Peptide-YY3-36/glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic β-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries

Molecular Metabolism

Arthur Suckow¹  Urmas Roostalu¹  Owen P. McGuinness¹  Jotham Austin²  Siobhan O'Brien³  Sadichha Sitaula⁴  Rhianna C. Laker⁵  Jens Christian Nielsen⁵  Sara Rubek Sejthen⁵  David C. Hornigold⁵  Christopher J. Rhodes⁵  James L. Trevaskis⁶  Louise Lantier⁷  Pernille Barkholt⁷  Ditte Dencker Thorbek⁷  Sarah Will⁸  Stephanie Oldham⁸  Benji M. Gill⁸  Philip Newton⁸  Victor G. Howard⁸  Nicole Burmeister⁸  Isabelle Sermadiras⁹  Jacob Hecksher-Sørensen⁹  Joseph S. Grimsby⁹  Brandon B. Boland⁹  Jacqueline Naylor⁹ 

[1] Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK;DTX Pharma, San Diego, CA, USA;Gubra ApS, Horsholm, Denmark;PRECISIONscientia, Yardley, PA, USA;Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK;Roche, Penzberg, Germany;Antibody and Protein Engineering, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA;Gubra ApS, Horsholm, Denmark;Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA;

关键词: Diabetes;    Obesity;    Insulin sensitivity;    Pancreatic β-cell;    Hypothalamus;    Glucagon-like peptide-1 (GLP-1);   

DOI  :  

来源: DOAJ

【 摘 要 】

Objective: Obesity-linked type 2 diabetes (T2D) is a worldwide health concern and many novel approaches are being considered for its treatment and subsequent prevention of serious comorbidities. Co-administration of glucagon like peptide 1 (GLP-1) and peptide YY3-36 (PYY3-36) renders a synergistic decrease in energy intake in obese men. However, mechanistic details of the synergy between these peptide agonists and their effects on metabolic homeostasis remain relatively scarce. Methods: In this study, we utilized long-acting analogues of GLP-1 and PYY3-36 (via Fc-peptide conjugation) to better characterize the synergistic pharmacological benefits of their co-administration on body weight and glycaemic regulation in obese and diabetic mouse models. Hyperinsulinemic-euglycemic clamps were used to measure weight-independent effects of Fc-PYY3-36 + Fc-GLP-1 on insulin action. Fluorescent light sheet microscopy analysis of whole brain was performed to assess activation of brain regions. Results: Co-administration of long-acting Fc-IgG/peptide conjugates of Fc-GLP-1 and Fc-PYY3-36 (specific for PYY receptor-2 (Y2R)) resulted in profound weight loss, restored glucose homeostasis, and recovered endogenous β-cell function in two mouse models of obese T2D. Hyperinsulinemic-euglycemic clamps in C57BLKS/J db/db and diet-induced obese Y2R-deficient (Y2RKO) mice indicated Y2R is required for a weight-independent improvement in peripheral insulin sensitivity and enhanced hepatic glycogenesis. Brain cFos staining demonstrated distinct temporal activation of regions of the hypothalamus and hindbrain following Fc-PYY3-36 + Fc-GLP-1R agonist administration. Conclusions: These results reveal a therapeutic approach for obesity/T2D that improved insulin sensitivity and restored endogenous β-cell function. These data also highlight the potential association between the gut–brain axis in control of metabolic homeostasis.

【 授权许可】

Unknown