Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long chain fatty acid uptake across the plasma membrane occurs, in part, via a protein-mediated process involving a number of fatty acid binding proteins known as fatty acid transporters. A critical step in furthering the understandings of fatty acid transport was the discovery that giant vesicles, prepared from tissues such as muscle and heart, provided a suitable system for measuring fatty acid uptake. These vesicles are large (10-15 microm diameter), are oriented fully right side out, and contain cytosolic FABP in the lumen, which acts as a fatty acid sink, while none of the fatty acid taken up is metabolized or associated with the plasma membrane. The key fatty acid transporters FAT/CD36 and FABPpm are expressed in muscle and heart and their plasma membrane content is positively correlated with rates of fatty acid transport. These transporters are regulated acutely (within minutes) and chronically (days). For instance, both muscle contraction and insulin can translocate FAT/CD36 from an intracellular pool to the plasma membrane, thereby increasing fatty acid transport. With obesity, fatty acid transport is increased along with a concomitant increase in plasmalemmal FAT/CD36 (heart, muscle) and FABPpm (heart only), but without change in the expression of these transporters. This latter observation suggests that some of the fatty acid transporters are permanently relocated to the plasma membrane. In other studies it also appears that fatty acid transport rates are altered in a reciprocal manner to glucose transport. Since disorders in lipid metabolism appear to be an important factor contributing to the etiology of a number of common human diseases such as diabetes and obesity, our evidence that protein-mediated fatty acid transport is a key step in lipid metabolism allows the speculation that malfunctioning of the fatty acid transport process could be a common critical factor in the pathogenesis of these diseases.
 ...
PMID:Regulation of fatty acid transport and membrane transporters in health and disease. 1247 84

Fatty acid translocase (FAT)/CD36 has been associated with diverse normal and pathologic processes. These include scavenger receptor functions (uptake of apoptotic cells and modified lipid), lipid metabolism and fatty acid transport, adhesion, angiogenesis, modulation of inflammation, transforming growth factor-beta activation, atherosclerosis, diabetes and cardiomyopathy. Although CD36 was identified more than 25 years ago, it is only with the advent of recent genetic technology that in vivo evidence has emerged for its physiologic and pathologic relevance. As these in vivo studies are expanded, we will gain further insight into the mechanism(s) by which CD36 transmits a cellular signal, and this will allow the design of specific therapeutics that impact on a particular function of CD36.
 ...
PMID:The impact of overexpression and deficiency of fatty acid translocase (FAT)/CD36. 1247 85

Increased platelet reactivity has been implicated in the vascular complications of myeloproliferative diseases and diabetes mellitus. The mechanisms of platelet hyperresponsiveness have not been fully explained. Expression of CD36 or fatty acid translocase (FAT) and its role in arachidonic acid (AA) uptake by platelets were examined in subjects with myeloproliferative disorders (MPD), those with non-insulin-dependent diabetes mellitus (NIDDM), and in normal, healthy, age-matched controls. Surface expression of CD36 on platelet membranes was increased in MPD (10.94 +/- 0.76 pmol/mg protein) compared with normal controls (6.94 +/- 0.48 pmol/mg protein), p < 0.001. Total platelet content of CD36 was also significantly higher (32.1 +/- 0.61 pmol/mg protein, p < 0.01) compared with those in sex and age matched normal controls (25.7 +/- 1.09 pmol/mg protein). In contrast, platelet surface expression of CD36 in NIDDM (6.5 +/- 0.56 pmol/mg protein) was not significantly different from those of normal controls despite higher total content of CD36 (32.8 +/- 1.2, pmol/mg protein, p < 0 .01). Intact MPD platelets bound significantly more arachidonic acid (AA) (1.53 +/- 0.16 nmol/mg protein, p < 0.05), compared with controls (1.12 +/- 0.07 nmol/mg protein) or NIDDM subjects (1.16 +/- 0.16 nmol/mg protein). The capacity of MPD platelet membranes to bind 14C-AA was also increased (1.72 +/- 0.25 nmol/mg protein, p < 0.05) compared with that of controls (1.62 +/- 0.05 nmol/mg protein) and of NIDDM (1.22 +/- 0.08 nmol/mg protein). This is consistent with higher surface expression of CD36 in MPD platelets. Membrane fatty acid analysis indicated that the % of AA in platelet phospholipids was significantly lower in MPD (3.15 +/- 0.81%) compared with the controls (5.62 +/- 1.7%, p < 0.05. The AA content of diabetic platelets (4.82 +/- 1.1%) was not significantly different from normal controls. In summary, both total and surface expression of CD36 are increased in MPD, consistent with an enhanced capacity for uptake of AA by platelets. Increased expression of CD36 in platelets may play a role in the vaso-occlusive manifestations of MPD.
 ...
PMID:Surface expression of fatty acid translocase (FAT/CD36) on platelets in myeloproliferative disorders and non-insulin dependent diabetes mellitus: effect on arachidonic acid uptake. 1247 87

Fatty acids are a major source of energy for cardiac myocytes. Changes in fatty acid metabolism have been implicated as causal in diabetes and cardiac disease. The mechanism by which long chain fatty acids (LCFAs) enter cardiac myocytes is not well understood but appears to occur predominantly by protein-mediated transport. Here we report the cloning, expression pattern, and subcellular localization of a novel member of the fatty acid transport protein (FATP) family termed FATP6. FATP6 is principally expressed in the heart where it is the predominant FATP family member. Similar to other FATPs, transient and stable transfection of FATP6 into 293 cells enhanced uptake of LCFAs. FATP6 mRNA was localized to cardiac myocytes by in situ hybridization. Immunofluorescence microscopy of FATP6 in monkey and murine hearts revealed that the protein is exclusively located on the sarcolemma. FATP6 was restricted in its distribution to areas of the plasma membrane juxtaposed with small blood vessels. In these membrane domains FATP6 also colocalizes with another molecule involved in LCFA uptake, CD36. These findings suggest that FATP6 is involved in heart LCFA uptake, in which it may play a role in the pathogenesis of lipid-related cardiac disorders.
 ...
PMID:Characterization of a heart-specific fatty acid transport protein. 1255 34

Uptake of modified low density lipoprotein (LDL) by monocyte-macrophages is mediated by the scavenger receptor CD36, which is upregulated in vitro by high glucose concentrations and oxidatively modified LDL. We hypothesised that monocyte CD36 expression would be higher in Type 2 diabetes, and would increase during acute hyperglycaemia. Sixteen subjects with Type 2 diabetes and 11 controls underwent a 75 g oral glucose load. Monocyte CD36 expression (by laser flow cytometry), plasma LDL diene conjugates, plasma LDL hydroxyoctadecadienoic acid-13 (a peroxisome proliferator activator receptor gamma agonist) were measured at 0, 2 and 4 h. Mean monocyte CD36 expression at baseline was 34% higher in the diabetes group (P=0.01), did not change during acute hyperglycaemia and plasma LDL conjugated diene concentration was the only variable directly related to CD36 expression (F=4.53; P=0.05; r=0.51). Higher baseline CD36 expression in Type 2 diabetes could reflect increased post-transcriptional efficiency of CD36 mRNA in response to chronic hyperglycaemia and could be a proatherogenic mechanism in Type 2 diabetes.
 ...
PMID:Increased expression of a scavenger receptor (CD36) in monocytes from subjects with Type 2 diabetes. 1261 77

Type 2 diabetes is characterized by increased plasma triglyceride levels and a fourfold increase in ischemic heart disease, but the mechanism is unclear. CD36 is a receptor/transporter that binds fatty acids of lipoproteins. CD36 deficiency has been linked with insulin resistance. There is strong evidence of in vivo interaction between platelets and atherogenic lipoproteins suggesting that atherogenic triglyceride-rich lipoproteins, such as VLDL, that are increased in diabetic dyslipidemia are important in this process. This study demonstrates that VLDL binds to the platelet receptor CD36, enhances platelet thromboxane A2 production, and causes increased collagen-mediated platelet aggregation. VLDL enhanced collagen-induced platelet aggregation by 1) shortening the time taken for aggregation to begin (lag time) to 70% of control (P = 0.001); 2) increasing maximum aggregation to 170% of control (P = 0.008); and 3) increasing thromboxane production to 3,318% of control (P = 0.004), where control represents platelets stimulated with collagen (100%). A monoclonal antibody against CD36 attenuated VLDL-enhanced collagen-induced platelet aggregation by 1) inhibiting binding of VLDL to platelets by 75% (P = 0.041); 2) lengthening lag time to 190% (P < 0.001); and 3) decreasing thromboxane production to 8% of control (P < 0.001). In support of this finding, platelets from Cd36-deficient rats showed no increase in aggregation, thromboxane production, and VLDL binding in contrast to platelets from rats expressing CD36. These data suggest that platelet Cd36 has a key role in VLDL-induced collagen-mediated platelet aggregation, possibly contributing to atherothrombosis associated with increased VLDL levels.
Diabetes 2003 May
PMID:A novel role for CD36 in VLDL-enhanced platelet activation. 1271 60

Contraction of rat cardiac myocytes induces translocation of fatty acid translocase (FAT)/CD36 and GLUT4 from intracellular stores to the sarcolemma, leading to enhanced rates of long-chain fatty acid (FA) and glucose uptake, respectively. Because intracellular AMP/ATP is elevated in contracting cardiac myocytes, we investigated whether activation of AMP-activated protein kinase (AMP kinase) is involved in contraction-inducible FAT/CD36 translocation. The cell-permeable adenosine analog 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and the mitochondrial inhibitor oligomycin, similar to 4-Hz electrostimulation, evoked a more than threefold activation of cardiomyocytic AMP kinase. Both AICAR and oligomycin stimulated FA uptake into noncontracting myocytes by 1.4- and 2.0-fold, respectively, but were ineffective in 4 Hz-contracting myocytes. These findings indicate that both agents stimulate FA uptake by a similar mechanism as electrostimulation, involving activation of AMP kinase, as evidenced from phosphorylation of acetyl-CoA carboxylase. Furthermore, the stimulating effects of both AICAR and oligomycin were antagonized by blocking FAT/CD36 with sulfo-N-succinimidylpalmitate, but not by inhibiting phosphatidylinositol 3-kinase with wortmannin, indicating the involvement of FAT/CD36, but excluding a role for insulin signaling. Subcellular fractionation showed that oligomycin was able to mobilize intracellularly stored FAT/CD36 to the sarcolemma. We conclude that AMP kinase regulates cardiac FA use through mobilization of FAT/CD36 from a contraction-inducible intracellular storage compartment.
Diabetes 2003 Jul
PMID:Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling. 1282 25

Disturbed cardiac lipid homoeostasis in obesity is regarded as a key player in the development of cardiovascular diseases. In this study, we show that FAT (fatty acid translocase)/CD36-mediated LCFA (long-chain fatty acid) uptake in cardiac myocytes from young adult obese Zucker rats is markedly increased, but insensitive to insulin. Basal and insulin-induced glucose uptake rates in these myocytes are not changed, suggesting that during the development from obesity to hyperglycaemic Type II diabetes, alterations in cardiac LCFA uptake precede alterations in cardiac glucose uptake.
 ...
PMID:Increased FAT (fatty acid translocase)/CD36-mediated long-chain fatty acid uptake in cardiac myocytes from obese Zucker rats. 1474 18

In obesity, the development of cardiomyopathy is associated with the accumulation of myocardial triacylglycerols (TAGs), possibly stemming from elevation of myocardial long-chain fatty acid (LCFA) uptake. Because LCFA uptake is regulated by insulin and contractions, we examined in cardiac myocytes from lean and obese Zucker rats the effects of insulin and the contraction-mimetic agent oligomycin on the initial rate of LCFA uptake, subcellular distribution of FAT/CD36, and LCFA metabolism. In cardiac myocytes from obese Zucker rats, under basal conditions, FAT/CD36 was relocated to the sarcolemma at the expense of intracellular stores. In addition, the LCFA uptake rate, LCFA esterification rate into TAGs, and the intracellular unesterified LCFA concentration each were significantly increased. All these metabolic processes were normalized by the FAT/CD36 inhibitor sulfo-N-succinimidyloleate, indicating its antidiabetic potential. In cardiac myocytes isolated from lean rats, in vitro administration of insulin induced the translocation of FAT/CD36 to the sarcolemma and stimulated initial rates of LCFA uptake and TAG esterification. In contrast, in myocytes from obese rats, insulin failed to alter the subcellular localization of FAT/CD36 and the rates of LCFA uptake and TAG esterification. In cardiac myocytes from lean and obese animals, oligomycin stimulated the initial rates of LCFA uptake and oxidation, although oligomycin only induced the translocation of FAT/CD36 to the sarcolemma in lean rats. The present results indicate that in cardiac myocytes from obese Zucker rats, a permanent relocation of FAT/CD36 to the sarcolemma is responsible for myocardial TAG accumulation. Furthermore, in vitro these cardiac myocytes, although sensitive to contraction-like stimulation, were completely insensitive to insulin, as the basal conditions in hyperinsulinemic, obese animals resemble the insulin-stimulated condition in lean littermates.
Diabetes 2004 Jul
PMID:Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. 1522 Jan 87

Mutations in CD36 / fatty acid translocase (FAT) gene are responsible for insulin resistance in the rat but contribution to human Type 2 diabetes is unknown. A nominal evidence for linkage of familial T2D at the CD36 locus led us to identify a rare nonsense mutation c.1079T>G (p.L360X) in one Caucasian pedigree presenting with autosomal dominant diabetes. Adiponectin levels, as marker of insulin sensitivity, were found to be significantly lower in the p.L360X variant carriers compared to homozygous for wild type CD36. Furthermore, expression studies of the truncated protein showed a defective binding of acetylated-LDL. Thus, our findings suggest a possible role for CD36 in the pathogenesis of T2D associated with reduced insulin sensitivity.
 ...
PMID:A CD36 nonsense mutation associated with insulin resistance and familial type 2 diabetes. 1522 99


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>