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)

Diabetic cardiomyopathy is the result of maladaptive changes in energy homeostasis. However, the biochemical mechanisms underlying dysfunctional lipid metabolism in diabetic myocardium are incompletely understood. Herein, we exploit shotgun lipidomics to demonstrate a 4-fold increase in acylcarnitines in diabetic myocardium, which was reversible upon insulin treatment. Analysis of acylcarnitine molecular species in myocardium unexpectedly identified acylcarnitine molecular species containing a mass shift of 16 amu in comparison to the anticipated molecular species. Synthesis of 3-hydroxy acylcarnitine identified the natural products as the 3-hydroxylated acylcarnitines through comparisons of diagnostic fragmentation patterns of synthetic and naturally occurring constituents using tandem mass spectrometry. Diabetes induced an increase of both calcium-independent phospholipase A(2) (iPLA(2)) mRNA and iPLA(2) activity in rat myocardium. Cardiac ischemia in myocardium genetically engineered to overexpress iPLA(2) dramatically increased the amount of acylcarnitine present in myocardium. Moreover, mechanism-based inactivation of iPLA(2) in either wild-type or transgenic myocardium ablated a substantial portion of the acylcarnitine increase. Collectively, these results identify discrete insulin remediable abnormalities in mitochondrial fatty acid processing in diabetic myocardium and identify iPLA(2) as an important enzymatic contributor to the pool of fatty acids that can be used for acylcarnitine synthesis and energy production in myocardium.
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PMID:Accumulation of long-chain acylcarnitine and 3-hydroxy acylcarnitine molecular species in diabetic myocardium: identification of alterations in mitochondrial fatty acid processing in diabetic myocardium by shotgun lipidomics. 1579 60

Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) plays an important role in arachidonate pathway. To investigate the contribution of cPLA(2)alpha to autoimmune diabetes, we established non-obese diabetic (NOD) mouse, an excellent model for human type 1 diabetes, deficient in cPLA(2)alpha. These mice showed severe insulitis and a higher incidence of diabetes. In their macrophages, decreased prostaglandin E(2) (PGE(2)) induced by cPLA(2)alpha deficiency, and the increase in production of tumor necrosis factor (TNF)-alpha were observed. These results suggested that cPLA(2)alpha plays a protective role in progression of insulitis and development of autoimmune diabetes by suppression of TNF-alpha production from macrophages.
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PMID:Protective role for cytosolic phospholipase A2alpha in autoimmune diabetes of mice. 1599 60

Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis associated with coronary heart disease, vascular complications in diabetes, inflammatory vascular diseases, and tumor metastasis. The mechanism of VEGF-driven angiogenesis involving glycosphingolipids such as lactosylceramide (LacCer), however, is not known. To demonstrate the involvement of LacCer in VEGF-induced angiogenesis, we used small interfering RNA (siRNA)-mediated silencing of LacCer synthase expression (GalT-V) in human umbilical vein endothelial cells. This gene silencing markedly inhibited VEGF-induced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and angiogenesis. Second, we used D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of LacCer synthase and glucosylceramide synthase, that significantly mitigated VEGF-induced PECAM-1 expression and angiogenesis. Interestingly, these phenotypic changes were reversed by LacCer but not by structurally related compounds such as glucosylceramide, digalactosylceramide, and ceramide. In a human mesothelioma cell line (REN) that lacks the endogenous expression of PECAM-1, VEGF/LacCer failed to stimulate PECAM-1 expression and tube formation/angiogenesis. In REN cells expressing human PECAM-1 gene/protein, however, both VEGF and LacCer-induced PECAM-1 protein expression and tube formation/angiogenesis. In fact, VEGF-induced but not LacCer-induced angiogenesis was mitigated by SU-1498, a VEGF receptor tyrosine kinase inhibitor. Also, VEGF/LacCer-induced PECAM-1 expression and angiogenesis was mitigated by protein kinase C and phospholipase A2 inhibitors. These results indicate that LacCer generated in VEGF-treated endothelial cells may serve as an important signaling molecule for PECAM-1 expression and in angiogenesis. This finding and the reagents developed in our report may be useful as anti-angiogenic drugs for further studies in vitro and in vivo.
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PMID:Novel role of lactosylceramide in vascular endothelial growth factor-mediated angiogenesis in human endothelial cells. 1615 Oct 23

Recent prospective analysis identified secretory phospholipase A(2)-IIa (sPLA(2)IIa) as a coronary artery disease (CAD) risk predictor. This study aimed to examine the relationship between serum levels of sPLA(2)IIa and variation in the sPLA(2)IIa gene (PLA2G2A) in a cohort of patients with Type II diabetes (T2D) mellitus. Six tagging single nucleotide polymorphisms (tSNPs) accounting for > 92% of the genetic variability in PLA2G2A were identified and distinguished six common haplotypes (frequencies > 5%). In the 523 Caucasian T2D patients, levels of sPLA(2)IIa, independent of CRP, were negatively correlated with total antioxidant status (P = 0.003) and high-density lipoprotein cholesterol (P = 0.006) in men and correlated with CAD status in women (P = 0.002) (Odds ratio of top two tertiles versus bottom = 2.50) [95% CI (1.13-5.53) P = 0.024]. Overall, tSNP haplotypes showed a highly significant association with sPLA(2)IIa levels (P < 0.0001), explaining 6.3% of the variance. The most common haplotype (frequency 14.2%) was associated with 53% higher sPLA(2)IIa levels [3.25 ng/ml (+/- 0.14)] compared with the combined other haplotypes [2.13 ng/ml (+/- 0.09), P < 0.00001]. Five of the six tSNPs were associated with significant effects on sPLA(2)IIa levels but the raising haplotype could not be distinguished by a single tSNP and none are likely to be functional. These data confirm the relationship between elevated sPLA(2)IIa levels and CAD risk reported in both cases: control and prospective analyses. The strong impact of PLA2G2A haplotypic variation on sPLA(2)IIa levels will help clarify the causality of this association.
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PMID:Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study. 1636 10

Lipoprotein associated phospholipase A2 (Lp-PLA2) modulates low-density lipoprotein (LDL) oxidation by hydrolysing oxidised phospholipids present on particle surfaces. We investigated whether Lp-PLA2 activity and PLA2G7 A379V genotype were related to mediators of atherosclerosis in a diabetic study. Plasma Lp-PLA2 activity (taken in men only) and A379V genotype were investigated with regards to metabolic syndrome (MS), UKPDS risk score, and oxidised LDL (oxLDL/LDL), in a cohort of Caucasian men and women (n=783, age 62.5+/-13.7 years). After adjustment for type of diabetes, CHD status, and statin use, those individuals with features defining the MS (WHO guidelines) had higher Lp-PLA2 activity (35.6+/-11.9 nmol/min/ml) compared to those without (33.0+/-10.8 nmol/min/ml) (p=0.02). Quartiles of UKPDS coronary heart disease (CHD) risk score were also positively associated with Lp-PLA2 activity (p=0.006, p=0.004 linear trend). Those men in the highest quartile of oxLDL/LDL level had the lowest Lp-PLA2 activity (31.3+/-10.5 nmol/min/ml) when compared to the middle two (32.3+/-9.8 and 35.9+/-10.9 nmol/min/ml, respectively) and lowest quartile (35.6 +/-12.5 nmol/min/ml; p=0.03, p=0.004 linear trend). There was no significant association between A379V genotype and Lp-PLA2 enzyme activity (p=0.34) or oxLDL/LDL (p=0.32). Lp-PLA2 activity is an independent predictor of CHD risk and MS in a sample of subjects with diabetes mellitus. The association of Lp-PLA2 activity with oxLDL/LDL suggests that Lp-PLA2 may be a modulating factor in the process of atherosclerosis.
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PMID:Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus. 1643 75

The development of edema in the diabetic retina may be caused by vascular leakage and glial cell swelling. To determine whether diabetic retinopathy alters the swelling characteristics of retinal glial cells and changes the properties of the glial membrane K+ conductance, isolated retinas and glial cells of rats were investigated at 4 and 6 months of chemical diabetes. After 6 months of hyperglycemia, application of a hypotonic solution to retinal slices induced swelling of glial cell bodies, a response not observed in control retinas. The osmotic glial cell swelling was blocked by inhibitors of phospholipase A2 or cyclooxygenase and by a thiol-reducing agent. Glial cells from diabetic retinas displayed a decrease of K+ currents that was associated with an altered subcellular distribution of the K+ conductance and a loss of perivascular Kir4.1 protein. The observation that swelling of cells in control retinas was inducible with K+ channel-blocking Ba2+ ions suggests a relationship between decreased K+ inward currents and osmotic cell swelling in diabetic retinas. The data show that glial cells in diabetic retinas are more sensitive to osmotic stress, which is associated with a decrease of K+ currents, than cells in control retinas. It is suggested that these alterations may be implicated in the development of diabetic retinal edema.
Diabetes 2006 Mar
PMID:Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina. 1650 25

Postprandial hyperglycemia is an early indicator of abnormality in glucose metabolism leading to type 2 diabetes. However, mechanisms that contribute to postprandial hyperglycemia have not been identified. This study showed that mice with targeted inactivation of the group 1B phospholipase A2 (Pla2g1b) gene displayed lower postprandial glycemia than that observed in wild-type mice after being fed a glucose-rich meal. The difference was caused by enhanced postprandial glucose uptake by the liver, heart, and muscle tissues as well as altered postprandial hepatic glucose metabolism in the Pla2g1b-/- mice. These differences were attributed to a fivefold decrease in the amount of dietary phospholipids absorbed as lysophospholipids in Pla2g1b-/- mice compared with that observed in Pla2g1b+/+ mice. Elevating plasma lysophospholipid levels in Pla2g1b-/- mice via intraperitoneal injection resulted in glucose intolerance similar to that exhibited by Pla2g1b+/+ mice. Studies with cultured hepatoma cells revealed that lysophospholipids dose-dependently suppressed insulin-stimulated glycogen synthesis. These results demonstrated that reduction of lysophospholipid absorption enhances insulin-mediated glucose metabolism and is protective against postprandial hyperglycemia.
Diabetes 2006 Apr
PMID:Group 1B phospholipase A2-mediated lysophospholipid absorption directly contributes to postprandial hyperglycemia. 1656 14

During early pregnancy, long-chain polyunsaturated fatty acids (LC-PUFA) may accumulate in maternal fat depots and become available for placental transfer during late pregnancy, when the fetal growth rate is maximal and fetal requirements for LC-PUFAs are greatly enhanced. During this late part of gestation, enhanced lipolytic activity in adipose tissue contributes to the development of maternal hyperlipidaemia; there is an increase in plasma triacylglycerol concentrations, with smaller rises in phospholipid and cholesterol concentrations. Besides the increase in plasma very-low-density lipoprotein, there is a proportional enrichment of triacylglycerols in both low-density lipoproteins and high-density lipoproteins. These lipoproteins transport LC-PUFA in the maternal circulation. The presence of lipoprotein receptors in the placenta allows their placental uptake, where they are hydrolysed by lipoprotein lipase, phospholipase A(2) and intracellular lipase. The fatty acids that are released can be metabolized and diffuse into the fetal plasma. Although present in smaller proportions, maternal plasma non-esterified fatty acids are also a source of LC-PUFA for the fetus, their placental transfer being facilitated by the presence of a membrane fatty acid-binding protein. There is very little placental transfer of glycerol, whereas the transfer of ketone bodies may become quantitatively important under conditions of maternal hyperketonaemia, such as during fasting, a high-fat diet or diabetes. The demands for cholesterol in the fetus are high, but whereas maternal cholesterol substantially contributes to fetal cholesterol during early pregnancy, fetal cholesterol biosynthesis rather than cholesterol transfer from maternal lipoproteins seems to be the main mechanism for satisfying fetal requirements during late pregnancy.
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PMID:Maternal lipid metabolism and placental lipid transfer. 1661 15

Small, dense, electronegative low density lipoprotein [LDL(-)] is increased in patients with familial hypercholesterolemia and diabetes, populations at increased risk for coronary artery disease. It is present to a lesser extent in normolipidemic subjects. The mechanistic link between small, dense LDL(-) and atherogenesis is not known. To begin to address this, we studied the composition and dynamics of small, dense LDL(-) from normolipidemic subjects. NEFA levels, which correlate with triglyceride content, are quantitatively linked to LDL electronegativity. Oxidized LDL is not specific to small, dense LDL(-) or lipoprotein [a] (i.e., abnormal lipoprotein). Apolipoprotein C-III is excluded from the most abundant LDL (i.e., that of intermediate density: 1.034 < d < 1.050 g/ml) but associated with both small and large LDL(-). In contrast, lipoprotein-associated phospholipase A(2) (LpPLA(2)) is highly enriched only in small, dense LDL(-). The association of LpPLA(2) with LDL may occur through amphipathic helical domains that are displaced from the LDL surface by contraction of the neutral lipid core.
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PMID:Dynamics of dense electronegative low density lipoproteins and their preferential association with lipoprotein phospholipase A(2). 1710 49

The roles played by arachidonic acid and its cyclooxygenase (COX)-generated and lipoxygenase (LOX)-generated metabolites have been studied using rodent islets and insulin-secreting cell lines, but very little is known about COX and LOX isoform expression and the effects of modulation of arachidonic acid generation and metabolism in human islets. We have used RT-PCR to identify mRNAs for cytosolic phospholipase A(2) (cPLA(2)), COX-1, COX-2, 5-LOX, and 12-LOX in isolated human islets. COX-3 and 15-LOX were not expressed by human islets. Perifusion experiments with human islets indicated that PLA(2) inhibition inhibited glucose-stimulated insulin secretion, whereas inhibitors of COX-2 and 12-LOX enzymes enhanced basal insulin secretion and also secretory responses induced by 20 mmol/l glucose or by 50 mumol/l arachidonic acid. Inhibition of COX-1 with 100 mumol/l acetaminophen did not significantly affect glucose-stimulated insulin secretion. These data indicate that the stimulation of insulin secretion from human islets in response to arachidonic acid does not require its metabolism through COX-2 and 5-/12-LOX pathways. The products of COX-2 and LOX activities have been implicated in cytokine-mediated damage of beta-cells, so selective inhibitors of these enzymes would be expected to have a dual protective role in diabetes: they would minimize beta-cell dysfunction while maintaining insulin secretion through enhancing endogenous arachidonic acid levels.
Diabetes 2007 Jan
PMID:The role of arachidonic acid and its metabolites in insulin secretion from human islets of langerhans. 1719 82


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