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)

Glucokinase, the major enzyme that phosphorylates glucose upon entry into liver and islet beta-cells, has been considered a prime candidate for inherited defects predisposing to NIDDM. Now that the human gene has been isolated, this question has been addressed directly. Polymorphic markers flanking the gene were identified. These markers (microsatellites) are composed of variable numbers of dinucleotide repeats that vary in size, resulting in different alleles. Variably sized alleles can be typed rapidly from genomic DNA of individuals by the PCR. Studies of inheritance of glucokinase genes have revealed significant linkage in families with early-onset NIDDM, or MODY, and mutations have been identified within the coding region of the gene in some families. These studies are extremely encouraging, as they indicate that genes can be identified even in this heterogeneous genetic disorder. This study considers the phenotypes that result from glucokinase defects and the relationship of MODY to NIDDM, and it estimates the role of glucokinase defects in NIDDM in general.
Diabetes 1992 Nov
PMID:Glucokinase and NIDDM. A candidate gene that paid off. 139 13

Four overlapping DNA fragments spanning 32 kb containing the human GLUT4 facilitative glucose-transporter gene were isolated and characterized. The sequence of the GLUT4 gene (approximately 6.3 kb) and 2.0 kb of the promoter region was determined. The sequence of the promoter revealed potential binding sites for transcription factors known to regulate gene expression in muscle cells and adipocytes. However, transfection of constructs including 2 kb of the GLUT4 promoter fused to the bacterial CAT gene into 3T3-L1 adipocytes displayed only weak promoter activity. Because insulin resistance plays a prominent role in the development of NIDDM, genetic variation in the sequence of GLUT4 also was evaluated. Oligonucleotide primer pairs were selected that allowed the protein-coding region of the human GLUT4 gene to be amplified by PCR. The sequence of the protein-coding region of the GLUT4 gene and all intron-exon junctions was determined for a single diabetic Pima Indian and was identical to that of the cloned gene and cDNA. SSCP analysis was used to screen patients with diabetes mellitus and normal, healthy nondiabetic individuals for mutations at the GLUT4 locus. In addition to the silent substitution in the codon for Asn130 (AAC or AAT) and a Val383 (GTC)-->Ile(ATC) replacement described previously, two new variants were identified. One was a T-->A substitution in intron 1 that was found in 1 of 36 NIDDM patients who were typed for this variant. The second was a Ile385(ATT)-->Thr(ACT) replacement that occurred in 1 normal individual and was not found in any of 676 other normal and diabetic subjects. A large and racially diverse group of normal and diabetic individuals also was screened for the Ile383 polymorphism. It occurred in both diabetic and nondiabetic subjects. There is no indication from our data that these polymorphisms are associated with NIDDM.
Diabetes 1992 Nov
PMID:Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation. 139 19

To investigate whether malformations in the offspring of diabetic rats are related to a disturbed embryonic glucose metabolism, lactate production, lactate content and glucose oxidation in embryos of normal and manifestly diabetic rats were measured in vitro during the period of organogenesis. The embryonic production and content of lactate decreased by 90% between gestational days 10 and 11. On both gestational days the embryos of diabetic rats showed increased lactate production and content compared to the embryos of normal rats. The embryonic oxidation of glucose decreased slightly from gestational day 10 to day 11, and the embryos of diabetic rats exhibited a lower glucose oxidation rate than those of normal rats on both days. The lactate production and content in the embryos increased with increasing concentrations of glucose in the incubation medium, whereas the oxidation of glucose was unaffected by the glucose concentration. The results suggest that the embryonic metabolism of glucose is only marginally affected by changes in the availability of glucose. The lactate production rate was higher and the glucose oxidation rate lower in the embryos of diabetic than in those of normal rats, even when the values for these metabolic variables were normalized to the embryonic DNA content. Thus, a causative role for a disturbance of the glucose metabolism in diabetes-induced embryonic dysmorphogenesis could be envisaged.
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PMID:Glucose metabolism in embryos of normal and diabetic rats during organogenesis. 141 51

This study examined the effect of experimental diabetes mellitus on the dorsal tongue of rats which were made diabetic by tail-vein injections of streptozotocin (50 mg/kg) and then raised for either 5 or 10 months. Lingual papillae were observed by scanning electron microscopy (SEM) and light microscopy. Morphological changes in lingual mucosal capillaries in 10-month diabetic rats were observed by electron microscopy (TEM). In the study of cellular movement in the lingual dorsal epithelium, bromodeoxyuridine (BrdU) was applied as a tracer for studying DNA replication. In diabetic rats, lingual papillae showed morphological atrophic changes. The lingual mucosal capillaries' alterations included endothelial cells with numerous cell projections into the lumen, degenerated cell organs, increased basement membrane width, and narrowed capillary lumen. BrdU labeling index among the basal cells was reduced in diabetic rats which indicates a possible retardation of their epithelial-tissue activity. In diabetes mellitus, direct metabolic disturbances to the epithelia because of insulin deficiency first occurred, successively diabetic microangiopathy appeared on the lingual mucosal capillaries. The appearance of diabetic microangiopathy caused tissue hypoxia, which induced atrophic changes to the epithelia.
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PMID:A histological study of changes in the lingual papillae of streptozotocin-induced diabetic rats. 142 10

The DNA methylation state of the 5'-regulatory region of human HLA-DQ beta genes was examined. Two restriction enzymes were utilized to detect methylated (meCG) dinucleotides in the 5'-regulatory region of the DQ-beta genes: the restriction enzyme Msp I, which recognizes CCGG and CmeCGG, and Hpa II recognizes only the unmethylated CG sequence. DNA samples were prepared from 95 HLA-typed individuals including 40 B-lymphoblastoid cell lines and peripheral blood leukocytes of 55 individuals. Of these samples, 20 were from parents of individuals with insulin-dependent diabetes. Allele specific methylation was observed in particular DR-associated DQ-beta gene alleles. The DQw8 (DQw3.2) allele, most DQw7 (DQw3.1) alleles, and the DR3-associated DQw2 allele were all unmethylated. The parental methylation state was stably transmitted to offspring. Because these DQ alleles are highly associated with several autoimmune diseases, our results raise the possibility that the regulation of expression of these particular DQ-beta alleles might be different from that of other alleles, and that the 5'-regulatory DNA sequences of these particular DQ beta alleles may be responsible for, or contribute to, susceptibility to autoimmune diseases.
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PMID:Allele-specific methylation in the 5'-regulatory region of class II DQ beta genes in the human major histocompatibility complex (MHC): relationship to autoimmune disease susceptibility. 142 41

Subcutaneous injections of soluble human insulin and of the monomeric insulin analogue des-(B26-B30)-insulin-B25-amide were given to fasted rabbits, pigs and healthy man. The time course of blood glucose decline and the rate of appearance of the hormones in the peripheral circulation were studied for doses of 0.35 and 0.7 nmol/kg. In rabbits an identical time course with early glucose nadirs between 45 and 60 min and hormone peaks at about 20 min were observed for both hormones. Similar results were obtained for insulin and the analogue in pigs. When injected into humans, slightly earlier peaks of the analogue at 30 to 45 min were measured compared to insulin peaks at 60 min. In addition, a trend towards faster decline in blood glucose could be demonstrated after analogue injection. In contrast to monomeric insulin analogues produced by recombinant DNA technology, s.c. injections of des-(B26-B30)-insulin-B25-amide do not appear to meet mealtime insulin requirements better than soluble insulin.
Diabetes Res Clin Pract 1992 Jun
PMID:Comparison of subcutaneously administered soluble insulin and des-(B26-B30)-insulin-B25-amide in rabbit, pig and healthy man. 142 37

A panel of somatic cell hybrid cell lines containing different parts of human chromosome 20 and fluorescence in situ hybridization have been used to physically localize markers to human chromosome 20. Through these complementary approaches and genetic linkage analysis, D20S16, which is closely linked to the maturity onset diabetes of the young (MODY) locus, was mapped to band 20q12 --> q13.1. The gene for growth hormone-releasing factor (GHRF) was physically mapped and reassigned to 20q11, suggesting that GHRF plays no direct role in MODY. In addition, the genes for the chromosome 20-linked glycogen phosphorylase (GYPB) and the bone morphogenetic protein (BMP2A) have been assigned to chromosome 20p, and the interleukin-6-dependent DNA-binding protein (TCF5) has been assigned to 20q12 --> q13 by hybridization to genomic DNA from the panel of somatic cell hybrid cell lines. These approaches are useful for rapid localization of candidate genes for MODY and other DNA markers mapped to chromosome 20.
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PMID:Physical localization of chromosome 20 markers using somatic cell hybrid cell lines and fluorescence in situ hybridization. 142 75

The hypothesis presented here is that cancer is not a phenomenon where the normal functions of the human body break down (like diabetes mellitus or renal failure) but rather a well planned and well coordinated physiological response (similar to the inflammatory response). 'Cancer initiating genes' are presumed neoplastic DNA sequences involved in sensing genome deterioration, consequently enhancing preservation. This genetic trait, different from the concept of oncogenes, actively triggers the neoplastic transformation once genome deterioration is sensed. This self destructive, altruistic phenomenon, obviously devastating to the organism, is nevertheless shown to be a possible mechanism of natural selection. The survival advantage of cancer initiation is discussed using both the concepts of group selection and gene selection. Natural selection, the driving force of evolution, is believed to operate solely on the basis of phenotype differences among individuals. In this paper cancer is hypothesized to be a mechanism that directly scrutinizes the gene contents of the individual, therefore representing natural selection based on genotype differences.
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PMID:Could cancer be a physiological phenomenon rather than a pathological misfortune? 766 35

Recently, linkage between the ADA gene locus and MODY, a subtype of NIDDM, has been reported. The possibility that the region of chromosome 20q containing the ADA locus also may play a role in susceptibility to NIDDM needs to be investigated. Therefore, we examined the linkage between the ADA locus and NIDDM in affected siblings of 50 European white diabetic pedigrees--21 Italian and 29 British. Departure from independent segregation of the disease and an Alu VpA polymorphism within the 5' flanking region of the ADA locus was tested in the affected sib-pairs with the APM statistical method. After DNA amplification by the PCR and PAGE, five alleles were identified in the ALU VpA tract at the ADA locus in the two populations. Allele frequencies did not differ significantly between the two populations (chi 2 = 2.426, P > 0.05 [NS]). Analysis of the 50 diabetic sib sets, and independently of the Italian and British groups of affected sib pairs, revealed no segregation distortion between the marker locus and NIDDM. We conclude that mutations within or around the ADA locus are unlikely to play a major role in the etiology of NIDDM.
Diabetes 1992 Dec
PMID:Sib-pair analysis of adenosine deaminase locus in NIDDM. 144 5

Up to now, little is known about the self-perpetuating mechanism leading to terminal renal failure in chronic renal disease. The common pathological feature of progressive renal insufficiency is focal and segmental glomerulosclerosis. The experimental counterpart of this process is represented for instance by the models of streptozotocin diabetes, Adriamycin nephropathy and Goldblatt hypertension. In fact, the main initiating hallmark of glomerulosclerosis is an accumulation of glomerular proteins, whose balance is apparently influenced by the activity of glomerular proteinases. In isolated glomeruli of kidneys from the experimental animals, the total proteinase activity was assayed with the unspecific but sensitive azocasein assay. In fact, the activity was significantly reduced in all experimental models at acid and neutral pH when relating enzyme activity to the glomerular protein and DNA content. We believe, that our data of reduced glomerular proteinase activity in the animal models of glomerulosclerosis represent perhaps a new additional common pathogenetic mechanism. The glomerular protein accumulation could be a result of a synergistical interaction between hemodynamic factors and biochemical ones; the latter, we suggest to be a decrease of glomerular proteinase activity.
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PMID:Effect of disease on glomerular proteinases. 145 96


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