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)

Chronic treatment with the antihypertensive drug hydralazine did not affect the hyperglycemic state of streptozotocin (STZ)-diabetic rats but did prevent the serum hyperlipidemia that is synonymous with these diabetic animals. After 6 weeks, untreated STZ-diabetic rats exhibited a 659% increase in serum triglycerides and 292% increase in serum cholesterol versus age-matched non-diabetic rats. Hydralazine-treated STZ-diabetic rats had serum triglyceride and cholesterol levels that did not differ from controls. Myocytes from control rats showed a preference for binding of the unsaturated fatty acid analog cis-parinaric acid vs the saturated fatty acid analog trans-parinaric acid. This preference was not altered in STZ-diabetic rat myocytes; hydralazine-treatment of STZ-diabetic rats also showed no change in fatty acid preference. STZ-diabetes caused a decrease in the affinity (Kd) for the trans, but not the cis-parinaric acid. However, total binding of both analogs was increased in STZ-diabetes. Hydralazine treatment of STZ-diabetic rats resulted in even greater total binding of both analogs. Affinity for the trans analog was further decreased in these hydralazine-treated rats, but the affinity for the cis analog was increased beyond control animals. These results suggest that the diabetic state influences the binding characteristics of the myocardial PM-FABP and that hydralazine, while reducing serum lipids in diabetes, has complex effects on the fatty acid binding by this protein.
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PMID:Effect of hydralazine on myocardial plasma membrane fatty acid binding protein (PM-FABP) during diabetes mellitus. 747 32

Heart fatty acid-binding protein (H-FABP) is present in a wide variety of tissues but is found in the highest concentration in cardiac and red skeletal muscle. It has been proposed that the expression of H-FABP correlates directly with the fatty acid-oxidative capacity of the tissue. In the present study, the expression of H-FABP was measured in red and white skeletal muscle under two conditions in which fatty acid utilization is known to be increased: streptozotocin-induced diabetes and fasting. Protein concentration, mRNA concentration and transcription rate were measured under both conditions. The level of both protein and mRNA increased approximately 2-fold under each condition. The transcription rate was higher in red skeletal muscle than in white muscle, was increased 2-fold during fasting, but was unchanged by streptozotocin-induced diabetes. In addition to supporting the hypothesis that H-FABP is induced during conditions of increased fatty acid utilization, these findings demonstrate that the regulation of H-FABP expression may or may not be at the level of transcription depending on the stimulus.
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PMID:Transcriptional regulation of muscle fatty acid-binding protein. 814 74

In order to define the major genetic factor(s) for the development of Type 2 (non-insulin-dependent) diabetes mellitus in Japanese subjects, a population association study of candidate genes involved in either glucose or lipid metabolism was carried out using microsatellite DNA polymorphisms. Each polymorphic locus near the four candidate genes, hexokinase II (HKII), glucagon-like peptide-1 receptor (GLP1R), fatty acid binding protein-2 (FABP-2), and apolipoprotein C-II (apoC-II) genes, were amplified by polymerase chain reaction (PCR) using 32P-labelled primers and each subject was genotyped for the association study. The HKII, GLP1R, FABP-2, and apoC-II polymorphisms exhibited 18, 10, 7, and 10 alleles, respectively. While polymorphism information contents (PICs) of these polymorphisms were relatively high, allele frequencies in these polymorphisms did not differ among subjects with Type 2 diabetes, impaired glucose tolerance (IGT) and non-diabetic controls. These results suggest that the HKII, GLP1R, FABP-2, and apoC-II genes are not the major inherited factors for the development of Type 2 diabetes or IGT in Japanese subjects, although minor contribution cannot be ruled out.
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PMID:A population association study of four candidate genes (hexokinase II, glucagon-like peptide-1 receptor, fatty acid binding protein-2, and apolipoprotein C-II) with type 2 diabetes and impaired glucose tolerance in Japanese subjects. 891 86

Properties of the myocardial PM-FABP were studied in normal and STZ-diabetic rats. The fluorescent fatty acids trans-parinaric and cis-parinaric acids were used as analogs of straight-chain (saturated) and kinked-chain (unsaturated) fatty acids respectively. Parinaric acid binding was sensitive to trypsin. Trans-parinaric acid binding was more sensitive to this protease than the binding of cis-parinaric acid. Based on the difference in sensitivity of parinaric acid binding we believe that there are two separate binding sites associated with myocardial PM-FABP; one for unsaturated fats and the other for saturated fats. Diabetes enhanced both cis- and trans-parinaric acid binding capacity in cardiomyocytes; cis-parinaric acid by 2 fold and trans-parinaric acid by 2.6 fold. In addition, there was a concomitant accumulation of free fatty acids and triglycerides in the hearts of the diabetic animals. There was a 2.2 fold increase for fatty acids and a 1.6 fold increase for trigylcerides. This association between myocardial fatty acid build-up and enhanced myocardial PM-FABP during diabetes suggest that this carrier protein might have contributed to lipid accumulation in the hearts of the diabetic rats.
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PMID:Characteristics of the myocardial PM-FABP: effect of diabetes mellitus. 940 73

The hyperlipidemia associated with obesity and type 2 diabetes is caused by an increase in hepatic triglyceride synthesis and secretion that is secondary to an increase in de novo lipogenesis, a decrease in fatty acid (FA) oxidation, and an increase in the flux of peripherally derived FA to the liver. The uptake of FA across the plasma membrane may be mediated by three distinct proteins--FA translocase (FAT), plasma membrane FA binding protein (FABP-pm), and FA transport protein (FATP)--that have recently been characterized. Acyl-CoA synthetase (ACS) enhances the uptake of FAs by catalyzing their activation to acyl-CoA esters for subsequent use in anabolic or catabolic pathways. In this study, we examine the mRNA levels of FAT, FABP-pm, FATP, and ACS in the liver and adipose tissue of genetically obese (ob/ob) mice and their control littermates. FAT mRNA levels were 15-fold higher in liver and 60-80% higher in adipose tissue of ob/ob mice. FABP-pm mRNA levels were twofold higher in liver and 50% higher in adipose tissue of ob/ob mice. FATP mRNA levels were not increased in liver or adipose tissue. ACS mRNA levels were higher in adipose tissue but remained unchanged in liver. However, the distribution of ACS activity associated with mitochondria and microsomes in liver was altered in ob/ob mice. In control littermates, 61% of ACS activity was associated with mitochondria and 39% with microsomes, whereas in ob/ob mice 34% of ACS activity was associated with mitochondria and 66% with microsomes; this distribution would make more FA available for esterification, rather than oxidation, in ob/ob mouse liver. Taken together, our results suggest that the upregulation of FAT and FABP-pm mRNAs may increase the uptake of FA in adipose tissue and liver in ob/ob mice, which, coupled with an increase in microsomal ACS activity in liver, will enhance the esterification of FA and support the increased triglyceride synthesis and VLDL production that characterizes obesity and type 2 diabetes.
Diabetes 1999 Jan
PMID:Regulation of putative fatty acid transporters and Acyl-CoA synthetase in liver and adipose tissue in ob/ob mice. 989 32

Altered muscle fatty acid (FA) metabolism may contribute to the presence of muscle insulin resistance in the genetically obese Zucker rat. To determine whether FA uptake and disposal are altered in insulin-resistant muscle, we measured palmitate uptake, oxidation, and incorporation into di- and triglycerides in isolated rat hindquarters, as well as muscle plasma membrane fatty acid-binding protein (FABP(PM)) content of lean (n = 16, fa/+) and obese (n = 15, fa/fa) Zucker rats (12 weeks of age). Hindquarters were perfused with 7 mmol/l glucose, 1,000 micromol/l albumin-bound palmitate, and albumin-bound [1-(14)C]palmitate at rest (no insulin). Glucose uptake was 42% lower in the obese than in the lean rats and indicated the presence of muscle insulin resistance. Fractional and total rates of palmitate uptake were 42 and 74% higher in the obese than in the lean rats and were associated with higher muscle FABP(PM) content (r(2) = 0.69, P < 0.05). The percentage of palmitate oxidized was not significantly different between groups. FA disposal to storage was altered according to fiber type. When compared with lean rats, the rate of triglyceride synthesis in red muscle was 158% higher in obese rats, and the rate of palmitate incorporation into diglycerides in white muscle was 93% higher in obese rats. Pre- and postperfusion muscle triglyceride levels were higher in both red and white muscles of the obese rats. These results show that increased FA uptake and altered FA disposal to storage may contribute to the development of muscle insulin resistance in obese Zucker rats.
Diabetes 2001 Jun
PMID:Increased fatty acid uptake and altered fatty acid metabolism in insulin-resistant muscle of obese Zucker rats. 1137 40

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.
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PMID:Regulation of fatty acid transport and membrane transporters in health and disease. 1247 84

The metabolic syndrome is a cluster of metabolic and inflammatory abnormalities including obesity, insulin resistance, type 2 diabetes, hypertension, dyslipidemia, and atherosclerosis. The fatty acid binding proteins aP2 (fatty acid binding protein [FABP]-4) and mal1 (FABP5) are closely related and both are expressed in adipocytes. Previous studies in aP2-deficient mice have indicated a significant role for aP2 in obesity-related insulin resistance, type 2 diabetes, and atherosclerosis. However, the biological functions of mal1 are not known. Here, we report the generation of mice with targeted null mutations in the mal1 gene as well as transgenic mice overexpressing mal1 from the aP2 promoter/enhancer to address the role of this FABP in metabolic regulation in the presence or absence of obesity. To address the role of the second adipocyte FABP in metabolic regulation in the presence and deficiency of obesity, absence of mal1 resulted in increased systemic insulin sensitivity in two models of obesity and insulin resistance. Adipocytes isolated from mal1-deficient mice also exhibited enhanced insulin-stimulated glucose transport capacity. In contrast, mice expressing high levels of mal1 in adipose tissue display reduced systemic insulin sensitivity. Hence, our results demonstrate that mal1 modulates adipose tissue function and contributes to systemic glucose metabolism and constitutes a potential therapeutic target in insulin resistance.
Diabetes 2003 Feb
PMID:Role of the fatty acid binding protein mal1 in obesity and insulin resistance. 1254 Jun

Triglyceride (TG) hydrolases in the placental microvillous plasma membrane (MVM) release fatty acids from circulating lipoproteins and represent the critical initial step in transplacental fatty acid transfer. We investigated the activity of two TG hydrolases in MVM isolated from placentas of appropriately grown for gestational age pregnancies and pregnancies complicated by intrauterine growth restriction (IUGR), insulin-dependent diabetes mellitus (IDDM) or gestational diabetes mellitus (GDM). In addition, we measured protein expression of lipoprotein lipase (LPL) in MVM and two fatty acid binding proteins (L- and C-FABP) in placental homogenates. The TG hydrolase activities were assessed by measuring hydrolysis of (3)H-trioleic acid incorporated into intralipid micelles after incubation with MVM. The placenta-specific TG hydrolase activity (optimum at pH 6) did not differ in the patient groups studied. MVM LPL activity (optimum at pH 8) was reduced by 47% in preterm IUGR (n = 8, P < 0.05), compared with gestational age-matched controls. The LPL activity in placentas of IDDM pregnancies was increased by 39% (n = 8, P < 0.05), compared with controls. No significant differences were observed in cases of GDM. We found no alteration in protein expression of LPL or C-FABP. The expression of L-FABP was increased by 112% (n = 8, P < 0.05) in IDDM and 64% (n = 8, P < 0.05) in GDM. These results indicate that alterations in MVM LPL activity and expression of L-FABP may contribute to the altered lipid deposition and metabolism in IUGR and diabetic pregnancies.
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PMID:Triglyceride hydrolase activities and expression of fatty acid binding proteins in the human placenta in pregnancies complicated by intrauterine growth restriction and diabetes. 1535 70

Thiazolidinediones (TZDs) increase tissue insulin sensitivity in diabetes. Here, we hypothesize that, in adipose tissue, skeletal muscle, and heart, alterations in protein-mediated FA uptake are involved in the effect of TZDs. As a model, we used obese Zucker rats, orally treated for 16 days with 5 mg rosiglitazone (Rgz)/kg body mass/day. In adipose tissue from Rgz-treated rats, FA uptake capacity increased by 2.0-fold, coinciding with increased total contents of fatty acid translocase (FAT/CD36; 2.3-fold) and fatty acid transport protein 1 (1.7-fold) but not of plasmalemmal fatty acid binding protein, whereas only the plasmalemmal content of FAT/CD36 was changed (increase of 1.7-fold). The increase in FA uptake capacity of adipose tissue was associated with a decline in plasma FA and triacylglycerols (TAGs), suggesting that Rgz treatment enhanced plasma FA extraction by adipocytes. In obese hearts, Rgz treatment had no effect on the FA transport system, yet the total TAG content decreased, suggesting enhanced insulin sensitivity. Also, in skeletal muscle, the FA transport system was not changed. However, the TAG content remained unaltered in skeletal muscle, which coincided with increased cytoplasmic adipose-type FABP content, suggesting that increased extramyocellular TAGs mask the decline of intracellular TAG in muscle. In conclusion, our study implicates FAT/CD36 in the mechanism by which Rgz increases tissue insulin sensitivity.
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PMID:Divergent effects of rosiglitazone on protein-mediated fatty acid uptake in adipose and in muscle tissues of Zucker rats. 1577 29


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