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. 2015 Apr 13;10(4):e0120084.
doi: 10.1371/journal.pone.0120084. eCollection 2015.

Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal

Mimi Z Chen  1 , Claire A Hudson  1 , Emma E Vincent  2 , David A R de Berker  3 , Margaret T May  4 , Ingeborg Hers  5 , Colin M Dayan  6 , Robert C Andrews  1 , Jeremy M Tavaré  2
Affiliations

Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal

Mimi Z Chen et al. PLoS One. .

Abstract

Aims: Weight-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 methods: The 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/m(2)) 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.

Results: Pre-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).

Conclusions: Our 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.

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Conflict of interest statement

Competing Interests: RCA received honoraria for presenting at education days from GlaxoSmithKline, Novo Nordisk, Sanofi-Aventis, and Lilly, as well as travel expenses from Sanofi-Aventis to attend the European Association for the Study of Diabetes annual meeting in 2011. MZC received speaker honoraria for education events from Novo Nordisk, Bristol-Myers Squibb and AstraZeneca, as well as travel expenses from Sanofi-Aventis, Lilly, and Novo Nordisk. JMT and IH received funding from AstraZeneca, which, in part, supported the salary and consumables costs of EEV for this study. MTM has received funding from GlaxoSmithKline (in 2001 for work on HIV) and grants from MRC UK and NIH. CMD received consultancy fees from GlaxoSmithKline and Medtronic Advisory, speaker’s fees from Novo Nordisk and Bristol-Myers Squibb, travel expenses from Medtronic, and is named on a patent held by Novartis. The other authors have no competing interests to declare. The authors confirm that none of these interests alter their adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Glucose disposal rates in lean and obese volunteers before and after surgery.
A comparison of glucose concentration (panel A), insulin concentrations (panel B) and glucose disposal (panel C), between lean (filled triangles) and obese volunteers before (open circles; pre-op) and after (filled squares; post-op) surgery, measured during a 10 hour hyperinsulinaemic euglycaemic clamp. Insulin infusion rates of 0, 0.5, 1, 2 and 5 mU kg-1 min-1 were used. Data points represent the mean ± SEM where * represents P<0.05 determined by unpaired t tests, between lean and pre-op obese volunteers; + represents P<0.05 determined by unpaired t tests between lean and post-op obese volunteers; # represents P<0.05 determined by paired t tests between pre-op and post-op obese volunteers. Glucose disposal rates were different between lean and obese volunteers (MANCOVA, P<0.001), and in obese volunteers before and after surgery (MANCOVA, P<0.05).
Fig 2
Fig 2. Summary of glucose disposal rates and insulin signalling in lean and obese volunteers, pre and post weight loss surgery.
A comparison of glucose disposal (panel A), phosphorylation of Akt on Thr308 (panel B), phosphorylation of Akt on Ser473 (panel C) and phosphorylation of PRAS40 on T426 (panel D) between lean (filled triangles) and obese volunteers before (open circles; pre-op) and after (filled squares; post-op) surgery. The glucose disposal was measured during a 10 hour hyperinsulinaemic euglycaemic clamp with insulin infusion rates of 0.2, 0.5, 1, 2 and 5 mU kg-1 min-1. Data points represent the mean ± SEM with the glucose disposal plotted against the mean insulin concentration achieved at each insulin infusion rate.
Fig 3
Fig 3. Insulin signalling in obese volunteers, pre and post weight loss surgery.
Obese volunteers (pre and post-op) underwent a 3-hour euglycaemic hyperinsulinaemic clamp and muscle biopsies were taken at fasting (0) and insulin infusion rates predicted to achieve half maximal (GDR50) and maximal (GDR100) rates of glucose disposal. The extent of phosphorylation of Akt on Thr308, Ser473 and PRAS40 on T246 was determined by western blotting. The results shown are from a single individual, but are representative of the eight obese volunteers [see Materials and Methods].
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References

    1. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight-Gain as a Risk Factor for Clinical Diabetes-Mellitus in Women. Annals of internal medicine. 1995;122(7):481–6. - PubMed
    1. Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008;294(1):E15–26. - PubMed
    1. Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA. Obesity and insulin resistance in humans: a dose-response study. Metabolism. 1990;39(5):452–9. - PubMed
    1. Dugani CB, Klip A. Glucose transporter 4: cycling, compartments and controversies. EMBO Rep. 2005;6(12):1137–42. - PMC - PubMed
    1. Watson RT, Pessin JE. Bridging the GAP between insulin signaling and GLUT4 translocation. Trends in Biochemical Sciences. 2006;31(4):215–22. - PubMed

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