Dataset Information

Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle.

ABSTRACT:

Aims/hypothesis

Homozygous staggerer (sg/sg) mice, which have decreased and dysfunctional Ror? (also known as Rora) expression in all tissues, display a lean and dyslipidaemic phenotype. They are also resistant to (high fat) diet-induced obesity. We explored whether retinoic acid receptor-related orphan receptor (ROR) ? action in skeletal muscle was involved in the regulation of glucose metabolism.

Methods

We used a three-armed genomic approach, including expression profiling, ingenuity analysis and quantitative PCR validation to identify the signalling pathway(s) in skeletal muscle that are perturbed in sg/sg mice. Moreover, western analysis, functional insulin and glucose tolerance tests, and ex vivo glucose uptake assays were used to phenotypically characterise the impact of aberrant v-AKT murine thymoma viral oncogene homologue (AKT) signalling.

Results

Homozygous and heterozygous (sg/sg and sg/+) animals exhibited decreased fasting blood glucose levels, mildly improved glucose tolerance and increased insulin sensitivity. Illumina expression profiling and bioinformatic analysis indicated the involvement of ROR? in metabolic disease and phosphatidylinositol 3-kinase-AKT signalling. Quantitative PCR and western analysis validated increased AKT2 (mRNA and protein) and phosphorylation in sg/sg mice in the basal state. This was associated with increased expression of Tbc1d1 and Glut4 (also known as Slc2a4) mRNA and protein. Finally, in agreement with the phenotype, we observed increased (absolute) levels of AKT and phosphorylated AKT (in the basal and insulin stimulated states), and of (ex vivo) glucose uptake in skeletal muscle from sg/sg mice relative to wild-type littermates.

Conclusions/interpretation

We propose that Ror? plays an important role in regulation of the AKT2 signalling cascade, which controls glucose uptake in skeletal muscle.

SUBMITTER: Lau P

PROVIDER: S-EPMC3071927 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Publications

Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle.

Lau P P Fitzsimmons R L RL Pearen M A MA Watt M J MJ Muscat G E O GE

Diabetologia 20110129 5

<h4>Aims/hypothesis</h4>Homozygous staggerer (sg/sg) mice, which have decreased and dysfunctional Rorα (also known as Rora) expression in all tissues, display a lean and dyslipidaemic phenotype. They are also resistant to (high fat) diet-induced obesity. We explored whether retinoic acid receptor-related orphan receptor (ROR) α action in skeletal muscle was involved in the regulation of glucose metabolism.<h4>Methods</h4>We used a three-armed genomic approach, including expression profiling, ing ...[more]

PMID: 21279323

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Project description:BackgroundThe triglyceride-glucose index (TyG) has been proposed as a surrogate marker of insulin resistance, which is a typical trait of pregnancy. However, very few studies analyzed TyG performance as marker of insulin resistance in pregnancy, and they were limited to insulin resistance assessment at fasting rather than in dynamic conditions, i.e., during an oral glucose tolerance test (OGTT), which allows more reliable assessment of the actual insulin sensitivity impairment. Thus, first aim of the study was exploring in pregnancy the relationships between TyG and OGTT-derived insulin sensitivity. In addition, we developed a new version of TyG, for improved performance as marker of insulin resistance in pregnancy.MethodsAt early pregnancy, a cohort of 109 women underwent assessment of maternal biometry and blood tests at fasting, for measurements of several variables (visit 1). Subsequently (26 weeks of gestation) all visit 1 analyses were repeated (visit 2), and a subgroup of women (84 selected) received a 2 h-75 g OGTT (30, 60, 90, and 120 min sampling) with measurement of blood glucose, insulin and C-peptide for reliable assessment of insulin sensitivity (PREDIM index) and insulin secretion/beta-cell function. The dataset was randomly split into 70% training set and 30% test set, and by machine learning approach we identified the optimal model, with TyG included, showing the best relationship with PREDIM. For inclusion in the model, we considered only fasting variables, in agreement with TyG definition.ResultsThe relationship of TyG with PREDIM was weak. Conversely, the improved TyG, called TyGIS, (linear function of TyG, body weight, lean body mass percentage and fasting insulin) resulted much strongly related to PREDIM, in both training and test sets (R2 > 0.64, p < 0.0001). Bland-Altman analysis and equivalence test confirmed the good performance of TyGIS in terms of association with PREDIM. Different further analyses confirmed TyGIS superiority over TyG.ConclusionsWe developed an improved version of TyG, as new surrogate marker of insulin sensitivity in pregnancy (TyGIS). Similarly to TyG, TyGIS relies only on fasting variables, but its performances are remarkably improved than those of TyG.

Dataset Information

Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle.

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Publications

Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle.

Similar Datasets

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