Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In obesity, impaired glucose tolerance (IGT), non-insulin-dependent diabetes mellitus (NIDDM), and gestational diabetes mellitus (GDM), defects in glucose transport system activity, contribute to insulin resistance in target tissues. In adipocytes from obese and NIDDM patients, we found that pretranslational suppression of the insulin-responsive GLUT4 glucose transporter isoform is a major cause of cellular insulin resistance; however, whether this process is operative in skeletal muscle is not clear. To address this issue, we performed percutaneous biopsies of the vastus lateralis in lean and obese control subjects and in obese patients with IGT and NIDDM and open biopsies of the rectus abdominis at cesarian section in lean and obese gravidas and gravidas with GDM. GLUT4 was measured in total postnuclear membrane fractions from both muscles by immunoblot analyses. The maximally insulin-stimulated rate of in vivo glucose disposal, assessed with euglycemic glucose clamps, decreased 26% in obesity and 74% in NIDDM, reflecting diminished glucose uptake by muscle. However, in vastus lateralis, relative amounts of GLUT4 per milligram membrane protein were similar (NS) among lean (1.0 +/- 0.2) and obese (1.5 +/- 0.3) subjects and patients with IGT (1.4 +/- 0.2) and NIDDM (1.2 +/- 0.2). GLUT4 content was also unchanged when levels were normalized per wet weight, per total protein, and per DNA as an index of cell number. Levels of GLUT4 mRNA were similarly not affected by obesity, IGT, or NIDDM whether normalized per RNA or for the amount of an unrelated constitutive mRNA species. Because muscle fibers (types I and II) exhibit different capacities for insulin-mediated glucose uptake, we tested whether a change in fiber composition could cause insulin resistance without altering overall levels of GLUT4. However, we found that quantities of fiber-specific isoenzymes (phopholamban and types I and II Ca(2+)-ATPase) were similar in all subject groups. In rectus abdominis, GLUT4 content was similar in the lean, obese, and GDM gravidas whether normalized per milligram membrane protein (relative levels were 1.0 +/- 0.2, 1.3 +/- 0.1, and 1.0 +/- 0.2, respectively) or per wet weight, total protein, and DNA. We conclude that in human disease states characterized by insulin resistance, i.e., obesity, IGT, NIDDM, and GDM, GLUT4 gene expression is normal in vastus lateralis or rectus abdominis. To the extent that these muscles are representative of total muscle mass, insulin resistance in skeletal muscle may involve impaired GLUT4 function or translocation and not transporter depletion as observed in adipose tissue.
Diabetes 1992 Apr
PMID:Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM. 153 55

To determine whether diabetes alters chromatin structure in vivo, micrococcal nuclease digestion kinetics were analyzed in cerebral cortical and hepatic nuclei of streptozotocin-induced diabetic rats. Cerebral nuclei of diabetic rats maintained for 6 weeks were less susceptible to micrococcal nuclease digestion compared with control rats. Insulin treatment reversed diabetes-related changes in nuclease digestion kinetics. There were no changes in the kinetics of digestion in hepatic nuclei. The reduced digestibility of cerebral DNA in diabetes could not be attributed to altered DNA fluorescence spectra, or altered distribution of most abundant chromatin proteins that were either solubilized or that remained insoluble immediately following nuclease digestion. It is concluded that chronic, uncontrolled hyperglycemia can alter chromatin structure of some tissues in vivo, and this change is probably related to subtle alterations in DNA-protein interactions.
 ...
PMID:Altered chromatin structure of cerebral nuclei in experimental diabetes mellitus. 153 30

To study whether insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus is due to a defect in the expression of the insulin-responsive glucose transporter gene (GLUT-4) in human skeletal muscle, we measured the level of GLUT-4 mRNA and (in some of the subjects) its protein in muscle biopsies taken from 14 insulin-resistant patients with Type 2 diabetes, 10 first-degree relatives of the diabetic patients and 12 insulin-sensitive control subjects. Insulin sensitivity was measured with a + 45 mU.m2(-1).min-1 euglycaemic insulin clamp in combination with indirect calorimetry and infusion of [3-3H]glucose. GLUT-4 mRNA was measured using a human GLUT-4 cDNA probe and GLUT-4 protein with a polyclonal antibody specific for the 15 amino acid carboxy-terminal peptide. Both Type 2 diabetic patients and their relatives showed impaired stimulation of total-body glucose disposal by insulin compared with control subjects (29.5 +/- 2.1 and 34.0 +/- 4.8 vs 57.9 +/- 3.1 mumol.kg lean body mass-1.min-1; p less than 0.01). This impairment in glucose disposal was primarily accounted for by a reduction in insulin-stimulated storage of glucose as glycogen (13.0 +/- 2.4 and 15.6 +/- 3.9 vs 36.9 +/- 2.2 mumol.kg lean body mass-1.min-1; p less than 0.01). The levels of GLUT-4 mRNA expressed both per microgram of total RNA and per microgram DNA, were higher in the diabetic patients compared with the control subjects (116 +/- 25 vs 53 +/- 10 pg/microgram RNA and 177 +/- 35 vs 112 +/- 29 pg/microgram DNA; p less than 0.05, p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Insulin resistance in type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle. 154 18

We report the isolation and sequencing of cDNAs encoding two human glutamate decarboxylases (GADs; L-glutamate 1-carboxy-lyase, EC 4.1.1.15), GAD65 and GAD67. Human GAD65 cDNA encodes a Mr 65,000 polypeptide, with 585 amino acid residues, whereas human GAD67 encodes a Mr 67,000 polypeptide, with 594 amino acid residues. Both cDNAs direct the synthesis of enzymatically active GADs in bacterial expression systems. Each cDNA hybridizes to a single species of brain mRNA and to a specific set of restriction fragments in human genomic DNA. In situ hybridization of fluorescently labeled GAD probes to human chromosomes localizes the human GAD65 gene to chromosome 10p11.23 and the human GAD67 gene to chromosome 2q31. We conclude that GAD65 and GAD67 each derive from a single separate gene. The cDNAs we describe should allow the bacterial production of test antigens for the diagnosis and prediction of insulin-dependent diabetes mellitus.
 ...
PMID:Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. 154 70

Carbohydrate administration rapidly regulates hepatic mRNA-S14 content. Both sucrose and fructose but not glucose increase the transcription of hepatic mRNA-S14 in vivo. In primary hepatocyte cultures, mRNA-S14 transcription responds to either fructose or glucose. To test the hypothesis that the difference in hexose response is due to differences in cellular metabolism, we studied the regulation of this gene with a transient transfection assay system in Chinese hamster ovary (CHO) cells, hamster pancreatic beta-cells (HIT), and primary hepatocytes. In HIT cells, glucose stimulation of the expression vector pS14CAT (5 kilobases [kb]) containing 4.9 kb of 5'-flanking DNA was threefold greater than fructose. Glucose also gave a fourfold greater response at 27.5 mM than at 2.2 mM. In CHO cells, pS14CAT (5 kb) showed a twofold greater response to fructose than to glucose. The differential response to the hexoses in the two cell lines is a result of cell-specific metabolism. Without glucose in the media, both CHO and HIT cells used pyruvate for energy. However, glucose addition to CHO cells enhances glycolysis and hexose shunt pathway activity while inhibiting pyruvate oxidation and S14 gene transcription. In contrast, addition of glucose to HIT cells leads to enhanced tricarboxylic acid cycle activity to oxidize pyruvate and an associated stimulation of S14 transcription. We confirmed these conclusions in primary hepatocyte cultures. Addition of 27.5 mM glucose led to a twofold increase in endogenous mRNA-S14 accumulation, a twofold increase in transfected pS14LUC (5 kb) activity, and a parallel twofold increase in pyruvate oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Mar
PMID:Cell-specific carbohydrate metabolism regulates S14 gene transcription. 155 93

Polymorphisms were sought between HLA B and tumor necrosis factor (TNF) using three genomic probes. Extensive polymorphism was detected within a panel of 50 cell lines including 37 homozygotes representing 21 different ancestral haplotypes (AH). Following Taq I digestion of genomic DNA, we observed three allelic patterns with probe X (R17A) and four with probe V (R9A). Seven different allelic patterns were found with probe Y (M20A) after Taq I + Rsa I digestion. Family studies showed that the Y, X, and V alleles were inherited and segregated with HLA haplotypes. A striking feature of the allelic patterns detected by these probes was that cells with the same AH had identical Y, X, and V alleles (i.e., the alleles were haplotypic). Of 15 different Y-X-V haplotypes observed, 11 were found to be specific for a particular AH (i.e., were haplospecific). Four were shared by more than one AH, but in these instances there were extensive similarities in other regions within the major histocompatibility complex (MHC), for example, the Japanese 46.2 (HLA Bw46-DRw8) and the Chinese 46.1 (Bw46-DR9) share all alleles between HLA C and C4 and differ only in class II, suggesting their relatively recent divergence by recombination between C4 and DR. Surprisingly, two insulin-dependent diabetes mellitus (IDDM)-resistant but race-specific AHs 52.1 (Bw52-DRB1*1502, Japanese) and 7.1 (B7-DRB1*1501, Caucasoid) carry the same Y-X-V haplotype, suggesting the possibility of localizing gene(s) relevant to IDDM. The present study confirms that MHC AHs have been conserved en bloc, including the region between HLA B and TNF.
 ...
PMID:Haplospecific polymorphism between HLA B and tumor necrosis factor. 156 85

To test the hypothesis that alterations in regulatory regions of the insulin gene occur in a subset of patients with non-insulin-dependent diabetes mellitus (NIDDM), the promoter region was studied by polymerase chain reaction (PCR) amplification directly from genomic DNA, followed by high-resolution polyacrylamide gel electrophoresis under nondenaturing conditions. By using this method a previously identified HincII polymorphism (GTTGAC to GTTGAG at position-56) in American Blacks was readily detected, indicating that single base changes could be observed. In the course of screening the insulin promoter from 40 American Black subjects with NIDDM, an apparent larger allele was found in two individuals. Both patients were shown to have in addition to a normal allele, a larger allele containing an 8-bp repeat, TGGTCTAA from positions -322 to -315 of the insulin promoter. To facilitate rapid screening for the 8-bp repeat, a high-resolution agarose gel electrophoretic analysis was adopted. DNA from American Black NIDDM subjects (n = 100) and nondiabetic subjects (n = 100) was PCR amplified and analyzed. The 8-bp repeat was present in five NIDDM subjects, and one nondiabetic subject. DNA from Mauritius Creoles, also of African ancestry, was analyzed, and the 8-bp repeat was present in 3 of 41 NIDDM subjects, and 0 of 41 nondiabetic subjects. Analysis of glucose metabolism in three presumed normal sibs of an NIDDM patient with an 8-bp repeat revealed that one sib had overt diabetes, and two sibs were glucose intolerant, but there was no consistent segregation of the insulin promoter variant with the diabetes phenotype. The variant promoter was not present in 35 Caucasian NIDDM patients or in 40 Pima Indians. To test the biological consequences of the 8-bp repeat sequence in the insulin promoter, a normal and variant promoter were subcloned into a luciferase plasmid, and reporter gene activity assessed by transient transfection into mouse insulinoma (beta TC1) and hamster insulinoma (HIT) cells. The promoter activity of the variant allele was found to be reduced to 37.9 +/- 10.3% of the activity of the normal promoter in HIT cells (P less than 0.01, n = 4), and 49.1 +/- 6.4% in beta TC1 cells (P less than 0.01, n = 6). These data thus suggest that a naturally occurring variant of the insulin promoter may contribute to the diabetes phenotype in 5-6% of Black NIDDM patients.
 ...
PMID:A variant insulin promoter in non-insulin-dependent diabetes mellitus. 156 97

Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM) which is characterized by an early age at onset and an autosomal dominant mode of inheritance. Except for these features, the clinical characteristics of patients with MODY are similar to those with the more common late-onset form(s) of NIDDM. Previously we observed tight linkage between DNA polymorphisms in the glucokinase gene on the short arm of chromosome 7 and NIDDM in a cohort of sixteen French families having MODY. Glucokinase is an enzyme that catalyses the formation of glucose-6-phosphate from glucose and may be involved in the regulation of insulin secretion and integration of hepatic intermediary metabolism. Because the glucokinase gene was a candidate for the site of the genetic lesion in these families, we scanned this gene for mutations. Here we report the identification of a nonsense mutation in the gene encoding glucokinase and its linkage with early-onset diabetes in one family. To our knowledge, this result is the first evidence implicating a mutation in a gene involved in glucose metabolism in the pathogenesis of NIDDM.
 ...
PMID:Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. 157 17

Antigen processing for presentation of peptide epitopes by major histocompatibility complex (MHC) class I molecules involves genes in the MHC class II region. Among these, PSF1 and PSF2 encode subunits of a transporter, which presumably delivers cytosolic peptides across the endoplasmic reticulum membrane to class I molecules. This close functional relationship of the transporter and class I heavy chain genes and their linkage within the MHC raise the question of whether PSF1 and PSF2, like most class I genes, are polymorphic. By single-strand conformation polymorphism analysis and DNA sequencing, a small number of amino acid sequence variants of both PSF1 and PSF2 was identified in a panel of cell lines. This limited polymorphism may contribute to a higher degree of variability at the level of the functional transporter, in which different alleles of the PSF1 and PSF2 subunits may be combined. A possible involvement of the PSF1 and PSF2 genes in susceptibility to MHC-associated diseases was examined in a preliminary assessment in patients with ankylosing spondylitis, insulin-dependent diabetes mellitus, or celiac disease.
 ...
PMID:Allelic variants of the human putative peptide transporter involved in antigen processing. 157 Mar 16

The diabetogenic effects of glucocorticoid excess are due in part to peripheral resistance to insulin. To test the hypothesis that glucocorticoid-induced peripheral insulin resistance might be attributable to a decreased number of glucose transporters, we examined the effects of dexamethasone treatment on the expression of the GLUT4 (insulin regulatable) glucose transporter in skeletal muscle, the major site of insulin-mediated glucose uptake. Dexamethasone treatment of rats (1 mg/day for 1 wk) induced hyperglycemia and hyperinsulinemia. At dosages of either 0.1 or 1 mg/day, insulin-stimulated 2-deoxyglucose uptake in isolated soleus muscle was reduced by greater than or equal to 50%, demonstrating the presence of insulin resistance in skeletal muscle. Immunoblots of crude membranes from deep quadriceps muscle showed that dexamethasone treatment (1 mg/day) increased the amount of GLUT4 protein by 84%. GLUT4 mRNA abundance was similarly increased when expressed per unit RNA but was unchanged when expressed on a DNA basis because the tissue RNA content was decreased by dexamethasone. In contrast to quadriceps, GLUT4 protein concentration in soleus and extensor digitorum longus extracts was not significantly increased by dexamethasone treatment. Because glucocorticoids cause selective atrophy of type IIb muscle fibers, which express relatively less GLUT4 protein, the apparent increase in GLUT4 content in quadriceps muscle from dexamethasone-treated animals may have resulted from inadvertent increased sampling of GLUT4-enriched type I and IIA fibers, caused by a glucocorticoid-induced decrease in the relative mass of the GLUT4-poor type IIb fibers. We conclude that glucocorticoids do not decrease GLUT4 content in skeletal muscle and that glucocorticoid-induced insulin resistance in this tissue is not due to suppression of glucose transporter gene expression.
Diabetes 1992 Jun
PMID:Role of glucose transporters in glucocorticoid-induced insulin resistance. GLUT4 isoform in rat skeletal muscle is not decreased by dexamethasone. 158 99


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>