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)

A mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene with a cytosine to guanine substitution results in an exchange of proline (Pro) with alanine (Ala) in exon B (codon 12) of this gene. This polymorphism has been associated with high insulin sensitivity and low body weight, but no data have been published to date about its effect on early atherosclerosis. We investigated the relationship of the Pro(12)Ala polymorphism to early atherosclerosis, measured by the intima-media thickness (IMT). A total of 622 subjects were included, aged 40-70 yr, who were participants of the RIAD (Risk factors in Impaired glucose tolerance for Atherosclerosis and Diabetes) study and were at risk of developing type 2 diabetes. Altogether, 449 of the subjects had the common genotype (Pro(12)Pro), 162 had the Pro(12)Ala genotype, and 11 the Ala(12)Ala genotype. IMT was significantly decreased in subjects with the Ala(12)Ala genotype compared with subjects with the other two genotypes. Body mass index, free fatty acid levels, and leukocyte count were lower in subjects with the Ala(12)Ala genotype compared with subjects with the Pro(12)Pro or Pro(12)Ala genotypes. In multivariate analysis, the Ala(12)Ala genotype was a significant independent determinant of IMT. Furthermore, we demonstrated specific expression of the PPARgamma2 gene in human atherosclerotic lesions as well as in cultured primary macrophages and foam cells. In conclusion, our data suggest that the Ala(12)Ala genotype of the PPARgamma2 gene may protect from early atherosclerosis in subjects at risk for diabetes.
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PMID:Ala12Ala genotype of the peroxisome proliferator-activated receptor gamma2 protects against atherosclerosis. 1535 13

Several genetic variants of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), a molecule known to be involved in transcription of target genes, have been identified. Pro12Ala, a missense mutation in exon 2 of the gene, is highly prevalent in Caucasian populations. Conflicting conclusions about the association between this mutation and complex traits such as obesity, insulin sensitivity, and T2DM have been reported. We have investigated the association of PPAR-gamma2 Pro12Ala polymorphism with measures of insulin sensitivity in a population of Italian obese children (n = 200; mean age, 10.38 +/- 2.8 y) in whom clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated in all subjects. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. The frequency of Ala carriers was 17%, similar to that reported in other adult Caucasian populations. The X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared with Pro/Pro (p = 0.008). Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (p = 0.023). In conclusion, our observations demonstrate that the X12Ala variant is significantly associated with greater insulin sensitivity in childhood obesity. Because obesity is one of the most important risk factors for cardiovascular diseases and type 2 diabetes, obese children, who are presumably at a higher risk, may be protected from these diseases by the phenotypic effect of the Ala 12 allele on insulin resistance.
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PMID:PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity in childhood obesity. 1553 38

D-mannose is an essential monosaccharide constituent of glycoproteins and glycolipids. However, it is unknown how plasma mannose is supplied. The aim of this study was to explore the source of plasma mannose. Oral administration of glucose resulted in a significant decrease of plasma mannose concentration after 20 min in fasted normal rats. However, in fasted type 2 diabetes model rats, plasma mannose concentrations that were higher compared with normal rats did not change after the administration of glucose. When insulin was administered intravenously to fed rats, it took longer for plasma mannose concentrations to decrease significantly in diabetic rats than in normal rats (20 and 5 min, respectively). Intravenous administration of epinephrine to fed normal rats increased the plasma mannose concentration, but this effect was negated by fasting or by administration of a glycogen phosphorylase inhibitor. Epinephrine increased mannose output from the perfused liver of fed rats, but this effect was negated in the presence of a glucose-6-phosphatase inhibitor. Epinephrine also increased the hepatic levels of hexose 6-phosphates, including mannose 6-phosphate. When either lactate alone or lactate plus alanine were administered as gluconeogenic substrates to fasted rats, the concentration of plasma mannose did not increase. When lactate was used to perfuse the liver of fasted rats, a decrease, rather than an increase, in mannose output was observed. These findings indicate that hepatic glycogen is a source of plasma mannose.
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PMID:Hepatic glycogen breakdown is implicated in the maintenance of plasma mannose concentration. 1553 4

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the pathophysiology of various human diseases such as type 2 diabetes and obesity. IL-6 signals via a heterodimeric receptor complex consisting of a soluble IL-6 alpha-subunit (IL-6 receptor [IL6R]) and a signal transducing subunit (gp130). The IL6R gene maps to an important candidate locus for type 2 diabetes on chromosome 1q21. An Asp358Ala polymorphism of the IL6R has been reported to associate with obesity in Pima Indians. We investigated the Asp358Ala polymorphism in relation to type 2 diabetes, obesity, and other pre-diabetic quantitative traits among Danish whites. By applying a recessive genetic model in a case-control study of 1,349 type 2 diabetic patients and 4,596 glucose-tolerant control subjects, we found a significant difference in genotype distribution (P = 0.008) and in allele frequency (Ala-allele 38.3% [95% CI 36.5-40.1] in diabetic subjects vs. 41.2% [40.2-42.2] in control subjects; P = 0.007). The odds ratio for the Asp/Asp carriers versus Ala/Ala carriers was 1.38 (1.09-1.71). Among 4,251 middle-aged glucose-tolerant subjects, the Asp358Ala polymorphism was not associated with estimates of obesity, post-oral glucose tolerance test serum insulin release, or the homeostasis model assessment of insulin resistance index. In conclusion, the Asp358Ala polymorphism of the IL6R associates with type 2 diabetes in Danish whites.
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PMID:Variation in the interleukin-6 receptor gene associates with type 2 diabetes in Danish whites. 1556 70

To clarify the contribution of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma (PPARgamma) gene to susceptibility to insulin resistance and related diseases, 505 unrelated Japanese subjects were investigated, including 175 normotensive non-diabetic (NN) subjects, 125 normotensive diabetic (ND) subjects, 102 hypertensive non-diabetic (HN) subjects, and 103 hypertensive diabetic (HD) subjects. Ala phenotype frequency was lowest in patients with both type 2 diabetes and hypertension (3.9% in HD group), followed by patients with either one of these conditions (5.6% in ND group, 7.8% in HN group), and highest in subjects without these conditions (9.7% in NN group). When stratified by hypertensive status, the Ala phenotype was negatively associated with diabetes, giving an odds ratio of 0.53 (95% confidence interval: 0.25-1.09). In contrast, when stratified by diabetic status, the odds ratio of the Ala phenotype for hypertension was 0.75 (95% confidence interval: 0.37-1.54). In non-diabetic hypertensive subjects, glucose and insulin levels during oral glucose tolerance test as well as M-value estimated by glucose-clamp test were not significantly different according to the genotype. The data suggest a contribution of the Pro12Ala polymorphism of PPARgamma to genetic susceptibility to type 2 diabetes mellitus and hypertension, but not to insulin sensitivity in hypertensive subjects.
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PMID:Association of Pro12Ala polymorphism of PPARgamma gene with insulin resistance and related diseases. 1556 83

The ability of glycogen synthase kinase-3 (GSK-3) to phosphorylate insulin receptor substrate-1 (IRS-1) is a potential inhibitory mechanism for insulin resistance in type 2 diabetes. However, the serine site(s) phosphorylated by GSK-3 within IRS-1 had not been yet identified. Using an N-terminal deleted IRS-1 mutant and two IRS-1 fragments, PTB-1 1-320 and PTB-2 1-350, we localized GSK-3 phosphorylation site(s) within amino acid sequence 320-350. Mutations of serine 332 or 336, which lie in the GSK-3 consensus motif (SXXXS) within PTB-2 or IRS-1, to alanine abolished their phosphorylation by GSK-3. This suggested that Ser332 is a GSK-3 phosphorylation site and that Ser336 serves as the "priming" site typically required for GSK-3 action. Indeed, dephosphorylation of IRS-1 prevented GSK-3 phosphorylation. Furthermore, the phosphorylated peptide derived from the IRS-1 sequence was readily phosphorylated by GSK-3, in contrast to the nonphosphorylated peptide, which was not phosphorylated by the enzyme. When IRS-1 mutants S332A(IRS-1), S336A(IRS-1), or S332A/336A(IRS-1) were expressed in Chinese hamster ovary cells overexpressing insulin receptors, their insulin-induced tyrosine phosphorylation levels increased compared with that of wild-type (WT) IRS-1. This effect was stronger in the double mutant S332A/336A(IRS-1) and led to enhanced insulin-mediated activation of protein kinase B. Finally, immunoblot analysis with polyclonal antibody directed against IRS-1 phosphorylated at Ser332 confirmed IRS-1 phosphorylation in cultured cells. Moreover, treatment with the GSK-3 inhibitor lithium reduced Ser332 phosphorylation, whereas overexpression of GSK-3 enhanced this phosphorylation. In summary, our studies identify Ser332 as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling.
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PMID:Serine 332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling. 1557 12

The aim of this initial case-control study was to determine the association between common Pro12Ala polymorphism in the PPARgamma2 gene and type 2 diabetes in the Czech Republic. Furthermore, the effect of this polymorphism on phenotypic characteristics and on levels of lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides) was studied. One hundred thirty-three patients with type 2 diabetes and 97 control subjects were investigated. PCR and RFLP analysis were used for identification of individual genotypes. In the group of patients, three samples (2.26%) were identified as homozygous for the Ala/Ala genotype and 99 samples (74.44%) were homozygotes for the Pro/Pro genotype. Thirty-one samples (23.31%) were identified as Pro12Ala heterozygous. In the control group, six samples (6.19%) were homozygous for the Ala/Ala genotype and 61 samples (62.89%) were homozygotes for the Pro/Pro genotype. Thirty samples (30.93%) were identified as Pro12Ala heterozygous. The allele frequency for the Ala allele was lower in the type 2 diabetic group than in the control group (13.91% vs. 21.43%, P = 0.022). There was no difference (at P < 0.05) between the phenotypic characteristics (BMI, sex) studied in the group of patients according to the Pro12Ala genotype. There was no significant effect of the Pro12Ala polymorphism on lipid levels.
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PMID:The frequency of alleles of the Pro12Ala polymorphism in PPARgamma2 is different between healthy controls and patients with type 2 diabetes. 1558 Oct 66

Patients with gout are at a high risk for drug-induced complications associated with the use of nonsteroidal anti-inflammatory drugs due to the baseline renal and hepatic abnormalities, metabolic disturbances, and concomitant diseases, such as arterial hypertension or type 2 diabetes mellitus. In this connection, it is expedient to use safer selective cycloxygenase-2 (COG-2) inhibitors. However, there are only single reports dealing with studies of the effectiveness and safety of selective COG-2 inhibitors in gout. The study was undertaken to evaluate the effectiveness and safety of the selective COG-2 inhibitor nimesulide (nimesile) in acute gouty arthritis (GA). Twenty male patients (whose mean age was 51.1 +/- 8.4 years) with PA were examined. Seven patients were found to have monoarthritis of 1 metatarsophalangeal joint, oligoarthritis was present in 9 patients and 4 patients had polyarthritis. The history of arthritis was as long as 6 days in 16 patients and 21-30 days in 4. Nimesulide was given in a dose of 200 mg/day for at least 14 days. The time course of changes in the objective and subjective symptoms of arthritis was studied. The tolerability of the drug was evaluated by its effect on renal (the levels of creatinine and urea, creatinine clearance) and hepatic (alanine transferase (ALT), aspartate transferase (AST), gamma-glutamyltranspeptidase (gamma-GTP)) functions, and blood pressure (BP) [24-hour BP monitoring (24-h BPM) before and after treatment. There were clear positive changes in the major parameters of arthritis: the swelling index was 4.5 +/- 2.7 and 0.5 +/- 0.5 scores before and after treatment, respectively; hyperemia, 3.5 +/- 2.5 and 0.1 +/- 0. 1 scores; articular index, 3.6 +/- 2.0 and 0.7 +/- 0.6 scores; pain (visual analogue scale) when resting, 53.8 +/- 17.6 and 4.7 +/- 4.6 scores, and that when moving, 68.3 +/- 16.0 and 9.0 +/- 8.8 mm, respectively. Negative changes in the levels of creatinine and uric acid and a reduction in creatinine clearance were not observed. There were no increases in the levels of ACT, ALT, gamma-GTP. 24-h BPM did not reveal any significant changes in the mean 24-hour, mean diurnal and nocturnal variables of BP. The 24-hour BP profile became better in some patients. Thus, nimesulide is an effective and safe drug for the treatment of PA.
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PMID:[The effectiveness and safety of nimesulide (nimesile) in patients with gouty arthritis]. 1573 21

Aerobic endurance training improves insulin sensitivity, and is of great importance in the prevention and treatment of type 2 diabetes. The improvement in insulin sensitivity and cardiovascular function through exercise is highly variable among individuals, and is probably partly determined by genetic components. This study evaluated the peroxisome proliferation-activated receptor-gamma2 ( PPAR-gamma2) Pro12Ala polymorphism and the angiotensin converting enzyme ( ACE) I/D polymorphism with respect to any potential influence that these highly prevalent polymorphisms may impose on changes in insulin sensitivity and maximal aerobic capacity induced by exercise. Seventy-nine healthy first-degree relatives of type 2 diabetic patients were compared to a control group consisting of 54 subjects without any family history of type 2 diabetes. All subjects had a normal OGTT. The groups were comparable with respect to age (34 +/- 7 vs. 33 +/- 7 years), gender ((m/f) 43/36 vs. 30/24) and BMI (25.7 +/- 2.6 vs. 25.3 +/- 2.5 kg/m (2)); p (all) = NS. Furthermore, a subgroup of 29 offspring and 17 control subjects were engaged in a standardized training program lasting ten weeks. Insulin sensitivity (hyperinsulinemic euglycemic clamp technique) and VO (2)max (exhaustive exercise test) was assessed before and after the training period. We will demonstrate the allelic frequency of the Ala-allele of the Pro12Ala polymorphism to be lower in offspring to type 2 diabetic patients (13.3 %) compared to control subjects (21.3 %); p < 0.05. In offspring only, the Pro12Ala polymorphism of the PPAR-gamma2 gene appeared to enhance weight changes brought about by exercise (Deltaweight = - 0.3 +/- 1.4 kg vs. - 1.8 +/- 1.8 kg; p < 0.05; (Pro/Pro vs. Pro/Ala + Ala/Ala) - suggesting possible gene-environment or gene-gene interactions. The ACE I/D polymorphism was not of significant importance in determining the capability of responding to exercise in terms of improvement in insulin sensitivity or maximal aerobic capacity.
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PMID:Influence of the PPAR-gamma2 Pro12Ala and ACE I/D polymorphisms on insulin sensitivity and training effects in healthy offspring of type 2 diabetic subjects. 1577 27

The Gly972Arg substitution of the insulin receptor substrate-1 (IRS-1) gene and the Pro12Pro genotype of the peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene have been suggested to be associated with type 2 diabetes mellitus. In this study, the influence of these two polymorphisms on serum adiponectin concentrations was investigated. The Pro12Ala polymorphism of the PPARgamma2 gene and the Gly972Arg polymorphism of the IRS-1 gene were genotyped in 252 young Finnish servicemen. The Ala12Ala genotype of PPARgamma2 was associated with a higher adiponectin level compared to the Pro12Ala genotype (p=0.02) and the Pro12Pro genotype (p=0.02). Total (p=0.02) and low-density lipoprotein (LDL) cholesterol (p=0.03) levels were higher in subjects with the Pro12Pro genotype compared to the Pro12Ala genotype. No difference was observed in serum adiponectin level between the IRS-1 genotype groups. The subjects with X972Arg of this gene had high total and LDL cholesterol levels (p<0.05). The interaction between the PPARgamma2 and IRS-1 genes with respect to their effects on adiponectin levels was statistically significant (p=0.02). Adiponectin was significantly higher (p<0.05) in subjects who simultaneously had the Ala/Ala (PPARgamma2)+Gly/Gly (IRS-1) genotype combination compared to subjects with the Pro/Pro+Gly/Gly and Pro/Ala+Gly/Gly genotype combinations. Total and LDL cholesterol was higher (p<0.05) in subjects with Pro/Pro+X/Arg compared to subjects with the two before mentioned genotype combinations. We conclude that the Ala12Ala genotype of PPARgamma2 is associated with elevated adiponectin level, and that the PPARgamma2 and IRS-1 genes have a possible interaction in their effects on adiponectin concentration.
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PMID:Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. 1578 Nov 95


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