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)

Atypical carcinoid tumor of the lung with amyloid stroma seen in a 43-year-old woman is reported. The 47 x 45 x 33 mm tumor, located at the periphery of the S8 segment of the resected left lower lobe, revealed Dylon-positive amyloid deposition in the stroma. The argyrophilic tumor cells with occasional mitoses and focal venous involvement predominantly showed immunoreactivity of cytokeratin, neuron-specific enolase, cystatin C, chromogranin A, calcitonin and neuropeptide Y (NPY). Fewer cells were immunoreactive for calcitonin gene-related peptide (CGRP), the alpha-subunit of human chorionic gonadotropin, gastrin-releasing peptide, serotonin, methionine-enkephalin and gastrin. Immunoreactive CGRP or NPY were co-localized in calcitonin-positive cells. The amyloid substance was positively labeled only for CGRP. Immunostaining for amylin, a polypeptide isolated from insular amyloid in type II diabetes mellitus or insulinoma showing a 50% homology with CGRP, was negative. The specificity of immunostaining for calcitonin, CGRP and amylin was confirmed by immunoabsorption tests using synthetic human antigens. Immunoelectron microscopic studies disclosed peptide localization in neurosecretory-type granules and CGRP immunoreactivity in extracellular amyloid fibrils. This is the first report describing CGRP as a component of amyloid of endocrine origin.
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PMID:Atypical carcinoid tumor of the lung with amyloid stroma. 160 16

Methionine and serine in combination enhanced the inhibitory effect of selenite on cell growth and DNA synthesis of the MOD mammary epithelial cell line. These amino acids also increased the levels of a 58-kd selenoprotein which has been correlated with selenite's effects in previous studies. The use of the amino acids accelerated the onset of inhibition of DNA synthesis by selenite and increased the rate of actual selenoprotein synthesis. The mechanism of enhancement of selenite's effects was possibly due to the amino acids increasing the levels of essential precursors (i.e. seryltRNA(UGA), HSe-) needed for selenoprotein synthesis.
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PMID:Serine and methionine enhancement of selenite inhibition of DNA synthesis in a mouse mammary epithelial cell line. 313 18

Sulfonylurea drugs are widely used in the therapy of NIDDM. The improvement of glucose tolerance after long-term treatment of NIDDM patients with the drug can be explained by stimulation of glucose utilization in peripheral tissues that are characterized by insulin resistance in these patients. We studied whether the novel sulfonylurea drug, glimepiride, stimulates glucose transport into isolated insulin-resistant rat adipocytes. After long-term incubation of the cells in primary culture with high concentrations of glucose, glutamine, and insulin, stimulation of glucose transport by insulin was significantly reduced both with respect to maximal responsiveness (65% decrease of Vmax) and sensitivity (2.6-fold increase of ED50) compared with adipocytes cultured in medium containing a low concentration of glucose and no insulin. This reflects insulin resistance of glucose transport. In contrast, both responsiveness and sensitivity of glucose transport toward stimulation by glimepiride were only marginally reduced in insulin-resistant adipocytes (15% decrease of Vmax; 1.2-fold increase of ED50) versus control cells. Glimepiride, in combination with glucose and glutamine during the primary culture, caused desensitization of the glucose transport system toward stimulation by insulin, but to a lesser degree than insulin itself (50% reduction of Vmax; ninefold increase of ED50). Again, the maximal responsiveness and sensitivity of glucose transport toward stimulation by glimepiride were only slightly diminished. The presence of glimepiride during primary culture did not antagonize the induction of insulin resistance of glucose transport. The stimulation of glucose transport in insulin-resistant adipocytes by glimepiride is caused by translocation of glucose transporters from low-density microsomes to plasma membranes as demonstrated by subcellular fractionation and immunoblotting with anti-GLUT1 and anti-GLUT4 antibodies. Immunoprecipitation of GLUT4 from 32Pi- and [35S]methionine-labeled adipocytes revealed that the insulin resistance of GLUT4 translocation is accompanied by increased (three- to fourfold) phosphorylation of GLUT4 in both low-density microsomes and plasma membranes. Short-term treatment of desensitized adipocytes with glimepiride or insulin reduced GLUT4 phosphorylation by approximately 70 and 25%, respectively, in both fractions. We conclude that glimepiride activates glucose transport by stimulation of GLUT1 and GLUT4 translocation in rat adipocytes via interference at a site downstream of the putative molecular defect in the signaling cascade between the insulin receptor and the glucose transport system induced by high concentrations of glucose and insulin. The molecular site of glimepiride action is related to GLUT4 phosphorylation/dephosphorylation, which may regulate glucose transporter activity and translocation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro. 824 32

INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM. We previously have screened members of 18 familial NIDDM pedigrees for mutations in exons encoding the tyrosine kinase domain of the INSR gene (exons 13-21) by SSCP. That analysis initially detected only patterns consistent with silent polymorphisms, but on direct sequence analysis of exon 17 we detected a Met-for-Val substitution at position 985 in 1/18 pedigrees. We confirmed the substitution by sequence analysis of subcloned, PCR-amplified DNA from two pedigree members and by hybridization to labeled primers for the normal and mutant sequences. We did not find the mutation in any other individuals. Pedigree members were typed for presence or absence of the Met985 substitution by hybridization of PCR-amplified exon 17 DNA to allele-specific oligonucleotide probes, and typing was confirmed by segregation of INSR haplotypes and by SSCP analysis. The substitution was present in 3 NIDDM individuals in 3 generations, including a lean individual with onset at age 24. The substitution was present in only 50% of NIDDM siblings in generation 2, however. To determine the clinical effect of the Met985 substitution, we compared the 5 nondiabetic pedigree members who carried the mutation with the 9 nondiabetic pedigree members without the mutation and with 266 members of other pedigrees. Fasting and 1-h postglucose insulin levels were not different between carriers and noncarriers (fasting, 71.4 pM vs. 74.5 pM; 1-h, 381 pM vs. 354 pM), even after correction for age, sex, and BMI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM. 843 14

In the setting of an outpatient diabetic clinic, we determined whether macrovascular disease in patients with diabetes mellitus is associated with hyperhomocysteinemia (elevated plasma homocysteine [H(e)] concentrations) following a methionine load. Methionine-load tests were performed in 18 healthy controls, 11 diabetics without vascular disease (five insulin-dependent [IDDM] and six non-insulin-dependent [NIDDM]); and 17 diabetics with vascular disease (five IDDM and 12 NIDDM). All subjects were male, and there was no significant difference in mean age among the three groups. We measured plasma H(e) concentrations before and 2, 4, 6, 8, and 24 hours after an oral methionine load. Hyperhomocysteinemia (peak plasma H(e) concentration > control mean +/- 2 SD) occurred with significantly greater frequency (seven of 18, 39%) in patients with NIDDM as compared with age-matched controls (7%), being more common in those with macrovascular disease (five of 12, 41%). The area under the curve (AUC) over 24 hours, reflecting the total period of exposure to H(e), was also elevated with greater frequency in patients with NIDDM and macrovascular disease (33%) as compared with controls (0%). We conclude that hyperhomocysteinemia is associated with macrovascular disease in a significant proportion of patients with NIDDM. Further investigation of this association may determine whether hyperhomocysteinemia contributes to the increased frequency and accelerated clinical course of vascular disease in patients with diabetes mellitus.
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PMID:Hyperhomocysteinemia following a methionine load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease. 854 71

The aim of this study was determine the effect of a 15-week individualized exercise conditioning program on glycosylated hemoglobin (HbAlc) levels on Type 2 diabetes. Thirty-nine participants were sedantary, Type 2 diabetics, on an oral hypo-glycemic drug and no specified diet regimen at study onset. Pre and post 15 weeks subjects underwent: maximal incremental exercise tests, blood analysis, body composition analysis. Twenty-one subjects were prescribed an individualized exercise program for 15 weeks. Significant differences were found in the exercise group after 15 weeks in: total body fat, trunk fat, peak oxygen consumption and MET values. Correlations existed in the exercise group between HbAlc, arm muscle area and leg lean mass. Sixty-two percent of this group showed a reduction in HbAlc values. For this group, dietary intakes of riboflavin and potassium maybe associated with HbAlc levels. Exercise in conjunction with oral drug therapy prescribed for the NIDDM individual did not directly modify HbAlc levels, but did result in favorable effects on blood lipid values, fitness levels, and body composition values.
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PMID:The effect of exercise conditioning, diet, and drug therapy on glycosylated hemoglobin levels in type 2 (NIDDM) diabetics. 877 76

Phosphatidylinositol 3-kinase (PI3-K) may regulate the basal plasma membrane glucose transporter recycling and the organization of the transporter intracellular pool in addition to being an insulin signal for translocation of glucose transporters to the plasma membrane. The objectives of the present study were to examine for genetic variability in the human regulatory p85alpha subunit of PI3-K, to look for an association between gene variants and NIDDM in a case-control study, and to relate identified variability to potential changes in whole-body insulin sensitivity and glucose turnover in a phenotype study. Single-strand conformational polymorphism and heteroduplex analysis of the coding region of the regulatory p85alpha subunit in cDNA isolated from human muscle tissue from 70 insulin-resistant NIDDM patients and 12 control subjects revealed three silent polymorphisms and a missense mutation at nucleotide position 1020 (G-->A), changing a Met to Ile at codon 326. Using allele-specific oligohybridization, we found a similar allelic frequency of the codon 326Met-->Ile variant in 404 NIDDM patients (0.15 [95% CI 0.13-0.17]) and 224 matched glucose tolerant control subjects (0.16 [0.13-0.19]). In a random sample of 380 unrelated healthy young Caucasians aged 18-32 years, in whom we have performed a tolbutamide modified intravenous glucose tolerance test, we identified 263 wildtype subjects, 109 heterozygous subjects, and 8 subjects homozygous for the codon 326 variant (allelic frequency = 0.16 [0.13-0.19]). No difference in glucose disappearance constant (KG), insulin sensitivity index (SI), and glucose effectiveness (SG) was observed between wildtype and heterozygous subjects. However, compared with the combined values for wildtype and heterozygous carriers, KG was reduced by 40% (P = 0.004) and SG by 23% (P = 0.03) in homozygous carriers of the p85alpha variant. Moreover, in homozygous carriers, a 32% reduction was found in SI (P = 0.08). In conclusion, a codon 326Met-->Ile variant in the gene encoding the PI3-K p85alpha regulatory subunit is found in 31% of a random sample of young healthy Caucasians. About 2% of the subjects in this population carry the gene variant in its homozygous form, and these carriers are characterized by significant reductions in whole-body glucose effectiveness and intravenous glucose disappearance constant. In itself, the gene variant does not confer an increased risk of diabetes.
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PMID:Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index. 903 8

Autoantibodies to 65 kD glutamic acid decarboxylase (GADAA) and ICA512 (ICA512AA) were measured by radioimmunoassays using as antigens in vitro transcribed and translated [35S]-methionine-labeled human GAD65 and ICA512 (IA-2). The prevalence of GADAA and ICA512AA in sera from 87 patients with IDDM was 39 and 23%, respectively. The frequency and titer of ICA512AA declined sharply within 5 years after the onset of IDDM. Among patients tested within 4 years after diagnosis, the prevalence of ICA512AA was significantly higher in acute onset IDDM than in slowly progressive IDDM (37 versus 6%, P < 0.025) irrespective of age, while there was no difference in GADAA frequency between acute onset and slowly progressive subtypes (51 versus 63%). A total of two patients out of 121 patients with NIDDM were positive for GADAA, and two other NIDDM patients, who were suffering from sarcoidosis, were positive for ICA512AA. Neither of the antibodies were positive in sera from four atypical NIDDM patients, aged < 20 years, who showed ketosis at onset and required insulin followed by excellent metabolic control with diet restriction alone. These observations suggest that ICA512AA are associated with rapid progression of beta cell damage in IDDM. ICA512 radioassay, in combination with GAD assay may provide a useful diagnostic marker for IDDM especially in youth.
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PMID:Combined measurements of GAD65 and ICA512 antibodies in acute onset and slowly progressive IDDM. 917 63

Muscle glycogen synthase (GYS1) is a key enzyme of non-oxidative pathway of glucose metabolism that has been reported to be related to insulin resistance in non-insulin-dependent diabetic (NIDDM) patients. We scanned the GYS1 gene for mutation by single strand conformational polymorphism in 244 non-obese Japanese NIDDM patients and 181 non-diabetic control subjects, and found two missense mutations; Met to Val at position 416 in the exon 10 (M416V) and Pro to Ala at position 442 in the exon 11 (P442A). The P442A mutation was found in only one NIDDM patient treated with sulfonylureas. On the other hand, the M416V mutation was widely found in the Japanese population. The mutant allele frequency in the NIDDM patients (13.7%) was slightly higher but not statistically significant compared with that in non-diabetic subjects (9.7%). However, the insulin sensitivity index [SI: x 10(-4) x min(-1) x (microU/ml)(-1)] estimated by Minimal Model analysis in the NIDDM patients carrying the M416V mutation was significantly lower than that in those without the mutation (1.18 +/- 0.27, n = 21 vs 2.20 +/- 0.20, n = 60, mean +/- SEM, p < 0.01). Glucose effectiveness, age, body mass index, and levels of glycated haemoglobin and serum lipids were not significantly different between the two groups. The same trend could be seen in non-diabetic subjects (SI: 3.70 +/- 0.46, 9 subjects with the mutation vs 5.94 +/- 0.66, 19 subjects without the mutation, p < 0.05). These findings indicate that the M416V mutation of the GYS1 gene is one of the factors contributing to the insulin resistance in the Japanese population and may play some role in the pathogenesis of NIDDM.
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PMID:A missense mutation of the muscle glycogen synthase gene (M416V) is associated with insulin resistance in the Japanese population. 926 90

Human serum paraoxonase (PON1) is located on high density lipoprotein and has been implicated in the detoxification of organophosphates and possibly in the prevention of low density lipoprotein lipid peroxidation. PON1 has two genetic polymorphisms both due to amino acid substitution, one involving glutamine (A genotype) and arginine (B genotype) at position 192 and the other leucine (L genotype) and methionine (M genotype) at position 55. We investigated the effect of these polymorphisms on serum PON1 activity and concentration in 252 non-insulin dependent diabetes mellitus (NIDDM) individuals and 282 non-diabetic controls. Serum PON1 activity in the controls (214.6 nmol/min per ml (26.3-620.8)) was significantly higher than in NIDDM (158.7 nmol/min per ml (3.6-550.5) (P < 0.001) as was serum PON1 concentration (89.1 microg/ml (16.8-527.4)) compared to 76.7 microg/ml (3.6-443.8) (P < 0.01). In the control population MM homozygotes had significantly lower serum PON1 activity regardless of the 192 polymorphism whereas in NIDDM both LM and MM genotypes had lower serum PON1 activity than LL homozygotes only when the 192 AA genotype was present. Serum PON1 concentration was lower in NIDDM with AA/LM, AA/LL, AB/LL and AB/MM genotypes than in controls. Differences in PON1 activity were the major cause of differences in specific activity between genotypes. Neither the PON1 55 or 192 polymorphisms consistently influenced the serum lipid or lipoprotein concentrations in either population. Low serum PON1 activity in NIDDM may be related to an increased tendency to lipid peroxidation and may also increase susceptibility to toxicity from organophosphate exposure. Our findings thus raise the possibility that PON1 may be of importance in both the genetic and acquired predisposition to premature atherosclerosis and neuropathy in diabetes.
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PMID:Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus. 971 41


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