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Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase.

Ruiz-Alcaraz AJ, Lipina C, Petrie JR, Murphy MJ, Morris AD, Sutherland C, Cuthbertson DJ - PLoS ONE (2013)

Bottom Line: The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity.However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions.In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia, Spain.

ABSTRACT
Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20-37 kg/m(2)). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min(-1).m(-2).), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR.

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Relationship between whole body insulin sensitivity and body mass index, lean body mass and percentage fat mass.Whole body insulin sensitivity (M value; mg/kg/min) and A) body mass index (kg/m2), B) lean body mass (kg) and C) percentage fat mass.
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pone-0056928-g001: Relationship between whole body insulin sensitivity and body mass index, lean body mass and percentage fat mass.Whole body insulin sensitivity (M value; mg/kg/min) and A) body mass index (kg/m2), B) lean body mass (kg) and C) percentage fat mass.

Mentions: There was a highly significant inverse correlation between the whole body insulin sensitivity, M value and BMI (r = −0.85; p<0.0001), lean body mass (r = −0.8; p = 0.02) and percentage fat mass (r = −.68; p = 0.01) (Figure 1), confirming that the lean patients were insulin-sensitive and that there was an increasing degree of IR relative to increasing obesity.


Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase.

Ruiz-Alcaraz AJ, Lipina C, Petrie JR, Murphy MJ, Morris AD, Sutherland C, Cuthbertson DJ - PLoS ONE (2013)

Relationship between whole body insulin sensitivity and body mass index, lean body mass and percentage fat mass.Whole body insulin sensitivity (M value; mg/kg/min) and A) body mass index (kg/m2), B) lean body mass (kg) and C) percentage fat mass.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585240&req=5

pone-0056928-g001: Relationship between whole body insulin sensitivity and body mass index, lean body mass and percentage fat mass.Whole body insulin sensitivity (M value; mg/kg/min) and A) body mass index (kg/m2), B) lean body mass (kg) and C) percentage fat mass.
Mentions: There was a highly significant inverse correlation between the whole body insulin sensitivity, M value and BMI (r = −0.85; p<0.0001), lean body mass (r = −0.8; p = 0.02) and percentage fat mass (r = −.68; p = 0.01) (Figure 1), confirming that the lean patients were insulin-sensitive and that there was an increasing degree of IR relative to increasing obesity.

Bottom Line: The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity.However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions.In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, University of Murcia, Murcia, Spain.

ABSTRACT
Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20-37 kg/m(2)). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min(-1).m(-2).), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR.

Show MeSH
Related in: MedlinePlus