Abstract
AimsWeight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB), and compared this to lean volunteers.Materials and MethodsThe hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3±2.2 kg/m2) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7±0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity.ResultsPre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001). Weight-loss of 29.9±4 kg after surgery significantly improved GDR50 (P=0.004) but not GDR100 (P=0.3). These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001). Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA), and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA), and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively).ConclusionsOur data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.
Highlights
Weight gain is a major risk factor for the development of Type 2 Diabetes (T2DM) and the relative risk increases dramatically with even a small increase in weight [1]
Our data show that Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal
This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss
Summary
Weight gain is a major risk factor for the development of Type 2 Diabetes (T2DM) and the relative risk increases dramatically with even a small increase in weight [1]. Insulin-stimulated glucose uptake in skeletal muscle and adipocytes tissues is impaired in obesity and T2DM, causing peripheral insulin resistance (IR). Insulin resistant obese individuals have reduced insulin sensitivity and maximal insulin-stimulated glucose uptake when compared to lean individuals [2, 3]. Insulin increases glucose uptake into muscle and adipose tissue by promoting the translocation of GLUT4 (glucose transporter isoform 4) from the cell interior to the plasma membrane [4, 5]. The fact that GLUT4 expression is not reduced in those with insulin resistance, such as in the obese and T2DM [6, 7], suggests that the major underlying defects in this condition are likely to lie in the insulin signal transduction pathways and/or the translocation of GLUT4 to the plasma membrane in skeletal muscle. Reduction in insulin stimulated phosphorylation of the insulin receptor and IRS-1, and reduced activity of PI3-kinase in T2DM suggest that defective insulin signalling may be, at least in part, responsible for insulin resistance [8]
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