulin resistance (HOMA-R) and the urinary excretion of C-peptide (urine CPR). We found that Pr-LPL mass correlated significantly with Si ( r = 0.354, P < 0.01) in all the subjects. This correlation was still significant in the NGT group (P < 0.472, P < 0.05), DM group (r = 0.311, P < 0.01), and DM group with a fasting plasma glucose >150 mg/dl ( n = 20, r = 0.459. P < 0.05). Moreover, Pr-LPL mass correlated negatively with HOMA-R (r = -0.272. P < 0.05) and fasting IRI (r = -0.256, P < 0.05). By contrast, Pr-LPL mass was not correlated with either urine CPR or logAIRg that reflect the ability to secrete insulin. In conclusion, Pr-LPL mass reflects insulin sensitivity. We speculate that Pr-LPL mass might be used to assess insulin sensitivity not only in the general population but also in advanced diabetic patients.
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PMID:Lipoprotein lipase (LPL) mass in preheparin serum reflects insulin sensitivity. 1513 71

Lipoprotein lipase (LPL) secreted by macrophages in the arterial wall promotes atherosclerosis. We have shown that macrophages of patients with type 2 diabetes overproduce LPL and that metabolic factors, including glucose, stimulate macrophage LPL secretion. In this study, we determined the effect of advanced glycation end products (AGEs) on LPL expression by macrophages cultured in a high-glucose environment and the molecular mechanisms underlying this effect. Our results demonstrate that AGEs potentiate the stimulatory effect of high glucose on murine and human macrophage LPL gene expression and secretion. Induction of macrophage LPL mRNA levels by AGEs was identical to that elicited by physiologically relevant modified albumin and was inhibited by anti-AGE receptor as well as by antioxidants. Treatment of macrophages with AGEs resulted in protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activation. Inhibition of these kinases abolished the effect of AGEs on LPL mRNA levels. Finally, exposure of macrophages to AGEs increased the binding of nuclear proteins to the activated protein-1 consensus sequence of the LPL promoter. This effect was inhibited by PKC and MAPK inhibitors. These results demonstrate for the first time that AGEs potentiate the stimulatory effect of high glucose on macrophage LPL expression. This effect appears to involve oxidative stress and PKC/MAPK activation.
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PMID:Advanced glycation end products potentiate the stimulatory effect of glucose on macrophage lipoprotein lipase expression. 1521 Aug 47

A major factor contributing to cardiovascular mortality in type 2 diabetes is dyslipidemia, characterized by low HDL cholesterol and high triglycerides, rather than elevated LDL cholesterol. Lipoprotein lipase (LPL) is the rate-limiting enzyme of triglyceride removal from plasma and has been implicated in atherosclerosis. Since treatment with statins significantly reduces cardiovascular morbidity in diabetes, we analyzed the lipid profile and LPL activities in 61 patients with type 2 diabetes before and 8 weeks after initiation of atorvastatin (40 mg) or placebo treatment. Lipid parameters and LPL activity were unchanged under treatment with placebo. Atorvastatin treatment resulted in a 30% reduction of total and a 45% reduction of LDL cholesterol (6.06 +/- 1.39 mmol/L versus 4.14 +/- 1.27 mmol/L and 4.11 +/- 1.13 mmol/L versus 2.27 +/- 0.89 mmol/L, both P < 0.0001). Triglycerides and VLDL cholesterol were also significantly reduced by statin therapy (2.24 +/- 2.11 mmol/L versus 1.82 +/- 1.46 mmol/L and 1.08 +/- 1.56 mmol/L versus 0.67 +/- 0.66 mmol/L, both P < 0.05). HDL cholesterol was not different between the atorvastatin and the placebo group. Compared to baseline, LPL activity was increased by 25% after atorvastatin treatment (213.0 +/- 28.1 nmol/mL/min versus 171.9 +/- 17.7 nmol/mL/min, P < 0.01). Our data demonstrate that atorvastatin induces a significant improvement of diabetic dyslipidemia and a significant increase of LPL activity. Since low LPL activity indicates an increased cardiovascular risk, the statin-mediated increase in LPL activity may help to explain the reduction of CAD in diabetic patients treated with statins.
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PMID:Atorvastatin improves diabetic dyslipidemia and increases lipoprotein lipase activity in vivo. 1526 89

Elevated plasma levels of VLDL triglycerides (TGs) are characteristic of patients with type 2 diabetes mellitus (T2DM) and are associated with increased production rates (PRs) of VLDL TGs and apoB. Lipoprotein lipase-mediated (LPL-mediated) lipolysis of VLDL TGs may also be reduced in T2DM if the level of LPL is decreased and/or the level of plasma apoC-III, an inhibitor of LPL-mediated lipolysis, is increased. We studied the effects of pioglitazone (Pio), a PPARgamma agonist that improves insulin sensitivity, on lipoprotein metabolism in patients with T2DM. Pio treatment reduced TG levels by increasing the fractional clearance rate (FCR) of VLDL TGs from the circulation, without changing direct removal of VLDL particles. This indicated increased lipolysis of VLDL TGs during Pio treatment, a mechanism supported by our finding of increased plasma LPL mass and decreased levels of plasma apoC-III. Lower apoC-III levels were due to reduced apoC-III PRs. We saw no effects of Pio on the PR of either VLDL TG or VLDL apoB. Thus, Pio, a PPARgamma agonist, reduced VLDL TG levels by increasing LPL mass and inhibiting apoC-III PR. These 2 changes were associated with an increased FCR of VLDL TGs, almost certainly due to increased LPL-mediated lipolysis.
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PMID:Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. 1584 Dec 15

California mice (Peromyscus californicus) develop type II diabetes mellitus when fed a high-fat diet. We undertook the current studies to determine whether hyperlipidemia precedes the development of insulin resistance and to establish breeding colonies of hyperlipidemic and normolipidemic mice. For 6 wk, mice (n = 24) received a diet containing 25.8% of energy from fat. Mice representing the upper and lower quartiles of serum triacylglycerol (TAG) response (mean, >1000 mg/dl versus <300 mg/dl, respectively; 6 mice per group) were designated as high (HR) and low (LR) responders, respectively, and were used for further study. After 12 wk of consuming the high-fat diet, HR mice remained hypertriglyceridemic and developed hyperinsulinemia (5.1 +/- 1.3 ng/ml), hypercholesterolemia (309.3 +/- 31.0 mg/dl), and hyperglycemia (205.9 +/- 30.3 mg/dl) compared with LR mice. HR mice were not hyperphagic or obese. Offspring of HR x HR mice had elevated serum TAG concentrations (mean, 1752.2 +/- 209.7 mg/dl), hypercholesterolemia, hyperinsulinemia, and mild hyperglycemia by 5.5 mo of age. Mating HR male and LR female mice produced HR, intermediate, and LR progeny. HR mice had elevated serum concentrations of cholesterol, and plasma concentrations of high density lipoprotein cholesterol, and the very low density lipoprotein TAG compared with LR mice. Lipoprotein lipase and hepatic lipase activities did not differ between HR and LR mice. Studies of in vivo hepatic TAG production indicated that the hyperlipidemia of HR mice is a consequence of TAG hypersecretion.
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PMID:Heritable, diet-induced hyperlipidemia in California mice (Peromyscus californicus) is due to increased hepatic secretion of very low density lipoprotein triacylglycerol. 1721 76

Lipoprotein lipase is a central enzyme in the lipid metabolism, which catalyses the hydrolysis of the triacylglycerol component of chylomicrons and very low density lipoproteins, thereby providing fatty acids and monoacylglycerol for tissue utilisation. LPL gene mutation may affect the activity of LPL, and results in lipid metabolism disorder. It is associated with type 2 diabetes, hypertension, atherosclerosis, obesity and coronary artery disease. Here we review the structure, function, expression regulation of the LPL gene along with its association with complex diseases.
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PMID:[Research progress of lipoprotein lipase gene]. 1728 17


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