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)

Fatty acids of the omega-3 series (n-3 fatty acids) are a well established dietary component affecting plasma lipids (mainly triglycerides) and also major cardiovascular parameters, such as arrhythmogenesis. In view of their peculiar metabolic handling, it has been suggested that they may reduce glucose tolerance in patients predisposed to diabetes. On the other hand, insulin is required for the endogenous synthesis of the long chain n-3 fatty acids from precursors; the heart may thus be particularly susceptible to their depletion in diabetes. This review examines large population studies, carried out particularly by this research group, evaluating the risk of developing glucose intolerance/clearcut diabetes in large series of patients with predisposing conditions. While diabetes development was in no way accelerated in any of these studies, there was, instead, clear evidence of a significant hypotriglyceridemic activity of the supplements. In long-term treatments, there was also a tendency toward a significant reduction of low density lipoprotein (LDL) cholesterolemia, with positive effects on high density lipoprotein (HDL). These findings fit well with cellular changes indicative of improved glucose handling. Finally, recent data suggest an improvement of heart rate variability by fish intake in coronary patients, that is also exerted by the n-3 fatty acids given as ethyl esters, thus providing further indication for the potential benefit of such treatments in diabetic patients.
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PMID:N-3 fatty acids and diabetes. 1244 12

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.
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PMID:Characterization of a heart-specific fatty acid transport protein. 1255 34

It is suggested that the negative correlation between breast-feeding and insulin resistance and diabetes mellitus can be related to the presence of significant amounts of long-chain polyunsaturated fatty acids in the human breast milk. Based on this, it is proposed that provision of adequate amounts of long chain polyunsaturated fatty acids during the critical periods of brain growth and development can prevent or postpone the development diabetes mellitus.
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PMID:Can perinatal supplementation of long-chain polyunsaturated fatty acids prevent diabetes mellitus? 1257 52

Long-chain fatty acids (LCFAs) are not only important metabolites but contribute to many cellular functions including activation of protein kinase C (PKC) isoforms and nuclear transcription factors such as peroxisome proliferator-activated receptors (PPAPs). To assert their diverse effects LCFAs have first to traverse the plasma membrane, a process that can occur either through diffusion or be mediated by proteins. Considerable evidence has accumulated to show that in addition to a diffusional component, the intestine, heart, adipose tissue, and the liver express a saturable and specific LCFA transport system. Identifying the postulated fatty acid transporters is of considerable importance, since both increased and decreased fatty acid uptake have been implicated in diseases such as type-2 diabetes and acute liver failure. Fatty acid transport proteins (FATPs/solute carrier family 27) are integral transmembrane proteins that enhance the uptake of long-chain and very long chain fatty acids into cells. In humans FATPs comprise a family of six highly homologous proteins, hsFATP1-6, which are found in all fatty acid-utilizing tissues of the body. This review will focus on a brief discussion of FATP expression patterns, regulation, structure, and mechanism of transport.
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PMID:A current review of fatty acid transport proteins (SLC27). 1285 80

Insulin resistance in skeletal muscle is present in humans with type 2 diabetes (noninsulin-dependent diabetes mellitus) and obesity and in rodents with these disorders. Malonyl CoA is a regulator of carnitine palmitoyl transferase I (CPT I), the enzyme that controls the transfer of long chain fatty acyl CoA into mitochondria where it is oxidized. In rat skeletal muscle, the formation of malonyl CoA is regulated acutely (in minutes) by changes in the activity of acetyl CoA carboxylase (ACC), the enzyme that catalyzes malonyl CoA synthesis. ACC activity can be regulated by changes in the concentration of citrate which is both an allosteric activator of ACC and a source of its precursor, cytosolic acetyl CoA. Increases in cytosolic citrate leading to an increase in the concentration of malonyl CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation. In contrast, exercise lowers the concentration of malonyl CoA, by activating an AMP activated protein kinase (AMPK), which phosphorylates and inhibits ACC. Recently we have shown that the activity of malonyl CoA decarboxylase (MCD), an enzyme that degrades malonyl CoA, is also regulated by phosphorylation. The concentration of malonyl CoA in liver and muscle in certain circumstances correlates inversely with changes in MCD activity. This review will describe the current literature on the regulation of malonyl CoA/AMPK mechanism and its physiological function.
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PMID:Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. 1461 57

Although the heart is capable of extracting energy from different types of substrates such as fatty acids and carbohydrates, fatty acids are the preferred fuel under physiological conditions. In view of the presence of diverse defects in myocardial metabolism in the failing heart, changes in metabolism of glucose and fatty acids are considered as viable targets for therapeutic modification in the treatment of heart failure. One of these changes involves the carnitine palmitoyltransferase (CPT) enzymes, which are required for the transfer of long chain fatty acids into the mitochondrial matrix for oxidation. Since CPT inhibitors have been shown to prevent the undesirable effects induced by mechanical overload, e.g. cardiac hypertrophy and heart failure, it was considered of interest to examine whether the inhibition of CPT enzymes represents a novel approach for the treatment of heart disease. A shift from fatty acid metabolism to glucose metabolism due to CPT-I inhibition has been reported to exert beneficial effects in both cardiac hypertrophy and heart failure. Since the inhibition of fatty acid oxidation is effective in controlling abnormalities in diabetes mellitus, CPT-I inhibitors may also prove useful in the treatment of diabetic cardiomyopathy. Accordingly, it is suggested that CPT-I may be a potential target for drug development for the therapy of heart disease in general and heart failure in particular.
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PMID:Carnitine palmitoyltransferase-I, a new target for the treatment of heart failure: perspectives on a shift in myocardial metabolism as a therapeutic intervention. 1528 95

This study examined the effects of streptozotocin (STZ)-diabetes and dietary long chain polyunsaturated fatty acids (LC-PUFAs) on hippocampal N-methyl-D-aspartate (NMDA) receptor subunit expression and lipid peroxidation. MDA level was significantly increased after 8 weeks of STZ-diabetes. LC-PUFAs administration significantly reduced MDA levels in diabetic rats. NR2A and NR2B protein concentrations were significantly decreased by about 30% in diabetic rats. Dietary LC-PUFAs partially restored NR2A and NR2B in diabetic rats whereas the most significant increase was seen in nondiabetic rats. Consequently, dietary LC-PUFAs can partially restore hippocampal NMDA receptors and decrease lipid peroxidation in diabetes. LC-PUFAs are thus a possible prophylactic means for preventing the cognitive deficiencies of diabetes.
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PMID:Effects of dietary long chain PUFAs on hippocampal lipid peroxidation and NMDA receptor subunits A and B concentration in streptozotocin-diabetic rats. 1537 Jan 92

We have investigated the effects of hypertension associated with diabetes mellitus on polyunsaturated fatty acid biosynthesis. For this purpose, two rat models for these pathologies have been established: a type 1 diabetic hypertensive model obtained by streptozotocin injection to spontaneously hypertensive rat (SHR), followed or not by insulin treatment (experiment 1); a type 2 diabetic hypertensive model by feeding SHR with a fructose enriched diet (experiment 2). Liver gene expression of delta-6 desaturase (D6D), microsomal D6D activities and fatty acid composition of total lipids were estimated. In experiment 1, an increase of linoleic acid (18:2 n-6) level was observed in the streptozotocin group. D6D gene expression appeared depressed in both experimental groups. Insulin did not reverse the streptozotocin effect in SHR, as it does in insulin-dependent diabetic rats. In experiment 2, the results showed a decrease of 18:2 n-6 and of long chain products of desaturation in rats fed on fructose diet. Delta-6 n-3 desaturase activity was significantly increased, whereas gene expression tended to decrease. Feeding fructose induced a significant increase in delta-9 desaturated products, suggesting a stimulation of stearoyl-CoA desaturase. These changes in monounsaturated fatty acids strongly differ from those observed in the streptozotocin experiment, indicating that the effects on lipogenesis of hypertension linked to diabetes differ according to the type of diabetes. Then, these results indicate that the liver steatosis observed during genetic hypertension was reinforced by fructose feeding. All together, the present results showed that hypertension associated to type 1 or type 2 diabetes exacerbated the damage caused by diabetes or hypertension alone on liver lipid metabolism. The metabolic effects induced by fructose being very similar to those found in human NIDDM, SHR fed a fructose-rich diet appears to be an appropriate model for studying the consequences of the combination of hypertension and NIDDM in the metabolic syndrome diseases.
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PMID:Effects of streptozotocin and dietary fructose on delta-6 desaturation in spontaneously hypertensive rat liver. 1558 89

Synthetic molecules of the glitazone family are currently used in the treatment of type II diabetes. Glitazones also improve secondary pathologies that are frequently associated with insulin resistance such as the polycystic ovary syndrome (PCOS). Glitazones bind to the peroxysome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor which is highly expressed in adipose tissue. PPARgamma also binds natural ligands such as long-chain fatty acids. Recently, several groups have shown that PPARgamma is also highly expressed in ovarian granulosa cells, and that glitazones are able to modulate in vitro granulosa cell proliferation and steroidogenesis in several species. These recent data raise new questions concerning the underlying mechanism of the effect of glitazones on PCOS. One might hypothesize, as for other << glucophage >> molecules such as metformin, that it is the general improvement of glucose metabolism and insulin sensitivity by glitazones which indirectly, and via an unknown mechanism, ameliorates ovarian functionality. The data discussed here suggest now an alternative possibility, that glitazones act directly at the ovarian level. Moreover, PPARgamma also seems to play a key role in the maturation of the placenta. In particular, inactivation of PPARgamma in mice is lethal, since the foetus is unable to develop because of alterations of placental maturation. In women, the activation of PPARgamma in placenta leads to an increase of placental hormone secretion. Overall, these results raise some questions about the role of natural ligands of PPARgamma such as long chain fatty acids on female fertility and the interactions between energy metabolism and reproduction in general.
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PMID:[A role of PPARgamma in reproduction?]. 1588 1

The beta-cell ATP-sensitive potassium (KATP) channel controls insulin secretion by linking glucose metabolism to membrane excitability. Loss of KATP channel function due to mutations in ABCC8 or KCNJ11, genes that encode the sulfonylurea receptor 1 or the inward rectifier Kir6.2 subunit of the channel, is a major cause of congenital hyperinsulinism. Here, we report identification of a novel KCNJ11 mutation associated with the disease that renders a missense mutation, F55L, in the Kir6.2 protein. Mutant channels reconstituted in COS cells exhibited a wild-type-like surface expression level and normal sensitivity to ATP, MgADP, and diazoxide. However, the intrinsic open probability of the mutant channel was greatly reduced, by approximately 10-fold. This low open probability defect could be reversed by application of phosphatidylinositol 4,5-bisphosphates or oleoyl-CoA to the cytoplasmic face of the channel, indicating that reduced channel response to membrane phospholipids and/or long chain acyl-CoAs underlies the low intrinsic open probability in the mutant. Our findings reveal a novel molecular mechanism for loss of KATP channel function and congenital hyperinsulinism and support the importance of phospholipids and/or long chain acyl-CoAs in setting the physiological activity of beta-cell KATP channels. The F55L mutation is located in the slide helix of Kir6.2. Several permanent neonatal diabetes-associated mutations found in the same structure have the opposite effect of increasing intrinsic channel open probability. Our results also highlight the critical role of the Kir6.2 slide helix in determining the intrinsic open probability of KATP channels.
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PMID:A novel KCNJ11 mutation associated with congenital hyperinsulinism reduces the intrinsic open probability of beta-cell ATP-sensitive potassium channels. 1633 76


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