Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial NIDDM probably results from combined inherited defects of insulin secretion and action. Members of the facilitative glucose transporter family are strong candidates for both defects, and RFLPs for both GLUT1 (erythrocyte) and GLUT2 (liver/islet) genes have been associated with NIDDM in some populations. To test the hypothesis that GLUT1 and GLUT2 mutations contribute to the inherited predisposition to NIDDM, we examined linkage of these loci with NIDDM in 18 large Utah white pedigrees (two and three generation) ascertained for > or = 2 NIDDM siblings. We used two RFLPs detected with Xba1 and Stu1 for the GLUT1 transporter. For the GLUT2 (liver/beta-cell) transporter gene, we used an RFLP detected with EcoR1 and a highly polymorphic (6-allele) dinucleotide (microsatellite) repeat. Analysis was performed with the MLINK program of the LINKAGE package. We tested four models for each locus: dominant and recessive, with IGT alternately considered as unknown affection status, or affected if IGT was diagnosed < or = 45 yr of age and unknown if > 45 yr. Disease gene frequencies were chosen to give approximate disease prevalence in American whites (q = 0.03, dominant; q = 0.25, recessive). Linkage of GLUT1 and NIDDM was strongly and significantly rejected under all models, with total (pooled) LOD scores of -5.7 to -8.9, indicating > 500,000:1 odds against linkage. Pooled LOD scores were significantly negative (< -2.0, or 100:1 odds against linkage) to a recombination fraction of > 5%. No heterogeneity was apparent. Analysis of GLUT2 gave similar results, with LOD scores of < -4.0 under each model, indicating at least 10,000:1 odds against linkage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Linkage analysis of GLUT1 (HepG2) and GLUT2 (liver/islet) genes in familial NIDDM. 135 87

The significance of variation within the genes coding for three glucose transporter proteins in the aetiology of non-insulin dependent diabetes mellitus was assessed by analysing restriction fragment length polymorphisms in an English Caucasian population. Two polymorphisms at the HepG2/erythrocyte glucose transporter (GLUT1) locus, four at the liver/pancreatic glucose transporter (GLUT2) locus and one at the muscle/adipocyte glucose transporter (GLUT4) were analysed in a sample of diabetic and non-diabetic subjects. No significant differences in the allelic, genotypic or haplotypic frequencies of the polymorphisms at these three loci were observed between the diabetic or non-diabetic populations. No significant linkage disequilibrium was observed between the two GLUT1 polymorphic sites, whereas the four polymorphic sites at the GLUT2 locus, one of which appears to be due to a 100-200 base pair DNA insertion/deletion, were found to be in significant linkage disequilibrium. In order to study the possible role of glucose transporter gene variants contributing to the development of obesity, the body mass indexes were compared in the different genotypic groups of diabetic and non-diabetic subjects. No differences in body mass index between genotype groups were found at the p < 0.005 level of significance.
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PMID:Analysis of three glucose transporter genes in a Caucasian population: no associations with non-insulin-dependent diabetes and obesity. 136 30

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy. We have examined restriction fragment length polymorphisms (RFLPs) near "candidate diabetogenic genes" as one approach to identify molecular markers for GDM genes. Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity. Logistic regression analysis was used to explore the relationship between genotypes at these candidate gene loci and GDM, while adjusting for the effects of potential confounding variables. Among black subjects, the INSR allele 1 (P = 0.001) and interactions between INSR allele 1 with body mass index (BMI) (P = 0.002) and history of DM in subject's mother (P = 0.004) contributed significantly to GDM risk. Among Caucasian subjects, a similar relationship between the INSR allele 1 (P = 0.007) and INSR allele 1-BMI interactions (P = 0.011) on GDM risk were observed. In Caucasians, an additional significant risk factor was determined by an INSR allele 1-IGF2 allele 2 interaction (P = 0.018). No risk factors were identified in Hispanic subjects. These data continue to support the hypothesis that GDM is a heterogeneous disorder with respect to phenotypic and genotypic features. Furthermore, our data suggest that risk for GDM in black and Caucasian subjects is not due to obesity perse but to interactions between obesity and INSR alleles. In Caucasian women, INSR and IGF2 alleles interact to confer additional risk for GDM. Thus genes underlying susceptibility to GDM in some women may be similar to genes conferring risk to NIDDM, while in others novel genes may contribute to GDM risk.
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PMID:Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms. 257 27

One of the most rewarding examples for teaching hereditary metabolic disorders is classical phenylketonuria (PKU) caused by the deficient function of phenylalanine hydroxylase, the locus of which (PAH) is on the long arm of the twelfth chromosome. The twelfth chromosome has also the locus (VWF, F8VWF) the pathogenic alleles of which cause impaired blood clotting--Willebrand's disease and it is at the same time also the site of the family of keratin genes (KRT) responsible for epidermolysis bullosa simplex and other diseases. The question of the relationship between membrane glucose transmitters--GLUT and diabetes (NIDDM) is the subject of many investigations concerned with these loci.
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PMID:[The human genome--chromosome 12]. 755 42

Myoblasts from human skeletal muscle were isolated from needle biopsy samples of vastus lateralis and fused to differentiated multinucleated myotubes. Specific high-affinity insulin and insulin-like growth factor I (IGF-I) binding, glucose transporter proteins GLUT1 and GLUT4, glycogen synthase and pyruvate dehydrogenase proteins, and their specific mRNAs were identified in fused myotubes. Insulin and IGF-I stimulated 2-deoxyglucose uptake twofold with half-maximal stimulation by insulin at 0.98 +/- 0.12 nmol/l and maximal stimulation at 17.5 nmol/l. Acute insulin treatment (33 nmol/l) doubled glycogen synthase activity and glucose incorporation into glycogen while increasing pyruvate dehydrogenase approximately 30%. In cells cultured from NIDDM subjects, both basal (6.9 +/- 1.0 vs. 13.0 +/- 1.7 pmol.mg protein-1.min-1) and acute insulin-stimulated transport (13.5 +/- 2.0 vs. 22.4 +/- 1.3 pmol.mg protein-1.min-1) were significantly reduced compared with nondiabetic control subjects (both P < or = 0.005). GLUT1 protein content of total membranes from NIDDM subjects was decreased compared with control subjects, while GLUT4 levels were similar between groups. A significant correlation (r = 0.65, P < or = 0.05) was present when maximal rates of insulin-stimulated glucose transport in cell culture from subjects were compared with their corresponding in vivo glucose disposal determined by hyperinsulinemic glucose clamp. In summary, differentiated human skeletal muscle cultures exhibit biochemical and molecular features of insulin-stimulated glucose transport and intracellular enzyme activity comparable with the in vivo situation. Defective insulin-stimulated glucose transport persists in muscle cultures from NIDDM subjects and resembles the reduced insulin-mediated glucose uptake present in vivo. We conclude that this technique provides a relevant cellular model to study insulin action and glucose metabolism in normal subjects and determine the mechanisms of insulin resistance in NIDDM.
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PMID:Insulin action and glucose metabolism in nondiabetic control and NIDDM subjects. Comparison using human skeletal muscle cell cultures. 762

The author summarizes mechanisms by which insulin resistance and compensatory hyperinsulinism are manifested in the clinical picture. He divides the mechanisms into prereceptor, receptor and postreceptor mechanisms. The latter dominate in the population quantitatively and thus also by their impact because they create the so-called 5H syndrome (association of hyperinsulinism with hyperglycaemia (NIDDM), hyperlipoproteinaemia, hypertension, hirsutism and the polycystic ovary syndrome) or the so-called hormonal metabolic syndrome X, lethal tetrad, metabolic syndrome, syndrome of insulin resistance). The term syndrome X does not appear suitable as it is frequently mistaken for coronary X syndrome which probably is also conditioned by hyperinsulinism, for the hormonal metabolic X syndrome and probably also fot the "fragile X syndrome" in genetics. The 5H syndrome is caused by a postreceptor disorder of insulin efficiency for which so far the molecular basis and dominating organ site have not yet been defined adequately. Hyperinsulinism is conceived as an insulin resistance compensating phenomenon. In its development participates, however, in addition to compensatory hypersecretion also impaired insulin utilization (liver, muscles) and an impaired primary secretory response caused probably by a disorder of blood sugar control (glucokinase, GLUT 2). This is suggested by the frequently inadequate response of the blood sugar level, IRI and C-peptide during the oral glucose tolerance test (OGGT). A hyperinsulinaemic response may be encountered when the blood sugar curve is normal, flat, in impaired glucose tolerance and in diabetes. Thus OGGT alone is not suited for the early detection of the 5H syndrome unless concurrently the IRI and C-peptide response is recorded.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Clinical manifestations of the insulin resistance syndrome. The hormonal-metabolic syndrome X, the 5H syndrome and their etiopathogenesis]. 772 46

Glucokinase is a key enzyme of glucose metabolism that phosphorylates glucose to glucose-6-phosphate (G-6-P). This is the first step of glucose metabolism after the uptake of glucose by glucose transporter 2 (GLUT 2). Glucokinase is one of the hexo-kinases and is expressed only in pancreatic beta cells and hepatocytes. Recently it was reported that glucokinase gene is associated with some families with MODY (maturity-onset diabetes of the young). As MODY is a subtype of diabetes which is inherited autosomal dominantly, the correlation of diabetes with glucokinase gene was vigorously studied in many laboratories. The first mutation in exon 7 of the glucokinase gene was reported in 1992. Since the first report of the glucokinase gene mutation in exon 7, a number of mutations and a deletion were reported to be associated with MODY or late-onset NIDDM. But investigations by many groups revealed that glucokinase gene abnormalities are responsible for less than one per cent of NIDDM which is relatively small compared with diabetes with mitochondrial gene alterations.
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PMID:[Glucokinase gene abnormalities in maturity-onset diabetes of the young (MODY) and late-onset NIDDM]. 798 82

To assess the contribution of GLUT1 and GLUT4 genes to NIDDM susceptibility in Japanese population, we performed population studies using RFLP markers. We found the strong association between XbaI polymorphism at GLUT1 gene and NIDDM, but no association between KpnI polymorphism at GLUT4 gene and NIDDM. Based on these results, molecular scanning of GLUT1 gene was performed using SSCP and direct sequencing in Japanese population, to substantiate the gene defect predisposing to NDDM. Although silent mutations were found, the meaningful mutations within the coding regions were not demonstrated. Thus the positive association observed in population study may be spurious or due to the abnormalities in non-coding regions such as promoter or other regulatory elements at GLUT1 gene.
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PMID:[Defects of candidate genes in Japanese NIDDM--glucose transporter gene(GLUT1 gene, GLUT4 gene)]. 798

To examine whether sulphonylureas influence hyperglycaemia-induced glucose disposal and suppression of hepatic glucose production (HGP) in type 2 diabetes mellitus, a 150-min hyperglycaemic (plasma glucose 14 mmol/l) clamp with concomitant somatostatin infusion was used in eight type 2 diabetic patients before and after 6 weeks of glipizide (GZ) therapy. During the clamp a small replacement dose of insulin was given (0.15 mU/kg per min). Isotopically determined glucose-induced glucose uptake was similar before and after GZ administration which led to improved glycaemic control (basal plasma glucose 12.2 +/- 1.3 vs 8.9 +/- 0.7 mmol/l; P < 0.01). Glucose-induced suppression of HGP was, however, more pronounced during GZ treatment (0.96 +/- 0.14 vs 1.44 +/- 0.20 mg/kg per min; P < 0.02). Following GZ treatment hyperglycaemia failed to stimulate glycogen synthase activity. Moreover, GZ resulted in a significant increase in the immunoreactive abundance of the insulin-regulatable glucose transport protein (GLUT 4) (P < 0.02). In conclusion, these results suggest that GZ therapy in type 2 diabetic patients enhances hepatic sensitivity to hyperglycaemia, while glucose-induced glucose uptake remains unaffected. In addition, GZ tends to normalize the activity of glycogen synthase and increases the content of GLUT 4 protein in skeletal muscle.
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PMID:Effects of glipizide on glucose metabolism and muscle content of the insulin-regulatable glucose transporter (GLUT 4) and glycogen synthase activity during hyperglycaemia in type 2 diabetic patients. 804 94

The purpose of these experiments was to test the hypothesis that impaired glucose-stimulated insulin secretion in NIDDM is due to mutations in the islet beta cell/liver glucose transporter (GLUT 2) gene. Using oligonucleotide primers flanking each of the 11 exons, the structural portion of the gene was studied by PCR-SSCP analysis. DNA from African-American females (n = 48), who had gestational diabetes but developed overt NIDDM after delivery, was studied. Each SSCP variant was sequenced directly from genomic DNA. Two amino acid substitutions from the previously reported sequence were found, one in exon 3 and the other in exon 4B. Four additional silent mutations in the coding region, and six intron mutations outside the splice junction consensus sequences, were also identified. The mutation GTC x ATC in exon 4B substituted Val197 to Ile197. This amino acid substitution was found in only one NIDDM patient in a single allele, and was not found in 52 control subjects. This residue exists in the fifth membrane spanning domain, and Val at this position is conserved in mouse and rat GLUT 2, and human GLUT 1 to GLUT 4. The other codon change in exon 3, ACT x ATT, substituted Thr110 to Ile110 in the second membrane spanning domain. To determine the frequency of this non-conservative amino acid substitution, a PCR-LCR assay was developed. This assay was simple and highly specific for detection of this single nucleotide substitution. The allelic frequency of the ATT (Ile110) in NIDDM patients (39.6%, n = 48) and that in controls (47.1%, n = 52) did not differ (p = 0.32, Fisher's exact test).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Variability of the pancreatic islet beta cell/liver (GLUT 2) glucose transporter gene in NIDDM patients. 806 45


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