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)

The objectives of this study were 1) to evaluate glucose transport and its regulation by insulin in easily accessible human cells, 2) to investigate the glucose transporter isoforms involved, and 3) to establish whether a defect in glucose transport is associated with peripheral insulin resistance, which is common in insulin-dependent diabetes mellitus (IDDM) patients. We measured 2-deoxyglucose (2-DG) uptake in circulating mononuclear cells from 23 nondiabetic adults, 16 adults with IDDM, and 10 children with IDDM. Circulating mononuclear cells were separated from whole blood by Ficoll gradients and incubated with +/- 1 nM insulin. 2-DG uptake was measured after incubation with [3H]2-DG and cell separation through corn oil-phthalate. Cytochalasin B-inhibitable 2-DG uptake (basal and insulin stimulated) was higher in control than in IDDM subjects (P less than 0.001). Insulin significantly increased 2-DG uptake or 3-O-methylglucose uptake in both groups. Basal and insulin-stimulated 2-DG uptake was similar for adults and children with IDDM and did not correlate with age or body mass index in any group or disease duration, insulin dosage, or HbA1c in IDDM. In separated monocytes and lymphocytes, 2-DG uptake increased in response to insulin only in the monocyte population. Insulin dose-response curves indicated maximal stimulation of hexose uptake at 1-2 nM insulin for both control and diabetic subjects and demonstrated a significant decrease in maximal insulin response in the latter. Immunoblotting with specific antibodies revealed that circulating mononuclear cells and separated monocytes express the GLUT1 but not the GLUT4 isoform of the glucose transporter.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Feb
PMID:Insulin-stimulated glucose transport in circulating mononuclear cells from nondiabetic and IDDM subjects. 173 14

A major defect contributing to impaired insulin action in human obesity is reduced glucose transport activity in skeletal muscle. This study was designed to determine whether the improvement in whole body glucose disposal associated with weight reduction is related to a change in skeletal muscle glucose transport activity and levels of the glucose transporter protein GLUT4. Seven morbidly obese (body mass index = 45.8 +/- 2.5, mean +/- SE) patients, including four with non-insulin-dependent diabetes mellitus (NIDDM), underwent gastric bypass surgery for treatment of their obesity. In vivo glucose disposal during a euglycemic clamp at an insulin infusion rate of 40 mU/m2 per min was reduced to 27% of nonobese controls (P less than 0.01) and improved to 78% of normal after weight loss of 43.1 +/- 3.1 kg (P less than 0.01). Maximal insulin-stimulated glucose transport activity in incubated muscle fibers was reduced by approximately 50% in obese patients at the time of gastric bypass surgery but increased twofold (P less than 0.01) to 88% of normal in five separate patients after similar weight reduction. Muscle biopsies obtained from vastus lateralis before and after weight loss revealed no significant change in levels of GLUT4 glucose transporter protein. These data demonstrate conclusively that insulin resistance in skeletal muscle of mobidly obese patients with and without NIDDM cannot be causally related to the cellular content of GLUT4 protein. The results further suggest that morbid obesity contributes to whole body insulin resistance through a reversible defect in skeletal muscle glucose transport activity. The mechanism for this improvement may involve enhanced transporter translocation and/or activation.
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PMID:Restoration of insulin responsiveness in skeletal muscle of morbidly obese patients after weight loss. Effect on muscle glucose transport and glucose transporter GLUT4. 173 57

We investigated the prevalence of mutations in the gene encoding the major insulin-responsive facilitative glucose transporter (GLUT4) in patients with non-insulin-dependent diabetes mellitus (NIDDM). All 11 exons of the GLUT4 gene from 30 British white subjects with NIDDM were amplified using the polymerase chain reaction and screened for nucleotide sequence variation using the single-stranded conformation polymorphism (SSCP) method. No variation between the study subjects was detected in exons 1-3, 4b-8, and 10. Variant SSCP patterns were detected in exons 4a and 9. SSCP variation in exon 4a was revealed by direct nucleotide sequencing to be due to a common silent polymorphism (AAC----AAT at Asn130). One NIDDM patient demonstrated a variant SSCP pattern in exon 9. This was caused by a point mutation (GTC----ATC) at codon 383, which leads to the conservative substitution of isoleucine for valine in the putative fifth extracellular loop of the transporter. Allele-specific oligonucleotide hybridization was used to examine the frequency of this mutation in 240 Welsh white subjects (160 with NIDDM and 80 controls). The Val----Ile383 mutation was found in the heterozygous state in two diabetic subjects and no control subjects. We conclude that mutations of the GLUT4 coding sequence are very uncommon in this population of subjects with typical NIDDM. Determining whether the Ile383 GLUT4 variant present in 3 diabetic subjects contributes in any way to their disease will require further study.
Diabetes 1991 Dec
PMID:Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects. 175 12

Insulin-stimulated glucose transport activity and GLUT4 glucose transporter protein expression in rat soleus, red-enriched, and white-enriched skeletal muscle were examined in streptozotocin (STZ)-induced insulin-deficient diabetes. Six days of STZ-diabetes resulted in a nearly complete inhibition of insulin-stimulated glucose transport activity in perfused soleus, red, and white muscle which recovered following insulin therapy. A specific decrease in the GLUT4 glucose transporter protein was observed in soleus (3-fold) and red (2-fold) muscle which also recovered to control values with insulin therapy. Similarly, cardiac muscle displayed a marked STZ-induced decrease in GLUT4 protein that was normalized by insulin therapy. White muscle displayed a small but statistically significant decrease in GLUT4 protein (23%), but this could not account for the marked inhibition of insulin-stimulated glucose transport activity observed in this tissue. In addition, GLUT4 mRNA was found to decrease in red muscle (2-fold) with no significant alteration in white muscle. The effect of STZ-induced diabetes was time-dependent with maximal inhibition of insulin-stimulated glucose transport activity at 24 h in both red and white skeletal muscle and half-maximal inhibition at approximately 8 h. In contrast, GLUT4 protein in red and white muscle remained unchanged until 4 and 7 days following STZ treatment, respectively. These data demonstrate that red skeletal muscle displays a more rapid hormonal/metabolic-dependent regulation of GLUT4 glucose transporter protein and mRNA expression than white skeletal muscle. In addition, the inhibition of insulin-stimulated glucose transport activity in both red and white muscle precedes the decrease in GLUT4 protein and mRNA levels. Thus, STZ treatment initially results in a rapid uncoupling of the insulin-mediated signaling of glucose transport activity which is independent of GLUT4 protein and mRNA levels.
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PMID:Differential regulation of glucose transporter activity and expression in red and white skeletal muscle. 182 59

Insulin-stimulated glucose uptake into muscle and fat involves regulation of the subcellular distribution and the expression of a specific facilitative glucose transporter protein (GLUT4). Peripheral glucose uptake is lowered in diabetes, and the expression of GLUT4 is depressed in animals that have been made diabetic (i.e. insulin deficient) by destruction of the pancreatic beta-cells. In the present study we found that GLUT4 expression is also decreased in an animal model for type II diabetes mellitus (noninsulin-dependent diabetes mellitus), KKAY obese mice. These KKAY mice have elevated circulating insulin levels, but target cell resistance to the metabolic actions of insulin. Treatment of both types of diabetic animals with pioglitazone, a new antihyperglycemic compound, corrects deficits in glucose transport and GLUT4 mRNA and protein abundance. Such corrections are, however, more readily detected in fat than in muscle. Increases in GLUT4 mRNA and protein levels and glucose transport function by pioglitazone are dependent upon the presence of circulating insulin. Treatment with pioglitazone alone is sufficient for correction of glucose transport in hyperinsulinemic insulin-resistant animals, but hypoinsulinemic animals require insulin therapy along with pioglitazone treatment for similar corrections. In these insulin-deficient animals, neither treatment with the drug alone nor minimal insulin replacement therapy results in substantial correction. Since insulin and this antihyperglycemic agent seem to work synergistically, it is likely that pioglitazone acts to amplify cellular responses to insulin.
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PMID:Glucose transport deficiency in diabetic animals is corrected by treatment with the oral antihyperglycemic agent pioglitazone. 191 75

The liver/islet (GLUT2) and muscle/adipose tissue (GLUT4) glucose-transporter gene products, membrane proteins that facilitate glucose uptake into cells, are important molecules for normal carbohydrate metabolism. Recent isolation of the genes encoding these proteins provides a means to assess the role of possible defects that might contribute to impaired glucose-stimulated insulin secretion or impaired insulin-mediated glucose uptake, both prominent phenotypic features of non-insulin-dependent diabetes (NIDDM). A GLUT2 cDNA clone was isolated from a human liver cDNA library to search for polymorphisms at this locus in American Blacks. Three highly polymorphic sites were identified, one of which (EcoRI-Hae III) appears to be due to an insertion and/or deletion of 200 base pairs of DNA. Significant linkage disequilibrium between these sites over approximately 30 kilobases of genomic DNA suggested that these polymorphisms could be in linkage disequilibrium with mutations at this locus if they exist. A GLUT4 cDNA clone was also utilized to search for polymorphisms at this locus, but only one previously described polymorphism was observed. GLUT2 and GLUT4 cDNA probes were used to evaluate DNA polymorphisms in genomic DNA from American Blacks with NIDDM. The allelic, genotypic, and haplotypic frequencies of the DNA polymorphisms at these loci did not differ from the frequencies in nondiabetic subjects. Because no associations with NIDDM were found, it appears unlikely that mutations at these loci contribute in a major way to the genetic susceptibility to NIDDM observed in American Blacks.
Diabetes 1990 Dec
PMID:Polymorphisms of GLUT2 and GLUT4 genes. Use in evaluation of genetic susceptibility to NIDDM in blacks. 197 28

A radioimmunoassay for the GLUT1 glucose transporter was developed with a synthesized peptide based on the sequence of the cDNA for GLUT1. A peptide corresponding to the COOH-terminal domain of the GLUT1 glucose transporter (Thr-Pro-Glu-Glu-Leu-Phe-His-Pro-Leu-Gly-Ala-Asp-Ser-Gln-Val) was synthesized and conjugated to keyhole limpet hemocyanin through the NH2-terminal of the peptide. An antibody was raised against this complex and affinity purified with the immobilized peptide. A second peptide, with tyrosine residue added to the NH2-terminal of the above peptide, was synthesized and used as a standard and iodinated for preparation of the radioactive ligand. The assay is highly reproducible, sensitive, and specific for the COOH-terminal domain of the GLUT1 glucose transporter. It has no cross-reactivity with the other glucose-transporter isoforms GLUT2 and GLUT4. Furthermore, the results obtained with this radioimmunoassay on the number of glucose transporters in human erythrocytes were in good agreement with previous studies based on cytochalasin B binding, suggesting that this radioimmunoassay is able to quantify the number of glucose transporters. The assay is completed within 4 h and can be used for simultaneous measurement of GLUT1 in many samples. In addition, it can be applied to the measurement of GLUT1 in several types of tissue.
Diabetes 1991 Mar
PMID:Peptide-based radioimmunoassay specific for GLUT1 glucose transporter. 199 71

To investigate the cellular and subcellular distribution of glucose transporters in skeletal muscle, the glucose transporter isoform GLUT4 was localized in human muscle by electron microscopy via immunogold labeling with monoclonal (1F8) or COOH-terminal peptide polyclonal (ECU4) antibody and in isolated rat membranes by Western blot. There was no labeling of GLUT4 in endothelial cells of the capillaries. There also was no labeling of GLUT4 on the surface plasma membrane (sarcolemma) under either basal or insulin-stimulated conditions. Specific labeling for GLUT4 was clearly observed in two compartments: within the triad (on terminal cisternae and transverse tubules) and on an intracellular compartment, possibly sarcoplasmic tubules. Isolated triad membranes from rat muscle also contained substantial quantities of GLUT4 transporter, but there was no detectable GLUT4 protein in isolated sarcolemmal membranes. These data suggest a possible mechanism that involves glucose transport across the muscle cell at the transverse tubule membrane, not the sarcolemma.
Diabetes 1991 Jan
PMID:Immunolocalization of glucose transporter GLUT4 within human skeletal muscle. 201 71

We used a novel adaptation of the polymerase chain reaction to examine relative levels of mRNA encoding two members of the facilitative glucose transporter gene family, the GLUT1 or erythrocyte/HepG2/brain isoform and the GLUT4 or insulin-regulatable isoform. The method was fast (vs. hybridization methods), required no specific probe, and used total RNA samples of less than 1 microgram. Taking advantage of regions of structural similarity and differences between the two isoforms, we designed a single set of oligonucleotide primers capable of amplifying both GLUT1 and GLUT4 cDNAs such that their respective products could be resolved on the basis of a 12 base pair size differential. Hence, reverse transcription and complementary DNA amplification could be carried out for both transcripts using identical primers in the same reaction tube. Using this methodology, we examined the relative amounts of GLUT4 and GLUT1 mRNAs in several rat tissues. As expected based on prior reports using Northern analysis, rat brain contained only GLUT1 mRNA and skeletal muscle contained a large predominance of GLUT4 mRNA. Both isoform mRNAs were found in adipose tissue whereas adipose cells, heart and diaphragm contained predominantly GLUT4 mRNA. Induction of diabetes with streptozocin decreased the GLUT4 to GLUT1 ratio in adipose tissue 4-fold and 24 h of insulin treatment of the diabetic rats increased this ratio 9- to 10-fold. Insulin treatment of normal rats increased this ratio by 70%. Hindlimb skeletal muscle GLUT4 mRNA was quantified in diabetic and insulin-treated diabetic rats as a function of brain GLUT1 mRNA added as an internal standard. Using this methodology, no significant difference in muscle GLUT4 mRNA was noted as a result of 24 h of insulin therapy. In summary, quantitative PCR may be used to compare mRNA levels encoding specific members of a gene family either within given cells or tissues or as affected by physiological perturbations. Subject to certain limitations discussed within, this methodology may be useful in future measurements of glucose transporter mRNA, especially when only small tissue or cell samples are available.
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PMID:Assessment of glucose transporter gene expression using the polymerase chain reaction. 201 56

In order to investigate the regulation of glucose transporter gene expression in the altered metabolic conditions of obesity and diabetes, we have measured mRNA levels encoding GLUT2 in the liver and GLUT4 in the gastrocnemius muscle from various insulin resistant animal models, including Zucker fatty, Wistar fatty, and streptozocin(STZ)-treated diabetic rats. Northern blot analysis revealed that GLUT2 mRNA levels were significantly (P less than 0.001) elevated in 14 wk Zucker fatty and Wistar fatty rats relative to lean littermates but were similar in these two groups at 5 wk of age. Furthermore, there was significant increase (P less than 0.01) in GLUT2 mRNA levels in STZ diabetic rats at 3 wk after treatment. GLUT4 mRNA levels were not significantly different between control and insulin resistant rats in all animal models. These results indicate that neither hyperinsulinemia nor hyperglycemia affects GLUT4 mRNA levels in the muscle. However, GLUT2 mRNA levels in the liver were elevated in obesity and diabetes, although this regulatory event occurred independently from circulating insulin or glucose concentrations.
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PMID:Liver and muscle-fat type glucose transporter gene expression in obese and diabetic rats. 202 68


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