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 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

Abnormal amino acid metabolism is sometimes observed among patients with diabetes mellitus. Of many amino acids, alanine and branched-chain amino acids such as valine, leucine, isoleucine show characteristic changes. In diabetic ketoacidosis, plasma concentration of alanine decreases and that of branched-amino acid increases and the oxidation of branched-amino acids is enhanced. Splanchnic amino acid uptake is generally higher in diabetics and this level is partially restored by exercise. Some glycosylated proteins are used to estimate the condition of diabetes mellitus. Increment of urinary glycosylated amino acid excretion is reported in diabetics. Plasma homocysteine, reactive vascular-injuring amino acid, increases in diabetics with nephropathy. Those abnormal amino acid metabolism would be restored after good glycemic control is obtained.
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PMID:[Abnormal amino acid metabolism in diabetes mellitus]. 140 95

We examined the effects of a combined, local intra-arterial infusion of growth hormone (GH) and insulin on forearm glucose and protein metabolism in seven normal adults. GH was infused into the brachial artery for 6 h with a dose that, in a previous study, stimulated muscle protein synthesis (phenylalanine Rd) without affecting systemic GH, insulin, or insulinlike growth factor I concentrations. For the last 3 h of the GH infusion, insulin was coinfused with a dose that, in the absence of infused GH, suppressed forearm muscle proteolysis by 30-40% without affecting systemic insulin levels. Measurements of forearm glucose, amino acid balance, and [3H]phenylalanine and [14C]leucine kinetics were made at 3 and 6 h of the infusion. Glucose uptake by forearm tissues in response to GH and insulin did not change significantly between 3 and 6 h. By 6 h, the combined infusion of GH and insulin promoted a significantly more positive net balance of phenylalanine, leucine, isoleucine, and valine (all P less than 0.05). The change in net phenylalanine balance was due to a significant increase in phenylalanine Rd (51%, P less than 0.05) with no observable change in phenylalanine Ra. For leucine, a stimulation of leucine Rd (50%, P less than 0.05) also accounted for the change in leucine net balance, with no suppression of leucine Ra. The stimulation of Rd, in the absence of an observed effect on Ra, suggests that GH blunts the action of insulin to suppress proteolysis in addition to blunting insulin's action on Rd.
Diabetes 1992 Apr
PMID:Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin's antiproteolytic action in humans. 160 69

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

Hormonal changes and whole blood free amino acid levels and their relation to renal function were measured in 12 insulin-dependent diabetic patients after two 10-day periods with a diet consisting of 10% and 20% respectively of the energy as protein. The patients were 15-21 years old and mean duration of diabetes was 12 (5-20) years. Glomerular filtration rate, renal plasma flow, and albumin excretion rate were measured together with plasma concentrations of glucagon, growth hormone, insulin-like growth factor 1 (IGF-1), somatostatin, serum insulin and free amino acids in blood. Glomerular filtration rate was 123 +/- 3 ml/min/1.73 m2 on high protein diet and 113 +/- 3 ml/min/1.73 m2 on low protein diet (p = 0.02). Renal plasma flow was unchanged. Glucagon, IGF-1, branch chained amino acids (BCAA), tyrosine, phenylalanine, lysine, and methionine were increased after the high protein diet. Growth hormone, somatostatin, insulin, and other amino acids remained unchanged. The increase in glomerular filtration rate was significantly correlated to the increase in glucagon, isoleucine, and valine (glucagon r = 0.71, p = 0.01, isoleucine r = 0.59, p = 0.04, valine r = 0.62, p = 0.03). In a multiple regression model the increase in glomerular filtration correlated most strongly to the increase in isoleucine, followed by valine and glucagon. Together these variables explained 88% of the total variance of the change in glomerular filtration rate (r2 = 0.88, p = 0.001). Albumin excretion rate was correlated to IGF-1 (r = 0.86, p less than 0.001) on the high protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1991 Mar
PMID:Indications that branched chain amino acids, in addition to glucagon, affect the glomerular filtration rate after a high protein diet in insulin-dependent diabetes. 180 76

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

BioBreeding (BB) rats are derived from an outbred colony of Wistar rats and are used as a model of autoimmune diabetes mellitus. A corticosteroid binding globulin (CBG) variant with reduced affinity for glucocorticoids has now been found in the blood of these animals. The dissociation rate constants of BB CBG for cortisol (4.42 nM) and corticosterone (1.43 nM) are both about 50% higher than those associated with Wistar CBG, but no obvious difference in the steroid binding specificity of BB and Wistar CBGs was detected. Purified BB and Wistar CBGs exhibit the same size heterogeneity when examined by polyacrylamide gel electrophoresis under denaturing conditions, and the sizes of their respective hepatic mRNAs are identical. The genetic basis for this abnormality was therefore determined by comparing the cDNA sequences for BB and Wistar CBG, and this revealed a point mutation that results in a single amino acid substitution at residue 276 (Ile in BB CBG and Met in Wistar CBG). To confirm that this mutation is responsible for the reduced steroid binding affinity associated with BB CBG, the cDNAs for rat CBG-Ile276 and CBG-Met276 were expressed in Chinese hamster ovary cells. The steroid binding affinities of the CBGs secreted by these cells were essentially identical with those observed in the corresponding serum samples from these two rat strains. The amino acid substitution identified in BB rat CBG therefore clearly accounts for the reduction in its steroid binding affinity, and further analysis of this and other natural CBG variants may reveal important information about the CBG steroid binding site. It is also possible that this mutation may contribute to the etiology of pathological abnormalities that are characteristic of the BB rat.
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PMID:An amino acid substitution in biobreeding rat corticosteroid binding globulin results in reduced steroid binding affinity. 191 78

Insulin resistance is a common feature of non-insulin-dependent diabetes mellitus (NIDDM) and "diabetes susceptibility genes" may be involved in this abnormality. Two potential candidate genes are the insulin receptor (IR) and the insulin-sensitive glucose transporter (GLUT-4). To elucidate whether structural defects in the IR and/or GLUT-4 could be a primary cause of insulin resistance in NIDDM, we have sequenced the entire coding region of the GLUT-4 gene from DNA of six NIDDM patients. Since binding properties of the IRs from NIDDM subjects are normal, we also analyzed the sequence of exons 16-22 (encoding the entire cytoplasmic domain of the IR) of the IR gene from the same six patients. When compared with the normal IR sequence, no difference was found in the predicted amino acid sequence of the IR cytoplasmic domain derived from the NIDDM patients. Sequence analysis of the GLUT-4 gene revealed that one patient was heterozygous for a mutation in which isoleucine (ATC) was substituted for valine (GTC) at position 383. Consequently, the GLUT-4 sequence at position 383 was determined in 24 additional NIDDM patients and 30 nondiabetic controls and all showed only the normal sequence. From these studies, we conclude that the insulin resistance seen in the great majority of subjects with the common form of NIDDM is not due to genetic variation in the coding sequence of the IR beta subunit, nor to any single mutation in the GLUT-4 gene. Possibly, a subpopulation of NIDDM patients exists displaying variation in the GLUT-4 gene.
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PMID:Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus. 191 82

Islet amyloid polypeptide (IAPP), a putative polypeptide hormone, is a product of pancreatic beta-cells and the major constituent of the amyloid deposits seen mainly in islets of type 2 diabetic humans and diabetic cats. The connection between IAPP amyloid formation and diabetes is unknown, but a limited segment of the IAPP molecule, positions 20-29, seems responsible for the aggregation to fibrils. Differences in the amino acid sequence of this region probably determine whether or not islet amyloid can develop in a particular species. Amyloid fibril formation can be mimicked in vitro with the aid of synthetic peptides. With this technique we show that peptides corresponding to IAPP positions 20-29 of human and cat, species that develop IAPP-derived islet amyloid, form amyloid-like fibrils in vitro. The corresponding IAPP segment from three rodent species that do not develop IAPP-derived amyloid did not give rise to fibrils. Substitution of the human IAPP-(20-29) decapeptide with one or two amino acid residues from species without islet amyloid generally reduced the capacity to form fibrils. We conclude that the sequence Ala-Ile-Leu-Ser-Ser, corresponding to positions 25-29 of human IAPP, is strongly amyloidogenic and that a proline-for-serine substitution in position 28, as in several rodents, almost completely inhibits formation of amyloid fibrils.
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PMID:Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. 219 44


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