Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effect of spontaneous long-term (9-10 months) diabetes on the heart of Chinese hamsters (CHAD strain) to elucidate the relationship between diabetes mellitus and cardiomyopathy. The diabetic hamsters, aged approximately 11 months, showed body weight loss, hyperglycemia (mean fasting plasma glucose 402 mg/dl), hypoinsulinemia, hyperlipidemia and ketonemia. The diabetic hamsters showed reduced activities of cytoplasmic glycolytic key enzymes; hexokinase, pyruvate kinase and phosphofructokinase, increases in cardiac glycogen and glucose-6-phosphate contents and a 40% decrease in cardiac ATP content, indicating decreased energy production. An accumulation of myocardial triglyceride and cholesterol was found in the diabetic hamsters. In addition, the cardiac norepinephrine content was increased in the diabetic hamsters, suggesting the presence of autonomic nervous disorder. Increased heart weight and thickening of the septum and both ventricular walls were found in the diabetic hamsters. Light-microscopic analysis revealed that 42.9% of the diabetic hamsters had myocardial degeneration without any vascular lesion of extramural large and intramural small vessels, whereas the non-diabetic controls had no myocardial or vascular lesions. These data suggest that the diabetic Chinese hamsters had cardiomyopathy, which is possibly caused by extravascular factors such as metabolic or autonomic nervous disorder although conclusive evidence is lacking.
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PMID:Metabolic and morphological changes of the heart in Chinese hamsters (CHAD strain) with spontaneous long-term diabetes. 366 31

When whole body insulin-stimulated glucose disposal rate is measured in man applying the euglycaemic, hyperinsulinaemic clamp technique it has been shown that approximately 75% of glucose is taken up by skeletal muscle. After the initial transport step, glucose is rapidly phosphorylated to glucose-6-phosphate and routed into the major pathways of either glucose storage as glycogen or the glycolytic/tricarboxylic acid pathway. Glucose uptake in skeletal muscle involves-the activity of specific glucose transporters and hexokinases, whereas, phosphofructokinase and glycogen synthase hold critical roles in glucose oxidation/glycolysis and glucose storage, respectively. Glucose transporters and glycogen synthase activities are directly and acutely stimulated by insulin whereas the activities of hexokinases and phosphofructokinase may primarily be allosterically regulated. The aim of the review is to discuss our present knowledge of the activities and gene expression of hexokinase II (HKII), phosphofructokinase (PFK) and glycogen synthase (GS) in human skeletal muscle in states of altered insulin-stimulated glucose metabolism. My own experimental studies have comprised patients with disorders characterized by insulin resistance like non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) before and after therapeutic interventions, patients with microvascular angina and patients with severe insulin resistant diabetes mellitus and congenital muscle fiber type disproportion myopathy as well as athletes who are in a state of improved insulin sensitivity. By applying the glucose insulin clamp method in combination with nuclear magnetic resonance 31P spectroscopy to normoglycaemic or hyperglycaemic insulin resistant subjects impairment of insulin-stimulated glucose transport and/or phosphorylation in skeletal muscle has been shown. In states characterized by insulin resistance but normoglycaemia, the activity of HKII measured in needle revealed any genetic variability that contributes to explain the decreased muscle levels of GS mRNA or the decreased activity and activation of muscle GS in NIDDM patients and their glucose tolerant but insulin resistant relatives. Thus, the causes of impaired insulin-stimulated glycogen synthesis of skeletal muscle in normoglycaemic insulin resistant subjects are likely to be found in the insulin signalling network proximal to the GS protein. In insulin resistant diabetic patients the impact of these yet unknown abnormalities may be accentuated by the prevailing hyperglycaemia and hyperlipidaemia. Endurance training in young healthy subjects results in improved insulin-stimulated glucose disposal rates, predominantly due to an increased glycogen synthesis rate in muscle, which is paralleled by an increased total GS activity, increased GS mRNA levels and enhanced insulin-stimulated activation of GS. These changes are probably due to local contraction-dependent mechanisms. Likewise, one-legged exercise training has been reported to increase the basal concentration of muscle GS mRNA in NIDDM patients to a level similar to that seen in control subjects although insulin-stimulated glucose disposal rates remain reduced in NIDDM patients. In the insulin resistant states examined so far, basal and insulin-stimulated glucose oxidation rate at the whole body level and PFK activity in muscle are normal. In parallel, no changes have been found in skeletal muscle levels of PFK mRNA and immunoreactive protein in NIDDM or IDDM patients. In endurance trained subjects insulin-stimulated whole body glucose oxidation rate is often increased. However, depending on the intensity and frequency, physical exercise may induce an increased, a decreased or an unaltered level of muscle PFK activity. In athletes the muscle PFK mRNA is similar to what is found in sedentary subjects whereas the immunoreactive PFK protein concentration is decreased.
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PMID:Studies of gene expression and activity of hexokinase, phosphofructokinase and glycogen synthase in human skeletal muscle in states of altered insulin-stimulated glucose metabolism. 1008 51

Cytoplasmic citrate is the prime carbon source for fatty acid, triacylglycerol, and cholesterol biosyntheses, and also regulates glucose metabolism via its allosteric inhibition of phosphofructokinase. It originates either via the efflux of citrate from the mitochondrial matrix on the inner membrane citrate transport protein (CTP) or via the influx of extracellular citrate on the plasma membrane citrate transporter (PMCT). Despite their common substrate, the two transport proteins share little sequence similarity and they transport citrate via fundamentally different mechanisms. We tested the ability of a set of previously identified CTP inhibitors, to inhibit the PMCT. We found that of the top 10 CTP inhibitors only one substantially inhibited the PMCT. Conversely, we identified two other inhibitors that inhibited the PMCT but had little effect on the CTP. All three identified PMCT inhibitors displayed a noncompetitive mechanism. Furthermore, models to explain inhibitor interactions with the CTP are proposed. As part of the present studies a PMCT homology model has been developed based on the crystal structure of the leucine transporter, and a possible citrate binding site has been identified and its composition compared with the two known citrate binding sites present within the CTP. The ability to selectively inhibit the PMCT may prove key to the pharmacologic amelioration of metabolic disorders resulting from the synthesis of excess lipid, cholesterol, and glucose, including human obesity, hyperlipidemia, hyper-cholesterolemia, and Type 2 diabetes.
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PMID:Mitochondrial and Plasma Membrane Citrate Transporters: Discovery of Selective Inhibitors and Application to Structure/Function Analysis. 2068 72