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)

Muscle homogenates representing slow-twitch oxidative, fast-twitch oxidative-glycolytic, fast-twitch glycolytic, and mixed fiber types were prepared from normal, diabetic, and insulin-treated diabetic rats. Diabetes was induced by injection of 80 mg . kg-1 of streptozotocin. The activities of citrate synthase, succinate dehydrogenase, and 3-hydroxyacyl-CoA dehydrogenase were employed as markers of oxidative potential, whereas phosphorylase, hexokinase, and phosphofructokinase activities were used as an indication of glycolytic capacity. Diabetes was associated with a general decrement in the activity of oxidative marker enzymes for all fiber types except the fast-twitch glycolytic fiber. In contrast, the fast-twitch glycolytic fibers demonstrated the greatest decline in glycolytic enzymatic activity. Insulin-treated animals, either trained or untrained, exhibited enzyme activities similar to their normal counterparts. Exercise training of diabetic rats mimicked the effect of insulin treatment and caused a near normalization of the activity of the marker enzymes. These findings suggest that the enzymatic potential of all skeletal muscle fiber types of diabetic rats may be normalized by exercise training even in the absence of significant amounts of insulin.
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PMID:Influence of training on skeletal muscle enzymatic adaptations in normal and diabetic rats. 293 94

Cytoplasmic fatty acid-binding protein (FABP) was assayed immunochemically in hearts from rats with insulin-dependent (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). FABP contents were 34% higher in IDDM and 103% higher in NIDDM hearts than in respective age-matched controls. FABP levels returned to control values when islets of Langerhans were transplanted into diabetic IDDM animals. In the diabetic hearts the activity of fructose-6-phosphate kinase decreased (IDDM and NIDDM animals), while that of 3-hydroxyacyl-CoA dehydrogenase increased (NIDDM animals only). These data indicate that experimental diabetes induces a marked increase of the FABP content of rat heart and suggests that this protein is involved in the enhanced fatty acid utilization by the diabetic heart.
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PMID:Rat heart fatty acid-binding protein content is increased in experimental diabetes. 813 5

The sand rat (Psammomys obesus) is an animal model for non-insulin dependent diabetes mellitus, which is induced by a regular chow diet. The total activity of liver pyruvate dehydrogenase complex in the sand rats under normoglycemic and normoinsulinemic conditions was one half as high as that in the albino rats, but the activity of liver 3-hydroxyacyl-CoA dehydrogenase was more than 4 times greater in the former than in the latter, suggesting a low capacity for glucose oxidation and a high capacity for fatty acid oxidation in the sand rats. These metabolic conditions may be related to the predisposition of the animals towards diabetes. Diet-induced diabetes in the sand rats resulted in decreasing the active form of liver pyruvate dehydrogenase complex and in increasing the activity of liver 3-hydroxyacyl-CoA dehydrogenase, suggesting that the diabetic conditions further suppress glucose oxidation and promote fatty acid oxidation.
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PMID:Activities of liver pyruvate dehydrogenase complex and 3-hydroxyacyl-CoA dehydrogenase in sand rat (Psammomys obesus). 899 32

The fiber type-specific expression of skeletal muscle GLUT4 and the effect of 2 weeks of low-intensity training were investigated in 8 young untrained male subjects. Single muscle fibers were dissected from a vastus lateralis biopsy sample. Based on myosin heavy chain (MHC) expression, fibers were pooled into 3 groups (MHC I, MHC IIA, and MHC IIX), and the GLUT4 content of 15-40 pooled fibers was determined using SDS-PAGE and immunological detection. The GLUT4 content in pooled muscle fibers expressing MHC I was approximately 20% higher (P < 0.05) than that in muscle fibers expressing MHC IIA or MHC IIX. No difference in GLUT4 could be detected between fibers expressing MHC IIA or MHC IIX. Two weeks of exercise training increased (P < 0.05) the peak power output of the knee extensors by 13%, the maximal activities of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase by 21 and 18%, respectively, and the GLUT4 protein content by 26% in a muscle homogenate. Furthermore, a 23% increase (P < 0.05) in GLUT4 was seen in fibers expressing the MHC I isoform after exercise training for 2 weeks. No change was seen in fibers expressing MHC IIA or MHC IIX. In conclusion, our data directly demonstrate that GLUT4 is expressed in a fiber type-specific manner in human skeletal muscle, although fiber type differences are relatively small. In addition, low-intensity exercise training recruiting primarily fibers expressing MHC I increased GLUT4 content in these fibers but not in fibers expressing MHC IIA or MHC IIX, indicating that GLUT4 protein content is related more to activity level of the fiber than to its fiber type, which is defined by expression of contractile protein.
Diabetes 2000 Jul
PMID:Fiber type-specific expression of GLUT4 in human skeletal muscle: influence of exercise training. 1090 63

The effects of insulin treatment on skeletal muscle characteristics were studied in 18 patients (62 +/- 11 years) with poorly controlled diabetes mellitus type 2 (mean duration 7.5 +/- 6 years). Skeletal muscle biopsy samples were taken from the lateral portion of the quadriceps muscle before and after a period of insulin treatment of 40 +/- 14 days. Enzyme activities (phosphofructokinase, 3-hydroxyacyl-CoA dehydrogenase, citrate synthase, lactate dehydrogenase and creatine kinase) and myoglobin content were assessed. In a subgroup of 11 patients (60 +/- 11 years), skeletal muscle fibre type composition (type I, IIA, IIB and IIC) and fibre type cross-sectional area were also analysed. Following insulin treatment there were 32 and 38% increases, respectively, in the cross-sectional areas of type IIA and IIB fast-twitch fibres (P<0. 02). The fibre type distribution did not change. The myoglobin content in muscle decreased by 20% (P<0.01). Of the enzymes tested, the 3-hydroxyacyl-CoA dehydrogenase activity decreased by 10% (P<0. 04). Serum glucose, HbA1C and serum triglyceride levels decreased (P<0.001) and body weight and arm muscle circumference increased (P<0.02). In conclusion, insulin treatment of patients with poorly controlled non-insulin-dependent diabetes mellitus increased the fast-twitch fibre area, reduced myoglobin levels and decreased muscle enzyme activity related to fatty acid oxidation.
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PMID:Insulin treatment increases skeletal muscle fibre area in patients with diabetes mellitus type 2. 1097 46

Inappropriately elevated insulin secretion is the hallmark of persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also denoted congenital hyperinsulinism. Causal mutations have been uncovered in genes coding for the beta-cell's ATP-sensitive potassium channel and the metabolic enzymes glucokinase and glutamate dehydrogenase. In addition, one hyperinsulinemic infant was recently found to have a mutation in the gene encoding short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), an enzyme participating in mitochondrial fatty acid oxidation. We have studied a consanguineous family with severe neonatal hypoglycemia due to increased insulin levels and where well-established genetic causes of hyperinsulinism had been eliminated. A genome-wide, microsatellite-based screen for homozygous chromosomal segments was performed. Those regions that were inherited in accordance with the presupposed model were searched for mutations in genes encoding metabolic enzymes. A novel, homozygous deletion mutation was found in the gene coding for the SCHAD enzyme. The mutation affected RNA splicing and was predicted to lead to a protein lacking 30 amino acids. The observations at the molecular level were confirmed by demonstrating greatly reduced SCHAD activity in the patients' fibroblasts and enhanced levels of 3-hydroxybutyryl-carnitine in their blood plasma. Urine metabolite analysis showed that SCHAD deficiency resulted in specific excretion of 3-hydroxyglutaric acid. By the genetic explanation of our family's cases of severe hypoglycemia, it is now clear that recessively inherited SCHAD deficiency can result in PHHI. This finding suggests that mitochondrial fatty acid oxidation influences insulin secretion by a hitherto unknown mechanism.
Diabetes 2004 Jan
PMID:Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. 1469 19

5'-AMP-activated protein kinase (AMPK) is important for metabolic sensing. We used AMPKgamma3 mutant-overexpressing Tg-Prkag3(225Q) and AMPKgamma3-knockout Prkag3-/- mice to determine the role of the AMPKgamma3 isoform in exercise-induced metabolic and gene regulatory responses in skeletal muscle. Mice were studied after 2 h swimming or 2.5 h recovery. Exercise increased basal and insulin-stimulated glucose transport, with similar responses among genotypes. In Tg-Prkag3(225Q) mice, acetyl-CoA carboxylase (ACC) phosphorylation was increased and triglyceride content was reduced after exercise, suggesting that this mutation promotes greater reliance on lipid oxidation. In contrast, ACC phosphorylation and triglyceride content was similar between wild-type and Prkag3-/- mice. Expression of genes involved in lipid and glucose metabolism was altered by genetic modification of AMPKgamma3. Expression of lipoprotein lipase 1, carnitine palmitoyl transferase 1b, and 3-hydroxyacyl-CoA dehydrogenase was increased in Tg-Prkag3(225Q) mice, with opposing effects in Prkag3-/- mice after exercise. GLUT4, hexokinase II (HKII), and glycogen synthase mRNA expression was increased in Tg-Prkag3(225Q) mice after exercise. GLUT4 and HKII mRNA expression was increased in wild-type mice and blunted in Prkag3-/- mice after recovery. In conclusion, the Prkag3(225Q) mutation, rather than presence of a functional AMPKgamma3 isoform, directly promotes metabolic and gene regulatory responses along lipid oxidative pathways in skeletal muscle after endurance exercise.
Diabetes 2005 Dec
PMID:Changes in exercise-induced gene expression in 5'-AMP-activated protein kinase gamma3-null and gamma3 R225Q transgenic mice. 1630 65

The short-chain l-3-hydroxyacyl-CoA dehydrogenase (SCHAD) protein is involved in the penultimate step of mitochondrial fatty acid oxidation. Previously, it has been shown that mutations in the corresponding gene (HADHSC) are associated with hyperinsulinism in infancy. The presumed function of the SCHAD enzyme in glucose-stimulated insulin secretion led us to the hypothesis that common variants in HADHSC on chromosome 4q22-26 might be associated with development of type 2 diabetes. In this study, we have performed a large-scale association study in four different cohorts from the Netherlands and Denmark (n = 7,365). Direct sequencing of HADHSC cDNA and databank analysis identified four tagging single nucleotide polymorphisms (SNPs) including one missense variant (P86L). Neither the SNPs nor haplotypes investigated were associated with the disease, enzyme function, or any relevant quantitative measure (all P > 0.1). The present study provides no evidence that the specific HADHSC variants or haplotypes examined do influence susceptibility to develop type 2 diabetes. We conclude that it is unlikely that variation in HADHSC plays a major role in the pathogenesis of type 2 diabetes in the examined cohorts.
Diabetes 2006 Nov
PMID:The HADHSC gene encoding short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) and type 2 diabetes susceptibility: the DAMAGE study. 1706 62

A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here, we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipids. C57BL/6J mice were fed a high-fat diet for either 5 or 20 weeks. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured, including (14)C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, beta-hydroxyacyl CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and carnitine palmitoyl-transferase 1), and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance. Compared with standard diet-fed controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 weeks +23%, P < 0.05, and 20 weeks +29%, P < 0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 weeks +49%, P < 0.01). Furthermore, oxidative enzyme activity and protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, uncoupling protein (UCP) 3, and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats, and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1alpha, UCP3, and subunits of the mitochondrial respiratory chain. These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.
Diabetes 2007 Aug
PMID:Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. 1751 22

To elucidate the molecular mechanisms behind physical inactivity-induced insulin resistance in skeletal muscle, 12 young, healthy male subjects completed 7 days of bed rest with vastus lateralis muscle biopsies obtained before and after. In six of the subjects, muscle biopsies were taken from both legs before and after a 3-h hyperinsulinemic euglycemic clamp performed 3 h after a 45-min, one-legged exercise. Blood samples were obtained from one femoral artery and both femoral veins before and during the clamp. Glucose infusion rate and leg glucose extraction during the clamp were lower after than before bed rest. This bed rest-induced insulin resistance occurred together with reduced muscle GLUT4, hexokinase II, protein kinase B/Akt1, and Akt2 protein level, and a tendency for reduced 3-hydroxyacyl-CoA dehydrogenase activity. The ability of insulin to phosphorylate Akt and activate glycogen synthase (GS) was reduced with normal GS site 3 but abnormal GS site 2+2a phosphorylation after bed rest. Exercise enhanced insulin-stimulated leg glucose extraction both before and after bed rest, which was accompanied by higher GS activity in the prior-exercised leg than the rested leg. The present findings demonstrate that physical inactivity-induced insulin resistance in muscle is associated with lower content/activity of key proteins in glucose transport/phosphorylation and storage.
Diabetes 2012 May
PMID:GLUT4 and glycogen synthase are key players in bed rest-induced insulin resistance. 2240 97


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