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)

In an attempt to define the pathogenesis of congenital malformations in diabetic pregnancy, a number of serum factors were determined in normal and diabetic pregnant rats and correlated to the outcome of gestation with the aid of multivariate linear regression analysis. The animals were from two different lines of Sprague-Dawley rats with documented differences in rates of fetal dysmorphogenesis in diabetic pregnancy. The diabetic rats increased less in body weight than the normal rats, yet displayed increased liver and kidney weights. The serum concentrations of glucose, beta-hydroxybutyrate, triglycerides, the branched-chain amino acids, and asparagine, proline, alanine, citrulline, tyrosine, and ornithine were increased by diabetes. In contrast, IGF-I, glutamic acid, glutamine, cystine, and lysine were decreased in the serum of the diabetic pregnant rats. The maternal metabolic imbalance exerted profound effects on embryonic development. Thus, the embryos of the diabetic rats were smaller, had fewer somites, and contained less DNA and protein than the control embryos. In addition, the resorption and malformation rates were increased in the embryos of the diabetic rats. The regression analysis of the data revealed significant interrelationships between adverse embryonic outcome (rates of malformations and resorptions) and the maternal serum concentrations of glucose, triglycerides, beta-hydroxybutyrate, branched-chain amino acids, and creatinine. This suggests that the maternal metabolism of the three major classes of nutrients covariates with the embryonic development in diabetic rat pregnancy. The monitoring of only one of these maternal parameters, e.g. the serum glucose concentration, may therefore not adequately predict the developmental status of the offspring. Our results suggest that the pathogenesis of fetal malformations in diabetic pregnancy is multifactorial. Thus, maintaining metabolites from all nutrient classes at a normal level may be important in preventing adverse fetal outcome.
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PMID:Correlations between maternal metabolism and deranged development in the offspring of normal and diabetic rats. 778 44

Variations in the coding regions of the insulin receptor substrate-1 (IRS-1) gene have recently been suggested to contribute to the susceptibility of non-insulin-dependent diabetes mellitus (NIDDM). The purpose of this study was to examine the role of the IRS-1 missense mutations at codons 972 (glycine to arginine) and 513 (alanine to proline) in two diverse populations from South India and Finland at high risk for NIDDM. DNA was amplified and digested with restriction enzymes BstN1 to detect the codon 972 mutation and Dra III to detect the codon 513 mutation. The codon 513 mutation was not found in the study subjects. The codon 972 mutation was present in 10.3% of 126 middle-aged NIDDM subjects and 5.3% of 95 matched control subjects in the South Indians (p = 0.17). In elderly Finnish subjects the frequency of the mutation was 7.5% in 40 NIDDM subjects and 7% in 42 matched control subjects. The frequency of codon 972 mutation in the South Indian NIDDM subjects was very similar to the two previously published studies in Danish and French subjects although each study individually fails to reach conventional levels of significance. The data from all four ethnic groups were analysed together after ascertaining that significant heterogeneity did not exist between the studies. Overall, the frequency of the codon 972 mutation is found in 10.7% NIDDM subjects and 5.8% control subjects (p = 0.02). These studies suggest that the codon 972 mutation of the IRS-1 gene might act as a susceptibility gene predisposing to NIDDM in certain ethnic groups.
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PMID:Insulin receptor substrate-1 gene mutations in NIDDM; implications for the study of polygenic disease. 779 90

Diet is the cornerstone of diabetes management, but nutritional interventions in diabetes are still being developed; hence, it is important to understand the effects of diet on nutrient metabolism. Dietary sugars stimulate intestinal sugar absorption in diabetic mice, but the effect of dietary protein on amino acid absorption in diabetes is unknown. We fed streptozotocin-diabetic (> 60 d diabetic) and nondiabetic mice high protein (70% casein) or low protein (15% casein) diets designed to elicit adaptation in amino acid uptake by the small intestine. A high protein diet significantly enhanced uptake per milligram of small intestine of the nonessential amino acids proline and aspartate in both diabetic and nondiabetic mice. Uptake per milligram of small intestine of the essential amino acids leucine and lysine and of the nonessential amino acid alanine which shares transporters with essential amino acids was independent of dietary protein. There was no effect of diabetes on uptake per milligram of any amino acid studied. Because weight per centimeter was greater in diabetic mice, uptake per centimeter of all amino acids tended to be greater in diabetics. Specific activity of alkaline phosphatase in the proximal and distal jejunum was independent of diabetes but varied with dietary protein. Changes in levels of dietary protein induce reversible adaptation of the intestinal uptake rate of nonessential but not of essential amino acids, an adaptive pattern typical of nondiabetics and apparently maintained in diabetics as well.
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PMID:Intestinal amino acid transport in mice is modulated by diabetes and diet. 791 22

The cellular redox state is altered in a number of pathological conditions, including various forms of glomerular injury and diabetes. For example, glucose, via the pentose phosphate pathway generates NADPH, which maintains glutathione (GSH) (part of a major intracellular reducing system) in its reduced state. GSH in turn influences the activity of transcription factors on gene expression. We therefore examined whether changes in cellular GSH influence total collagen synthesis and mRNA levels for collagen I, collagen IV and TGF-beta in SV-40 transformed mouse mesangial cells (MC) maintained in either 5 or 25 mM glucose media. Total intracellular GSH was increased by N-acetylcysteine (NAC; 10 mM) or decreased with the GSH synthesis inhibitor buthionine sulfoximine (BSO; 0.2 mM) in MC. NAC increased 3H-proline incorporation into collagenase-sensitive protein while BSO decreased it under both glucose conditions. The presence of BSO did not reverse the increased collagen synthesis seen in the NAC stimulated cells. Northern blot analysis showed increased mRNA levels for collagen I, collagen IV and TGF-beta in cells grown in high glucose (25 mM). NAC increased the mRNA for all three compounds while BSO alone had no effect on these mRNA levels. However, BSO reversed the increased mRNA levels for collagen I, IV and TGF-beta seen in the presence of NAC. These findings suggest that the cellular redox state may influence gene transcription in MC, and may have implications in explaining injury-associated alterations of mesangial matrix generation.
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PMID:Intracellular glutathione influences collagen generation by mesangial cells. 796 50

Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate gene that is ubiquitous in insulin-sensitive and insulin-like growth factor 1 (IGF1) sensitive tissues, including those that determine glucose production and clearance and those with regulatory effects on pancreatic beta-cell function. IRS-1 has a central role as an adaptor molecule that links the insulin-receptor and IGF1-receptor kinases with enzymes that regulate cellular metabolism and growth. Single-stranded conformation polymorphism analysis and direct nucleotide sequencing were applied to genomic DNA from 86 unrelated patients with NIDDM and 76 normoglycaemic controls. 10 of the patients with NIDDM and 3 of the controls were heterozygous at codon 972 for a polymorphism in which glycine was substituted with arginine. Moreover, at codon 513, 6 patients with NIDDM and 2 controls had a heterozygous polymorphism with a transition from alanine to proline. None of the polymorphism carriers had both aminoacid variants and the total allelic frequency of IRS-1 polymorphisms was about three times higher in patients with NIDDM than in controls (p = 0.02). Both aminoacid substitutions were located close to tyrosine phosphorylation motifs that are putative recognition sites for insulin and IGF1 signal transmission proteins. Analysis of the phenotypes showed that patients with NIDDM who had IRS-1 variants did not differ in their degree of insulin resistance compared with patients without known IRS-1 polymorphisms. However, carriers of the codon 972 variant had significantly lower plasma levels of fasting insulin and C-peptide. Our results suggest that aminoacid polymorphisms in IRS-1 may be involved in the aetiology of a subset of late-onset NIDDM.
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PMID:Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. 810 71

The role of the glucokinase gene in the development of diabetes in a group of 349 Japanese subjects with late-onset Type 2 diabetes was examined. These diabetic subjects and 197 non-diabetic controls were typed at two simple tandem repeat DNA polymorphisms in the glucokinase gene termed GCK2 and GCK3. Six and five alleles were evident in Japanese subjects at GCK2 and GCK3, respectively. There were no significant differences in allele, genotype or haplotype frequencies between diabetic and normal groups. In addition, the glucokinase gene of 340 diabetic and 170 non-diabetic Japanese subjects was screened for mutations using single strand conformation polymorphism analysis. Four nucleotide substitutions were identified: a silent substitution in exon 4 in the codon for proline 145 (CCC-->CCG), and A-->T, C-->G, and C-->A substitutions in introns 1b, 3, and 5, respectively. There were no significant differences in the frequencies of these nucleotide substitutions between diabetic and non-diabetic groups. These results suggest that glucokinase gene defects are not a major cause of late-onset Type 2 diabetes in Japanese subjects.
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PMID:Mutations in the glucokinase gene are not a major cause of late-onset type 2 (non-insulin-dependent) diabetes mellitus in Japanese subjects. 820 Feb 6

The repertoire of V beta 5 and V beta 8 T-cell receptors in pancreatic lesions of autoimmune diabetic NOD mice was analysed by sequencing the CDR3 and adjacent regions. T-cell receptor mRNA isolated from four different cell populations (i.e. spleen, lymph node, infiltrated islets from male and female NOD mice) was amplified by PCR and cloned; out of these, 339 clones were sequenced. Of 170 beta chains sequenced from intra-islet T cells, nearly 90% were unique and six other sequences were found 2 to 4 times. These data argue against any oligoclonality of the islet infiltrate. Despite the lack of clonal restriction, we observed a bias in TcR usage which indicates the existence of some selective pressure with regard to TcR structure. Of the V beta 5 positive cells, 30% to 40% showed a rearrangement of V beta 5 to J beta 2.6 and a complete lack of V beta 5-J beta 1.6 combination. The selective J beta usage was not restricted to islets but was found in all tissues analysed. V beta 8 positive cells did not show such an overrepresentation of V beta-J beta combinations with the exception of clones of infiltrated islets of partially diabetes-resistant male NOD mice. There the rearrangement of V beta 8-J beta 1.1 was markedly over-expressed. Analysis of the CDR3 region did not show selection of specific TcR with regard to region length. However, we found a restricted use of amino acids in the second position of the CDR3 region. V beta 8 chains had conserved an aspartic acid from the germline configuration in about half of the cases in all tissues analysed. V beta 5 chains also showed diversity of position 2 but not islet specificity of rearrangements. Mutated chains had a clear bias towards proline indicating selective pressure in favour of this amino acid. In conclusion, sequence analysis of V beta 5 and V beta 8 TcRs excludes oligoclonality of T-cell receptors in pancreatic lesions. The bias found for J beta usage and CDR3 structure was seen also in extra-pancreatic tissues and thus probably is due to selective pressure during T-cell maturation in thymus or periphery.
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PMID:Molecular analysis of the T-cell receptor V beta 5 and V beta 8 repertoire in pancreatic lesions of autoimmune diabetic NOD mice. 821 86

Expansion of the mesangial matrix in diabetes occurs after prolonged exposure to the diabetic milieu. To mimic the long-term hyperglycemia of diabetes mellitus we developed tissue culture systems that might approximate the chronic state. This was accomplished in two ways: (1) by growing mesangial cells on extracellular matrix glycated and crosslinked in vitro and (2) by continuously growing cells on their own matrix on filters in elevated glucose medium (500 mg/dl) for up to eight weeks without passage. Synthesis of collagen and proteoglycans was evaluated in cells grown under these conditions. In both these situations, 3H-proline incorporation into collagenase sensitive protein and 35S incorporation into sulfated proteins were reduced compared to control cultures. Despite reduction in 35S incorporation into proteoglycans in the high glucose cultures, total glycosaminoglycan content was unchanged. However, proteoglycans generated by mesangial cells grown in elevated glucose media were of a lower negative charge than controls. In mesangial cells continuously grown on filters, the levels of messenger RNA for collagen types I and IV, biglycan and TGF-beta were not different in cells grown at elevated or standard glucose concentrations for two and four weeks. We conclude that crosslinking of mesangial matrix or continuous culture of cells for prolonged periods of time in high glucose medium, which may also crosslink matrix, suppresses collagen synthesis and reduces the negative charges on matrix proteoglycans without altering mRNA levels.
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PMID:Nonenzymatic glycation of mesangial matrix and prolonged exposure of mesangial matrix to elevated glucose reduces collagen synthesis and proteoglycan charge. 847 21

In the search for diabetes genes, the combined approaches of positional cloning with random markers and subsequent evaluation of candidate genes mapping to areas of interest will be increasingly used. For islet candidate genes of unknown function, expressed trinucleotide (triplet) repeats represent a unique subset. It is unlikely that abnormal expansion of expressed islet triplet repeats would be a major cause of diabetes, yet the triplet repeats are frequently polymorphic and can thus be used to map the genes in the human genome. In this study, a human islet cDNA library was screened with (CGG)7 and (CAG)7, and 23 triplet repeats were isolated. Sequencing revealed four known and six novel islet genes containing 4-15 triplet repeats. The four known cDNAs included ferritin, the major iron-binding protein in cells; HSGSA2R, a full-length clone of the alpha-subunit of the G-regulatory protein; HUMSATB1A, a DNA-binding protein expressed predominantly in thymus; and HUMPPA-PRO, a ribosomal protein. The triplet repeats in ferritin and HUMPPAPRO were found to be monomorphic. Characterization of the six unique novel expressed islet triplet cDNAs revealed that they were 0.6-1.5 kb in size, contained 4-15 triplet repeats, and were expressed in islets and all other tissues examined. Four of the novel clones, CGG-isl 10, CGG-isl 11, CAG-isl 6, and CAG-isl 7, were mapped to human chromosomes 19, 16, 12, and 3, respectively, via somatic cell hybrids. One islet cDNA, CAG-isl 7, contained a repeat that was highly polymorphic, with 14 alleles (4-18 triplets) in African-Americans (heterozygosity = 0.86) and 6 alleles (heterozygosity = 0.77) in whites. Northern analysis indicated that the mRNA was abundant in pancreatic islets. A putative full-length clone contained an open reading frame encoding 213 amino acids with a variable number of alanines (4-18) within the COOH-terminal. The gene was uniquely mapped with odds > 1,000:1 on chromosome 3p in Centre d'Etude du Polymorphisme Humain pedigrees. There were no differences in CAG-isl 7 allele frequencies between African-American patients with NIDDM (n = 108) and control subjects (n = 116), nor was expansion above 18 repeats noted. Linkage analysis in 14 nonglucokinase maturity-onset diabetes of the young pedigrees showed a cumulative logarithm of odds score of -33.19 at theta = 0.00. Abnormal expansion was not observed in 20 IDDM patients with one NIDDM parent. While these data suggest no major role for CAG-isl 7 in diabetes, at least four of the six novel islet triplet genes are coexpressed in pancreatic islets and neural tissue, and these genes can now be considered as candidates for diabetes and/or neuropsychiatric diseases.
Diabetes 1996 Feb
PMID:Identification of trinucleotide repeat-containing genes in human pancreatic islets. 854 59

Pyrraline (epsilon 2-(formyl-5-hydroxymethyl-pyrrol-1-yl)-L- norleucine) is an advanced Maillard reaction product derived from the reaction of glucose with lysine amino group on proteins. Its presence in plasma and tissue proteins has been established by immunological and chromatographic methods. The purified preparation of pyrraline obtained from the reaction of glucose with lysine when stored at room temperature or at refrigeration turned pink in color, suggesting spontaneous formation of degradation products. These products were analyzed by high-performance liquid chromatography and one of the products was isolated to purity. The structure of the compound was established to be a dipyrraline formed by an ether bond between two pyrraline molecules. This finding led us to investigate the reactivity of pyrraline with thiol and hydroxy amino acids. The hydroxy amino acids were in general nonreactive, except hydroxy lysine and hydroxy proline which formed minor condensation products. While the reaction of cysteine resulted in the formation of two distinct thioethers, the reaction of glutathione resulted in the formation of two major unidentified compounds which gradually degraded upon incubation. These data suggest that pyrraline formed in vivo can further react with other amino acids on proteins to form crosslinks, which may explain in part increased protein crosslinking associated with aging and diabetes.
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PMID:Pyrraline ether crosslinks as a basis for protein crosslinking by the advanced Maillard reaction in aging and diabetes. 856 92


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