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)

Renal substrate exchange was examined in five male patients with insulin-dependent diabetes mellitus of several years' duration. Insulin was withheld for twenty-four hours prior to the study. A renal vein was catheterized from the femoral vein, and PHA-clearance was employed for the determination of effective renal blood flow. None of the patients was in ketoacidosis, but all were moderately hyperglycemic in the fasting states (16.8 +/- 1.5 mmol/L.) (225-384 mg./100 ml.). Nevertheless, no net release of glucose from the kidney was detectable. Instead, there was a significant net renal uptake of glucose (320 +/- 80 mumol/min.). In addition, there was a significant net uptake of glycerol and a net release of pyruvate. Renal amino acid exchange was similar to that reported for healthy subjects: glutamine, glycine, proline, and citrulline were taken up and serine, alanine, cystine, tyrosine, and threonine were released by the kidney. It is concluded that (a) in nonketoacidotic diabetics there is no net production of glucose by the kidney; (b) renal amino acid exchange in diabetics is similar to that of healthy individuals; and (c) the kidney is not an important gluconeogenic organ in human diabetes.
Diabetes 1975 Aug
PMID:Renal substrate exchange in human diabetes mellitus. 115 36

The 2.2 A resolution crystal structure of recombinant human manganese superoxide dismutase, a homotetrameric enzyme that protects mitochondria against oxygen-mediated free radical damage, has been determined. Within each subunit, both the N-terminal helical hairpin and C-terminal alpha/beta domains contribute ligands to the catalytic manganese site. Two identical 4-helix bundles, symmetrically assembled from the N-terminal helical hairpins, form novel tetrameric interfaces that stabilize the active sites. Structurally altered polymorphic variants with reduced activity, such as tetrameric interface mutant Ile-58 to Thr, may produce not only an early selective advantage, through enhanced cytotoxicity of tumor necrosis factor for virus-infected cells, but also detrimental effects from increased mitochondrial oxidative damage, contributing to degenerative conditions, including diabetes, aging, and Parkinson's and Alzheimer's diseases.
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PMID:The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles. 139 26

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

DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in approximately 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228----Met and Gly-261----Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism.
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PMID:Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. 150 86

We have recently identified a point mutation in the mitochondrially encoded tRNA(Leu(UUR)) gene which associates with a combination of type II diabetes mellitus and sensorineural hearing loss in a large pedigree. To extend this finding to other syndromes which exhibit a combination of diabetes mellitus and hearing loss we have sequenced all mitochondrial tRNA genes from two patients with the Wolfram syndrome, a rare congenital disease characterized by diabetes mellitus, deafness, diabetes insipidus and optic atrophy. In each patient, a single different mutation was identified. One is an A to G transition mutation at np 12,308 in tRNA(Leu(CUN)) gene in a region which is highly conserved between species during evolution. This mutation has been described by Lauber et al. (1) as associating with chronic progressive external ophthalmoplegia (CPEO). The other is a C to T transition mutation at np 15,904 in tRNA(Thr) gene. Both mutations are also present in the general population (frequency tRNA(Leu(CUN)) mutation 0.16, tRNA(Thr) mutation 0.015). These findings suggest that evolutionarily conserved regions in mitochondrial tRNA genes can exhibit a significant polymorphism in humans, and that the mutation at np 12,308 in the tRNA(Leu(CUN)) gene is unlikely to be associated with CPEO and Wolfram syndrome.
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PMID:Mutations in mitochondrial tRNA genes: non-linkage with syndromes of Wolfram and chronic progressive external ophthalmoplegia. 154 64

Insulin resistance in skeletal muscle may be an expression of the genetic basis of a common form of non-insulin-dependent diabetes mellitus (NIDDM) in humans. Impaired insulin action results from an apparent postreceptor defect in insulin signal transduction that limits the influence of the hormone on various protein serine/threonine kinases and phosphatases that are thought to contribute to the mechanism by which insulin affects intracellular events. The fact that numerous responses to insulin are affected suggests that the cause of insulin resistance involves an early step in insulin action. Therefore, we examined the influence of insulin on protein tyrosine phosphatase (PTPase) activities, which may counteract the protein tyrosine kinase activity of the insulin receptor in skeletal muscle of insulin-sensitive and insulin-resistant humans. Insulin infusion in vivo produced a rapid 25% suppression of soluble-PTPase activity in muscle of insulin-sensitive subjects, but this response was severely impaired in subjects who were insulin resistant. Insulin did not affect PTPase activity in the particulate fraction of muscle from either group, but basal particulate activity was 33% higher in resistant subjects than in sensitive subjects. Either or both of these abnormal characteristics of PTPase activities could be central to the causes of insulin resistance and NIDDM.
Diabetes 1991 Jul
PMID:Abnormal regulation of protein tyrosine phosphatase activities in skeletal muscle of insulin-resistant humans. 164 97

The insulin resistance seen in diabetes mellitus has been attributed partly to impaired autophosphorylation of the insulin receptor. It has been suggested that the phosphorylation of serine and/or threonine residues of the insulin receptor may reduce tyrosine autophosphorylation in streptozotocin-induced diabetic rats (STZ-D rats). To elucidate the mechanisms of decreased autophosphorylation of the insulin receptor in diabetic rats, we have investigated the effect of dephosphorylation of the insulin receptor by alkaline phosphatase on the insulin- and protein kinase-stimulating incorporation of 32P into the receptor of the liver from STZ-D rats. Both basal and insulin-stimulated autophosphorylations of the insulin receptor from STZ-D rats were significantly impaired to those from normal rats. Dephosphorylation of the insulin receptor by alkaline phosphatase resulted in an increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats (43 +/- 13% to 66 +/- 14%, P less than 0.05), but not from normal rats (100% to 109 +/- 12%, NS). Although maximal autophosphorylation of the dephosphorylated insulin receptor was still lower in STZ-D rats than in normal rats, the increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats by dephosphorylation was higher than that from normal (159.2 +/- 27.2% vs 108.0 +/- 12.4%, p less than 0.01), supporting the idea that the residues of the insulin receptor of STZ-D rats was highly phosphorylated.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1991 May
PMID:Dephosphorylation of the insulin receptor partially restores the decreased autophosphorylation in streptozotocin induced diabetic rats. 181 77

Plasma and urinary concentrations of different amino acids were investigated during diabetic ketoacidosis (DKA) and 12, 24, 72 hours after initiation of therapy. In DKA, plasma concentration of glutamic acid, aspartic acid, valine, leucine and isoleucine significantly increased while that of asparagine and glutamine decreased compared to levels in well-controlled diabetic patients. The urinary excretion of branched-chain amino acids, histidine, serine and threonine was elevated while those of glutamic acid, glutamine, glycine and taurine were reduced. Among the different amino acids, histidine excretion had the highest variability. A strong correlation was found between the urinary excretion of several amino acids and that of the beta-2-microglobulin characterizing tubular dysfunction. Changes in the excretion of different amino acids reflect the altered metabolic state and renal function due to DKA.
Diabetes Res Clin Pract 1991 May
PMID:Changes in plasma and urinary amino acid levels during diabetic ketoacidosis in children. 190 67

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

This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. Improved understanding of the molecular basis of insulin resistance could ultimately lead to a better understanding of the causation of these conditions and the design of rational therapy to ameliorate them. Here, particular attention is devoted to the initial events that follow the binding of insulin to its receptor, including changes in insulin receptor phosphorylation. Receptor-mediated insulin resistance may be a consequence of various factors including increased serine/threonine phosphorylation of the receptor with decreased tyrosine phosphorylation, receptor desensitization, auto-antibodies to the receptor and inherited structural defects in the insulin receptor. Defects in insulin action could also arise at post-receptor events particularly glucose transport. Other circulating hormones, such as the newly characterised islet amyloid polypeptide (amylin), may also cause insulin resistance.
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PMID:Molecular mechanisms of insulin resistance. 202 55


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