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. 2019 Feb:40:67-76.
doi: 10.1016/j.ebiom.2018.12.040. Epub 2019 Jan 11.

PYY plays a key role in the resolution of diabetes following bariatric surgery in humans

Claudia Guida  1 , Sam D Stephen  1 , Michael Watson  2 , Niall Dempster  1 , Pierre Larraufie  3 , Thomas Marjot  2 , Tamsin Cargill  2 , Lisa Rickers  4 , Michael Pavlides  5 , Jeremy Tomlinson  1 , Jeremy F L Cobbold  2 , Chun-Mei Zhao  6 , Duan Chen  6 , Fiona Gribble  3 , Frank Reimann  3 , Richard Gillies  4 , Bruno Sgromo  4 , Patrik Rorsman  1 , John D Ryan  7 , Reshma D Ramracheya  8
Affiliations

PYY plays a key role in the resolution of diabetes following bariatric surgery in humans

Claudia Guida et al. EBioMedicine. 2019 Feb.

Abstract

Background: Bariatric surgery leads to early and long-lasting remission of type 2 diabetes (T2D). However, the mechanisms behind this phenomenon remain unclear. Among several factors, gut hormones are thought to be crucial mediators of this effect. Unlike GLP-1, the role of the hormone peptide tyrosine tyrosine (PYY) in bariatric surgery in humans has been limited to appetite regulation and its impact on pancreatic islet secretory function and glucose metabolism remains under-studied.

Methods: Changes in PYY concentrations were examined in obese patients after bariatric surgery and compared to healthy controls. Human pancreatic islet function was tested upon treatment with sera from patients before and after the surgery, in presence or absence of PYY. Alterations in intra-islet PYY release and insulin secretion were analysed after stimulation with short chain fatty acids (SCFAs), bile acids and the cytokine IL-22.

Findings: We demonstrate that PYY is a key effector of the early recovery of impaired glucose-mediated insulin and glucagon secretion in bariatric surgery. We establish that the short chain fatty acid propionate and bile acids, which are elevated after surgery, can trigger PYY release not only from enteroendocrine cells but also from human pancreatic islets. In addition, we identify IL-22 as a new factor which is modulated by bariatric surgery in humans and which directly regulates PYY expression and release.

Interpretation: This study shows that some major metabolic benefits of bariatric surgery can be emulated ex vivo. Our findings are expected to have a direct impact on the development of new non-surgical therapy for T2D correction.

Keywords: Bariatric surgery; Diabetes; Gut hormones; IL-22; PYY; Pancreatic hormone secretion.

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Conflict of interest statement

Dr. Dempster reports grants from the University of Oxford Novo Nordisk Clinical Research Fellowship, during the conduct of the study. Dr. Larraufie reports grants from Wellcome trust and UK government (MRC), during the conduct of the study. Dr. Gribble reports grants from Wellcome Trust and UK Government (MRC), during the conduct of the study; grants from MedImmune, grants from Wellcome Trust, grants from UK government (MRC and BBSRC), personal fees from Kallyope (New York), outside the submitted work; Dr. Reimann reports grants from Wellcome Trust and UK Government (MRC), during the conduct of the study; grants from MedImmune, grants from Wellcome Trust, grants from UK government (MRC and BBSRC), outside the submitted work. Dr. Cobbold reports personal fees from NovoNordisk, personal fees from Intercept, outside the submitted work. Dr. Pavlides reports other from Oxford NIHR Biomedical Research Centre, during the conduct of the study; other from Perspectum Diagnostics, outside the submitted work. All the other authors have nothing to disclose.

Figures

Fig. 1
Fig. 1
Changes in PYY concentrations in human serum samples. Serum total PYY in healthy volunteers (n = 20) and in patients before and 6 months after bariatric surgery (n = 25). Data are presented as mean ± SEM. (One-way ANOVA for multiple comparison) ⁎P < 0.05 for indicated comparison.
Fig. 2
Fig. 2
PYY mediates metabolic benefits of bariatric surgery. Insulin (a) and glucagon (c) secretion from human islets (n = 3 donors n = 3) treated for 72 h with serum from patients before (pre) and 6 months after surgery (post) in absence or presence of exendin [[9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]] or PYY antibody. Secretion was measured in islets stimulated with 1 mM (black bars) or 20 mM glucose (grey bars). Data are presented as percentage of basal secretion (mean ± SEM as percentage of content). Insulin (b) and glucagon (d) content in human islets treated for 72 h with serum from patients before (pre) and 6 months after surgery (post). (One-way ANOVA for multiple comparison) ⁎P < 0.05, ⁎⁎P < 0.01for indicated comparison.
Fig. 3
Fig. 3
Propionate and bile acids induce pancreatic PYY release. Human (donors n = 9) (a, c) and mouse (mice n = 3) (b, d) islets were incubated with 1 mM propionate, butyrate or acetate or 30 μM GPBAR-A for the indicated time length (included in culture medium). Ratio between total PYY in the medium and in the islets is reported. ⁎⁎⁎P < 0.001, ⁎P < 0.05 for indicated comparison.
Fig. 4
Fig. 4
IL-22 levels increase after bariatric surgery. Plasma IL-22 (a), IL-6 (b) and IL-23 (c) in healthy volunteers (n = 20) and in patients before and 6 months after bariatric surgery (n = 25). Data are presented as mean ± SEM. (One-way ANOVA for multiple comparison) ⁎P < 0.05 for indicated comparison.
Fig. 5
Fig. 5
IL-22 induces PYY gene expression and PYY secretion in pancreatic islets and primary colonic culture. (a, b) Expression of PYY gene (a) and protein (b) in colonic primary mouse culture non-treated (NT) or exposed to 100 ng/mL IL-22 for 6, 24, 48 and 72 h (mice n = 4). Data are presented as relative Pyy expression/protein to control (mean ± SEM). Human (b) and mouse (c) islets were treated with 100 ng/mL IL-22 for 24 h. Ratio between total PYY in the medium and in the islets is reported. ⁎P < 0.05 for indicated comparison.
Fig. 6
Fig. 6
Increased PYY levels in circulation and in islets occur via several factors and jointly contribute to restoration of islet function after bariatric surgery. GSIS = glucose-stimulated insulin secretion.
See this image and copyright information in PMC

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