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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerosis is the major complication of diabetes. Accumulating evidence indicates that lipoprotein lipase (LPL) produced by macrophages in the vascular wall may favor the development of atherosclerosis by promoting lipid accumulation within the lesion. We previously demonstrated that high glucose stimulates in vitro murine and human macrophage LPL production. In this study, we measured macrophage LPL mRNA expression, immunoreactive mass, and activity in normotriglyceridemic subjects with type 2 diabetes. Monocytes isolated from healthy control subjects and patients with type 2 diabetes were differentiated into macrophages in RPMI medium containing 20% autologous serum. After 5 days in culture, macrophage LPL mRNA expression, mass, and activity were determined. Macrophages of diabetic patients cultured in their own sera showed a significant increase in LPL mRNA levels, mass, and activity compared with macrophages of control subjects. Differentiation of macrophages of diabetic patients in sera obtained from control subjects significantly reduced these anomalies. Conversely, culturing macrophages of control subjects in sera of diabetic patients significantly increased LPL mass and activity in these cells. Besides LPL overproduction, macrophages of diabetic patients exhibited an increase in basal and LPL-induced tumor necrosis factor (TNF)-alpha release. TNF-alpha alterations were reduced by exposing these cells to sera of control subjects. Overall, these data demonstrate that macrophages of diabetic patients overexpress LPL and TNF-alpha and that peripheral factors dysregulated in diabetes are, at least in part, responsible for these alterations.
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PMID:Upregulation of macrophage lipoprotein lipase in patients with type 2 diabetes: role of peripheral factors. 1087 Nov 97

The Otsuka Long-Evans Tokushima fatty (OLETF) rat is an animal model of type 2 diabetes, characterized by abdominal obesity, insulin resistance, hypertension, and dyslipidemia. To elucidate the underlying molecular mechanism of obesity and its related complications, we used representational difference analysis and identified the genes more abundantly and specifically expressed in the visceral adipose tissue (VAT) of obese OLETF rats compared with the diabetes-resistant counterpart, that is, Long-Evans Tokushima Otsuka (LETO) rats. By Northern blot analysis, we confirmed the differential expression of 13 genes, including 3 novel genes. The upregulated expression of well-characterized lipid metabolic enzymes, such as lipoprotein lipase, phosphoenolpyruvate carboxykinase, and cholesterol esterase, were observed in VAT of OLETF rats. We demonstrated the differential expression of secreted proteins in VAT of OLETF rats, such as thrombospondin 1 and contrapsin-like protease inhibitor. In contrast to lipid enzymes, the secreted proteins revealed exclusive mRNA expression and they were not detected in VAT of LETO rats. Furthermore, the novel genes OL-16 and OL-64 were also expressed specifically in VAT of OLETF rats and were absent in that of LETO rats and other tissues, including subdermal and brown adipose tissues. The C-terminal partial amino acid sequence of OL-64 revealed that it showed approximately 40% homology with alpha(1)-antitrypsin and it seemed to be a new member of the serine proteinase inhibitor (SERPIN) gene family. VAT of OLEFT rats had a unique gene expression profile, and the accumulated VAT-specific known and novel secreted proteins may play a role(s) in the pathogenesis of obesity and its related complications.
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PMID:Identification of genes specifically expressed in the accumulated visceral adipose tissue of OLETF rats. 1101 3

Historically, extracts of the creosote bush have been used by native healers of the Southwest region of North America to treat symptoms of type 2 diabetes. More recently, we have shown that masoprocol (nordihydroguaiaretic acid), a pure compound isolated from the creosote bush (Larrea tridentata), decreases serum glucose and triglyceride (TG) levels when administered orally in rodent models of type 2 diabetes. The present studies were undertaken to determine if masoprocol also decreases TG concentrations in rats with fructose-induced hypertriglyceridemia (HTG), a nondiabetic model of HTG associated with insulin resistance and hyperinsulinemia. Serum TG levels, which were significantly higher after rats ate a fructose-enriched (60% by weight) diet for 14 days as compared with chow-fed controls (411 v 155 mg/dL, P < .01), decreased in a stepwise fashion in fructose-fed rats treated orally with masoprocol for 4 to 8 days over a dose range of 10 to 80 mg/kg twice daily. Using the nonionic detergent Triton WR 1339 to compare TG secretion rates in masoprocol- and vehicle-treated rats, masoprocol at a dose of 40 or 80 mg/kg twice daily, significantly reduced hepatic TG secretion (P < .01) and liver TG content (P < .001), whereas lower doses of masoprocol decreased serum TG without an apparent reduction in hepatic TG secretion. Administration of Intralipid (a fat emulsion) showed that the half-time for removal of TG from serum was also shorter in masoprocol-treated rats versus vehicle-treated controls (31 v 64 minutes, P < .05). In addition adipose tissue lipoprotein lipase (LPL) activity was increased in masoprocol-treated rats and adipose tissue hormone-sensitive lipase (HSL) activity was decreased. We conclude that masoprocol administration to rats with fructose-induced HTG results in lower serum TG levels associated with reduced hepatic TG secretion and increased peripheral TG clearance.
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PMID:Masoprocol decreases serum triglyceride concentrations in rats with fructose-induced hypertriglyceridemia. 1101 88

The hypolipidemic fibric acid drugs are peroxisome proliferator-activated receptor a (PPAR alpha) ligands. PPAR alpha activated by fibric acids form heterodimers with the 9-cis retinoic acid receptor (RXR). The PPAR/RXR heterodimers bind to peroxisome proliferator response elements (PPRE), which are located in numerous gene promoters and increase the level of the expression of mRNAs encoded by PPAR alpha target genes. Fibric acids decrease triglyceride plasma levels through increases in the expression of genes involved in fatty acid-beta oxidation. Furthermore, they decrease triglycerides by increasing lipoprotein lipase gene expression and by decreasing apolipoprotein C-III gene expression. Fibric acids increase high-density lipoprotein (HDL) cholesterol partly by increasing apolipoprotein A-I and apolipoprotein A-II gene expression. Fibric acids also reduce vascular wall inflammation and the expression of genes involved in different vascular functions (ie, vasomotricity, thrombosis). Fibric acids are used to treat primary hypertriglyceridemia and mixed hyperlipidemia. Some fibric acid molecules are active in essential hypercholesterolemia. Clinical evidence shows that fibric acids reduce coronary atherosclerosis progression in dyslipidemic patients (eg, bezafibrate, gemfibrozil) and in type 2 diabetic patients (fenofibrate). Gemfibrozil decreases coronary morbidity and mortality in patients with low HDL cholesterol, normal triglycerides,and normal low-density lipoprotein (LDL) cholesterol plasma levels. Further clinical studies are necessary to investigate if fibric acids decrease cardiovascular mortality in type 2 diabetes and in primary prevention of hypertriglyceridemia and hypolipidemia.
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PMID:The role of fibric acids in atherosclerosis. 1112 53

Type 2 diabetes is a heterogeneous condition that is not attributable to a single pathophysiological mechanism. In general, both insulin resistance and impaired insulin secretion are required for the disease to become manifest. Thus, as long as the pancreatic beta cells can compensate for the degree of insulin resistance, glucose tolerance remains normal. Clustering of type 2 diabetes in certain families and ethnic populations points to a strong genetic background for the disease. However, environmental factors such as obesity and a sedentary lifestyle are usually required to unmask the genes. Impaired insulin-stimulated glucose metabolism (particularly non-oxidative) in skeletal muscle represents a key feature of type 2 diabetes and is observed early in the pre-diabetic state. It is not clear, though, whether this represents an inherited defect in muscle or whether it develops secondarily, for example, to abdominal obesity. In favour of the latter hypothesis are findings that abdominal obesity and a low metabolic rate seem to precede the development of insulin resistance in offspring of type 2 diabetic patients. According to the thrifty gene hypothesis, individuals living in an environment with an unstable food supply could increase their probability of survival if they could maximize storage of surplus energy, for instance, as abdominal fat. Exposing this energy-storing genotype to the abundance of food typical of westernized societies is detrimental, causing insulin resistance and, subsequently, type 2 diabetes. There are a number of potential thrifty genes, including those that regulate lipolysis or code for the beta3-adrenergic receptor, the hormone-sensitive lipase, and lipoprotein lipase. Type 2 diabetes develops as a consequence of a collision between thrifty genes and a hostile affluent environment. Insulin resistance is a key trigger for the disease, and optimal management of type 2 diabetes should therefore aim to ameliorate insulin resistance early.
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PMID:Insulin resistance: the fundamental trigger of type 2 diabetes. 1122 Feb 83

It has been known for years that cardiovascular disease frequently precedes the development of type 2 diabetes, and that atherosclerosis might not be a complication of type 2 diabetes, but rather the consequence of common genetic and environmental factors (the common soil' hypothesis). The insulin resistance syndrome (IRS) is a cluster of closely associated and interdependent abnormalities, including insulin resistance, hyperinsulinaemia, android fat distribution, progressive glucose intolerance, dyslipidaemia (increased triglycerides, decreased HDL, increased small dense LDL), increased prothrombotic and antifibrinolytic factors, and hypertension. Many of these abnormalities are risk factors for type 2 diabetes, and most of them explain the predilection for atherosclerosis to occur in conjunction with IRS. Insulin resistance is a key feature of IRS, and has been suggested to be the common pathophysiological basis of atherosclerosis and type 2 diabetes. The term 'insulin resistance' denotes resistance to insulin-mediated glucose uptake into skeletal muscle, which can be measured by the glucose clamp technique. There are, however, other less understood sites of abnormal insulin action that may also be relevant in IRS. These include liver, adipose, and kidney tissue, and systems such as muscle perfusion, antilipolysis, lipoprotein lipase activity, and cation transport. The development of clinical cardiovascular end-points in a patient with insulin resistance is complex, as it includes the degree of the defect, its associated abnormalities, its consequences, and the ability to compensate for the underlying defect. It is therefore more appropriate to consider the different facets and risk factors of IRS in aggregate, rather than seeking 'independent' effects. Accordingly, treatment of insulin resistance per se has not yet been shown to reduce the incidence of cardiovascular complications. At the cellular level, excess insulin is involved in various elements of atherogenesis. It interacts with cytokines and growth factors in a cross talk among vascular wall cells and a variety of mediators that play a role in the establishment of atheroma. Excess insulin also plays an important role in concert with lipoproteins when they exhibit an abnormal pattern and become modified by oxidation and glycation. It is therefore currently hoped that the introduction of a new class of insulin-sensitizing agents, the thiazolidinediones, may attenuate these processes. The thiazolidinediones act through ligand activation of a nuclear transcription factor, the peroxisomal proliferator-activated receptor-gamma (PPARgamma). Although this receptor was initially linked to lipid and glucose metabolism, recent data suggest that PPARgamma is also involved in the differentiation of mononuclear phagocytes, their inflammatory reactions, and macrophage conversion to foam cells. Thus, PPARgamma ligands may also be important regulators of monocyte/ macrophage gene expression during atherogenesis.
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PMID:The relation between insulin resistance and cardiovascular complications of the insulin resistance syndrome. 1122 Feb 89

Atherosclerosis is a major complication of type 2 diabetes. The pathogenesis of this complication is poorly understood, but it clearly involves production in the vascular wall of macrophage (Mo) lipoprotein lipase (LPL). Mo LPL is increased in human diabetes. Peripheral factors dysregulated in diabetes, including glucose and free fatty acids (FAs), may contribute to this alteration. We previously reported that high glucose stimulates LPL production in both J774 murine and human Mo. In the present study, we evaluated the direct effect of FAs on murine Mo LPL expression and examined the involvement of peroxisome proliferator-activated receptors (PPARs) in this effect. J774 Mo were cultured for 24 h with 0.2 mmol/l unsaturated FAs (arachidonic [AA], eicosapentaenoic [EPA], and linoleic acids [LA]) and monounsaturated (oleic acid [OA]) and saturated FAs (palmitic acid [PA] and stearic acid [SA]) bound to 2% bovine serum albumin. At the end of this incubation period, Mo LPL mRNA expression, immunoreactive mass, activity, and synthetic rate were measured. Incubation of J774 cells with LA, PA, and SA significantly increased Mo LPL mRNA expression. In contrast, exposure of these cells to AA and EPA dramatically decreased this parameter. All FAs, with the exception of EPA and OA, increased extra- and intracellular LPL immunoreactive mass and activity. Intracellular LPL mass and activity paralleled extracellular LPL mass and activity in all FA-treated cells. In Mo exposed to AA, LA, and PA, an increase in Mo LPL synthetic rate was observed. To evaluate the role of PPARs in the modulatory effect of FAs on Mo LPL gene expression, DNA binding assays were performed. Results of these experiments demonstrate an enhanced binding of nuclear proteins extracted from all FA-treated Mo to the peroxisome proliferator-response element (PPRE) consensus sequence of the LPL promoter. PA-, SA-, and OA-stimulated binding activity was effectively diminished by immunoprecipitation of the nuclear proteins with anti-PPAR-alpha antibodies. In contrast, anti-PPAR-gamma antibodies only significantly decreased AA-induced binding activity. Overall, these results provide the first evidence for a direct regulatory effect of FAs on Mo LPL and suggest a potential role of PPARs in the regulation of Mo LPL gene expression by FAs.
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PMID:Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. 1124 88

Defects in the lipoprotein lipase (LPL) gene are associated with dyslipidemia in the general population. Several rare mutations in the gene, as well as two common coding region polymorphisms, D9N and N291S, exhibit deleterious effects on circulating lipid levels. Using a linkage-based approach, we have identified a large Utah kindred segregating the D9N variant in the LPL gene. The kindred was ascertained for premature coronary heart disease and was expanded based on familial dyslipidemia. A genomic scan identified a region of linkage including LPL, and mutation screening identified the segregating variant. In the kindred, the variant shows high penetrance for a hypoalphalipoproteinemia phenotype, but is also associated with hypertriglyceridemia and elevated insulin levels. The strength of linkage was dependent on the combination of phenotype definition and model parameters, favoring the use of a MOD score approach. Most other studies of LPL have proceeded by mutation screening of randomly chosen individuals or selected affected probands; this is the first example identifying a segregating LPL mutation using direct linkage.
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PMID:Identification of a common variant in the lipoprotein lipase gene in a large Utah kindred ascertained for coronary heart disease: the -93G/D9N variant predisposes to low HDL-C/high triglycerides. 1126 Feb 9

The aim of this study was to delineate the role of lipoprotein lipase (LPL) activity in the kinetic alterations of high density lipoprotein (HDL) metabolism in patients with type II diabetes mellitus compared with controls. The kinetics of HDL were studied by endogenous labeling of HDL apolipoprotein AI (HDL-apo AI) using a primed infusion of D(3)-leucine. The HDL-apo AI fractional catabolic rate (FCR) was significantly increased (0.32 +/- 0.07 vs. 0.23 +/- 0.05 pool/day; P < 0.01), and HDL composition was changed [HDL cholesterol, 0.77 +/- 0.16 vs. 1.19 +/- 0.37 mmol/L (P < 0.05); HDL triglycerides, 0.19 +/- 0.12 vs. 0.10 +/- 0.03 mmol/L (P < 0.05)] in diabetic patients compared with healthy subjects. HDL-apo AI FCR was correlated to plasma and HDL triglyceride concentrations (r = 0.82; P < 0.05 and r = 0.80; P < 0.05, respectively) and to homeostasis model assessment (r = 0.78; P < 0.05). Postheparin plasma LPL activity was decreased in type II diabetes (6.8 +/- 2.8 vs. 18.1 +/- 5.2 micromol/mL postheparin plasma.h; P < 0.005) compared with that in healthy subjects and was correlated to the FCR of HDL-apo AI (r = -0.63; P < 0.05). LPL activity was also correlated with HDL cholesterol (r = 0.78; P < 0.05), plasma and HDL triglycerides (r = -0.87; P < 0.005 and r = -0.83; P < 0.05, respectively), and homeostasis model assessment (r = -0.79; P < 0.05). In addition, the LPL to hepatic lipase ratio was correlated with the catabolic rate of HDL (r = -0.76; P < 0.06). These results suggest that a decrease in the LPL to hepatic lipase ratio in type II diabetes mellitus, mainly related to lowered LPL activity, could induce an increase in HDL catabolism. These alterations in HDL kinetics in type II diabetes proceed to some extent from changes in their composition, probably linked to an increase in triglyceride transfer from very low density lipoprotein particles, in close relationship with LPL activity and resistance to insulin.
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PMID:In vivo evidence for the role of lipoprotein lipase activity in the regulation of apolipoprotein AI metabolism: a kinetic study in control subjects and patients with type II diabetes mellitus. 1134 92

Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle-lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e., diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones.
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PMID:Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. 1139 Sep 66


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