Peroxisome proliferator-activated receptor-g coactivator-1 (PGC-1) is a novel transcriptional co-activator of a series of nuclear receptors including peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor involved in adipogenesis and a functional receptor for thiazolidinediones [1,2]. Similarly, PGC-1 is a coactivator of peroxisome proliferator-activated receptor-a (PPAR-a), which plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid beta-oxidation enzymes [3]. Studies in cultured muscle-cell lines show that PGC-1 stimulates mitochondrial biogenesis and respiration through an induction of uncoupling protein 2 and through regulation of the nuclear respiratory factors [2]. Thus, PGC-1 is a key factor in the stimulation of adaptive thermogenesis, e. g. during high caloric diets or cold exposure. It has recently Diabetologia (2001)
The E23K polymorphism of the pancreatic -cell ATPsensitive K ؉ (K ATP ) channel subunit Kir6.2 (KCNJ11) is associated with type 2 diabetes in whites, and a recent in vitro study of the E23K variant suggests that the association to diabetes might be explained by a slight inhibition of serum insulin release. In a study comprising 519 unrelated glucose-tolerant subjects, we addressed the question as to whether the E23K variant was related to reduced serum insulin release during an oral glucose tolerance test (OGTT). Furthermore, the polymorphism was examined in a case-control study comprising 803 type 2 diabetic patients and 862 glucosetolerant control subjects. The E23K variant was associated with significant reductions in the insulinogenic index (P ؍ 0.022) and serum insulin levels under the response curve during an OGTT (0 -120 min) (P ؍ 0.014) as well as with an increase in BMI (P ؍ 0.013). In the present study, the association of the E23K polymorphism with type 2 diabetes was not significant (P ؍ 0.26). However, the K23K genotype significantly associated with type 2 diabetes in a meta-analysis of white case and control subjects (n ؍ 2,824, odds ratio [OR] 1.49, P ؍ 0.00022). In conclusion, the widespread E23K polymorphism may have a diabetogenic effect by impairing glucose-induced insulin release and increasing BMI.
The detailed data presented reinforce the contention that the health profile of non-participants is typically worse than that of participants. The results also indicate that while data from public registers give easily accessible information about non-participants, these crude proxy measures of health may not be enough to document representativeness.
Type II (non-insulin-dependent) diabetes mellitus is phenotypically and genetically a heterogeneous disorder resulting from defects in insulin secretion and insulin action [1]. Mutations in several genes linked to monogenic forms of Type II diabetes have been identified [2±7] and recently, a common G®A transition within intron 3 of the CAPN10 gene (UCSNP-43) in combination with specific polymorphisms in other locations within CAPN10 was associated with Type II diabetes [8]. However, in the vast majority of Type II diabetic patients the genetic mechanism and the pathogenesis behind the disease are still not clear.The peroxisome proliferator-activated receptor-g (PPAR-g) is a transcription factor, involved in adipogenesis and in the regulation of adipocyte gene expression [9]. PPARg exists in three different isoforms [10]. Two mutations in the ligand-binding domain of PPAR-g, Pro467Leu and Val290Met, were found in Diabetologia (2001) Abstract Aims/hypothesis. We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-g2 (PPAR-g2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non-insulin-dependent) diabetes mellitus among Scandinavian Caucasians.Methods. The Pro12Ala polymorphism was examined using PCR-RFLP. Whole-body insulin sensitivity measured under hyperinsulinaemic-euglycaemic conditions was estimated in a population-based sample of 616 glucose tolerant Swedish Caucasian men at age 70. In addition, insulin sensitivity index was measured using IVGTT and Bergman minimal modelling in a population-based sample of 364 young healthy Danish Caucasians. Finally, we evaluated whether the polymorphism predicted Type II diabetes and IGT in 841 seventy-year-old Swedish men. A case-control study was carried out in 654 unrelated Danish Type II diabetic patients and 742 Danish glucose tolerant subjects matched for age and sex.
In the present study, we tested the hypothesis that variability in the protein tyrosine phosphatase-1B (PTP-1B) gene is associated with type 2 diabetes. Using single-strand conformational polymorphism analysis, we examined cDNA of PTP-1B from 56 insulin-resistant patients with type 2 diabetes as well as cDNA from 56 obese patients. Four silent variants, (NT CGA-->CGG) R199R, (NT CCC-->CCT) P303P, 3'UTR+104insG, and 3'UTR+86T-->G, and one missense variant, P387L, were found. Subsequent analysis on genomic DNA revealed two intron variants, IVS9+57C-->T and IVS9+58G-->A, and two missense variants, G381S and T420M. The G381S and 3'UTR+104insG insertion variants were not associated with type 2 diabetes. In an association study, the P387L variant was found in 14 of 527 type 2 diabetic subjects (allelic frequency 1.4%, 0.4-2.4 CI) and in 5 of 542 glucose-tolerant control subjects (allelic frequency 0.5%, CI 0.1-1.1), showing a significant association to type 2 diabetes (P = 0.036). In vitro, p34 cell division cycle (p34(cdc2)) kinase-directed incorporation of [gamma-(32)P]ATP was reduced in a mutant peptide compared with native peptide (387P: 100% vs. 387L: 28.4 +/- 5.8%; P = 0.0012). In summary, a rare P387L variant of the PTP-1B gene is associated with a 3.7 (CI 1.26-10.93, P = 0.02) genotype relative risk of type 2 diabetes in the examined population of Danish Caucasian subjects and results in impaired in vitro serine phosphorylation of the PTP-1B peptide.
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