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)

Reduced size at birth has been proposed to be a risk factor for insulin resistance and type 2 diabetes. It is, however, not known whether this association is explained by unfavorable intrauterine environment or by specific susceptibility genotypes predisposing for both reduced fetal growth and insulin resistance and type 2 diabetes. The present study was performed to evaluate whether previously identified amino acid polymorphisms of genes that from animal models have been suggested to play important roles during fetal development are associated with alterations in size at birth. The study population comprised 380 subjects randomly recruited from a population of young Danish Caucasian individuals, aged 18-32 yr. The original data of birth length and weight for 331 of 380 subjects were obtained from the midwife records. The Gly/Arg972 of insulin receptor substrate-1 (IRS-1), the Thr/Ile130 of the hepatocyte nuclear factor-4alpha (HNF-4alpha), the Pro/Ala75 of HNF-6, and the Ile/Leu27, Ala/Val93, and Ser/Asn4s7 polymorphisms of the HNF-lalpha gene were examined for association with birth weight and length and the ponderal index. Using a generalized linear model, including gender and the genotype as fixed variables, and applying Bonferroni correction for multiple testing, we could not demonstrate any significant differences in these estimates among wild-type, heterozygous, and homozygous carriers with respect to any of the gene variants. In conclusion, common variability in the genes encoding the IRS-1, HNF-lalpha, HNF-4alpha, and HNF-6 proteins can be excluded as major factors influencing size at birth among Danish Caucasian subjects.
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PMID:Variability of the insulin receptor substrate-1, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-4alpha, and HNF-6 genes and size at birth in a population-based sample of young Danish subjects. 1094 9

Our study of patients with type 2 diabetes mellitus residing in the Paris area (Ile-de-France) aged 70 years or younger included 1 591 patients examined by national health insurance expert physicians who also filled out a self-administrated questionnaire. Their primary care physicians also answered a questionnaire (79% participation, indicating their personal implication). We found that diabetes was most often discovered during regular check-ups. Single-drug regimens were the most widely used. Sulfamides were prescribed for 77% of the patients. Among the 912 patients who were overweight (BMI > 28 Kg/m2), 34.3% were taking sulfamides alone despite the fact that metformin is recommended as the first intention drug for these patients. Blood pressure control was not satisfactory in 30% of the patients who were treated or not for high blood pressure. This proportion rose to about 50% among treated patients alone. The patients appeared to be knowledgeable about the risk of complications, particularly ocular complications. They were aware of a certain number of messages but the results would suggest difficulty in application.
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PMID:[Description of type 2 diabetes mellitus in residents of Ile-de-France aged at most 70 years]. 1101 Dec 42

Familial genetic studies of type 2 diabetes (T2DM) of different human populations, including the French Caucasians, suggested evidence for linkage of T2DM and human chromosome 20q13, a region where maps the melanocortin 3 receptor gene (MC3R). Likewise, its homologous MC4R in human obesity, MC3R gene is also a good candidate for genetic susceptibility to glucose intolerance and T2DM. We therefore undertook a molecular study to assess the role of genetic variations of this gene in a large cohort of French families with T2DM. In these patients, we identified two missense mutations in the MC3R gene: Val(81)Ile and Lys(6)Thr. These two variants, which were in complete linkage disequilibrium, were also present in nondiabetic controls. Based on association and familial linkage disequilibrium tests results, we found that these MC3R gene-coding variants were not associated with diabetes or obesity. These variants were found, however, marginally associated with insulin and glucose levels during oral glucose tolerance testing in normoglycemic subjects. Overall, the present study provides no evidence for a major role of the MC3R coding mutations underlying the genetic linkages of T2DM and the MC3R gene region on chromosome 20q13 in T2DM families from France and other geographical origins.
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PMID:Naturally occurring mutations in the melanocortin receptor 3 gene are not associated with type 2 diabetes mellitus in French Caucasians. 1139 6

Platelet levels of 19 amino acids were measured in 20 outpatients with type 1 (age [mean +/- SE], 35.5 +/- 2.0 years) and 27 with type 2 (age, 58.4 +/- 1.4 years) diabetes, and 20 young (age 33.7 +/- 1.3 years) and 20 older (age 57.4 +/- 1.5 years) healthy volunteers. Platelet levels of most amino acids tended to be lower in patients with type 1 diabetes than in healthy controls. In particular, asparagine, glycine, taurine, alanine, valine, cysteine, leucine, phenylalanine, and lysine levels, expressed as nmol/10(8) platelets, were significantly lower. Only taurine significantly decreased in patients with type 2 diabetes, whereas threonine, alanine, and isoleucine increased.
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PMID:Preliminary report: Amino acid profile in platelets of diabetic patients. 1143 75

Adiponectin, an adipocyte-derived protein, consists of collagen-like fibrous and complement C1q-like globular domains, and circulates in human plasma in a multimeric form. The protein exhibits anti-diabetic and anti-atherogenic activities. However, adiponectin plasma concentrations are low in obese subjects, and hypoadiponectinemia is associated with the metabolic syndrome, which is a cluster of insulin resistance, type 2 diabetes mellitus, hypertension, and dyslipidemia. We have recently reported a missense mutation in the adiponectin gene, in which isoleucine at position 164 in the globular domain is substituted with threonine (I164T). Subjects with this mutation showed markedly low level of plasma adiponectin and clinical features of the metabolic syndrome. Here, we examined the molecular characteristics of the mutant protein associated with a genetic cause of hypoadiponectinemia. The current study revealed (1) the mutant protein showed an oligomerization state similar to the wild-type as determined by gel filtration chromatography and, (2) the mutant protein exhibited normal insulin-sensitizing activity, but (3) pulse-chase study showed abnormal secretion of the mutant protein from adipose tissues. Our results suggest that I164T mutation is associated with hypoadiponectinemia through disturbed secretion into plasma, which may contribute to the development of the metabolic syndrome.
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PMID:Disturbed secretion of mutant adiponectin associated with the metabolic syndrome. 1278 2

Here we report the first cloned N-ethyl-nitrosourea (ENU)-derived mouse model of diabetes. GENA348 was identified through free-fed plasma glucose measurement, being more than 2 SDs above the population mean of a cohort of >1,201 male ENU mutant mice. The underlying gene was mapped to the maturity-onset diabetes of the young (MODY2) homology region of mouse chromosome 11 (logarithm of odds 6.0). Positional candidate gene analyses revealed an A to T transversion mutation in exon 9 of the glucokinase gene, resulting in an isoleucine to phenylalanine change at amino acid 366 (I366F). Heterozygous mutants have 67% of the enzyme activity of wild-type littermates (P < 0.0012). Homozygous mutants have less enzyme activity (14% of wild-type activity) and are even less glucose tolerant. The GENA348 allele is novel because no mouse or human diabetes studies have described a mutation in the corresponding amino acid position. It is also the first glucokinase missense mutation reported in mice and is homozygous viable, unlike the global knockout mutations. This work demonstrates that ENU mutagenesis screens can be used to generate models of complex phenotypes, such as type 2 diabetes, that are directly relevant to human disease.
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PMID:A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene. 1516 64

Class I alpha phosphatidylinositol (PI) 3-kinase is an important enzyme in the early insulin signaling cascade, and plays a key role in insulin-mediated glucose transport. Despite extensive investigation, the genes responsible for the development of the common forms of type 2 diabetes remain unknown. This study was performed to identify variants in the coding region of p85 alpha, the regulatory subunit of PI 3-kinase. Fibroblasts from skin biopsies from type 2 diabetics and controls were established to address this issue. P85 alpha cDNA was sequenced, and a single point mutation at codon 326 was found. This mutation resulted in a homozygous missense amino acid change Met --> Ile in one subject with type 2 diabetes and heterozygous variant in two other diabetic patients and one with severe insulin resistance. Interestingly, those patients revealed an impaired insulin-mediated insulin receptor substrate (IRS)-1 binding to p85 alpha without any alteration in IRS-2/p85 alpha association. Furthermore, IRS-1, IRS-2, p85 alpha and MAPK protein contents were not significantly changed, and neither were MAPK or Akt phosphorylation. We conclude from our data that this variant may have only minor impact on signaling events; however, in combination with variants in other genes encoding signaling proteins, this may have a functional impact on early insulin signaling.
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PMID:Met326Ile aminoacid polymorphism in the human p85 alpha gene has no major impact on early insulin signaling in type 2 diabetes. 1552 93

TNF-alpha is a mediator of insulin resistance in sepsis, obesity, and type 2 diabetes and is known to impair insulin signaling in adipocytes. Akt (protein kinase B) is a crucial signaling mediator for insulin. In the present study we examined the posttranslational mechanisms by which short-term (<6-h) exposure of 3T3-L1 adipocytes to TNF-alpha decreases Akt levels. TNF-alpha treatment both increased the ubiquitination of Akt and decreased its protein level. The decrease in protein was associated with the presence of an (immunoreactive) Akt fragment after TNF-alpha treatment, indicative of Akt cleavage. The broad-spectrum caspase inhibitor t-butoxycarbonyl-Asp(O-Me)-fluoromethyl ketone markedly suppressed these effects of TNF-alpha. The caspase-6 inhibitor Z-Val-Glu(OMe)-Ile-Asp(OMe)-CH(2)F potently suppressed Akt ubiquitination, degradation, and fragment formation, whereas the proteasome inhibitor Z-Leu-Leu-Leu-CHO modestly attenuated the decline in Akt levels. Exposure to TNF-alpha also enhanced the association of Akt with an E3 ligase activity. Adipocytes preexposed to TNF-alpha for 5 h and then stimulated with insulin for 30 min exhibited decreased levels of Akt, phosphorylated Akt, as well as phosphorylated Mdm2, which is a known direct substrate of Akt, and glucose uptake. Caspase inhibition attenuated these inhibitory effects of TNF-alpha. Collectively, our results suggest that TNF-alpha induces the caspase-dependent degradation of Akt via the cleavage and ubiquitination of Akt, which results in its degradation through the 26S proteasome. Furthermore, the caspase- and proteasome-mediated degradation of Akt due to TNF-alpha exposure leads to impaired Akt-dependent insulin signaling in adipocytes. These findings expand the mechanism by which TNF-alpha impairs insulin signaling.
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PMID:Tumor necrosis factor-{alpha} decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt. 1574 49

Increased plasma levels of branched-chain amino-acids (BCAA) have been demonstrated in poorly controlled diabetes mellitus, and related to absolute or relative insulin deficiency. To study the pathogenesis of this alteration, the elimination of BCAA from plasma was measured in 8 patients with non-obese type 2 diabetes mellitus and in 8 age-matched control subjects during steady-state BCAA concentrations induced by a primed-continuous infusion. Fasting BCAA levels were increased by 40-50% in patients with diabetes. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady-state concentration, were reduced by 20% in diabetics, despite 50% hyperinsulinemia (P < 0.01). Basal BCAA levels and BCAA clearance were negatively correlated (r(2) = 0.46 - 0.56). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were normal in diabetics, and there was no difference in the apparent volumes of distribution of BCAA. The increased basal concentration of BCAA in poorly controlled type 2 diabetics (693 [SD 114; n = 8] mumol/l vs 479 [88; n = 8] in controls (P < 0.005) is attributable to changes in plasma clearances, without any change in the efflux of BCAA into plasma. This may be due to insulin resistance.
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PMID:Elimination of infused branched-chain amino-acids from plasma of patients with non-obese type 2 diabetes mellitus. 1683 4

Amyloid-associated diseases affect millions of people worldwide. Phenol red exhibits modest inhibition toward fibril formation of human Islet amyloid polypeptide (hIAPP) and its toxicity, which is associated with type II diabetes mellitus. However, the molecular level mechanisms of interactions remain elusive. The binding of phenol red molecules to the protofibrils of an amyloidogenic fragment (NFGAIL) of hIAPP has been investigated by molecular dynamics simulations with explicit solvent. The phenol red molecules were observed to bind primarily along either beta-sheet stacking or beta-strand directions. Through its three aromatic rings, the phenol red molecule preferentially interacted with the hydrophobic side chains of Phe, Leu, and Ile; and the polar sulfone and hydroxyl groups were mainly exposed in solvent. Thus, phenol red improves the solubility of the early protofibrils and represses further growth. Interestingly, there was no obvious preference toward the aromatic Phe residue in comparison to the hydrophobic Leu or Ile residues. The lack of binding along the hydrogen bond direction indicates that phenol red does not directly block the beta-sheet extension. Further free energy analysis suggested that a phenol red analog may potentially improve the binding affinity.
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PMID:Phenol red interacts with the protofibril-like oligomers of an amyloidogenic hexapeptide NFGAIL through both hydrophobic and aromatic contacts. 1693 48


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