4.7 Article

Benefits of Sustained Upregulated Unimolecular GLP-1 and CCK Receptor Signalling in Obesity-Diabetes

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FRONTIERS IN ENDOCRINOLOGY
卷 12, 期 -, 页码 -

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FRONTIERS MEDIA SA
DOI: 10.3389/fendo.2021.674704

关键词

GLP-1; exendin-4; CCK-8; diabetes; obesity

资金

  1. Department for the Economy, Northern Ireland
  2. European Foundation for the Study of Diabetes (Lilly European Diabetes Research Programme)

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The combined activation of GLP-1 and CCK1 receptors through [Lys(12)Pal]Ex-4/CCK showed enhanced beneficial effects on pancreatic beta-cells, leading to improved insulin secretion and glucose homeostasis in vitro and in mice models. This hybrid peptide therapy also resulted in reductions in energy intake and body weight, as well as improvements in glucose tolerance, insulin responsiveness, and pancreatic islet morphology, highlighting its potential for treating obesity-related diabetes.
Combined activation of GLP-1 and CCK1 receptors has potential to synergistically augment the appetite-suppressive and glucose homeostatic actions of the individual parent peptides. In the current study, pancreatic beta-cell benefits of combined GLP-1 and CCK1 receptor upregulation were established, before characterising bioactivity and antidiabetic efficacy of an acylated dual-acting GLP-1/CCK hybrid peptide, namely [Lys(12)Pal]Ex-4/CCK. Both exendin-4 and CCK exhibited (p<0.001) proliferative and anti-apoptotic effects in BRIN BD11 beta-cells. Proliferative benefits were significantly (p<0.01) augmented by combined peptide treatment when compared to either parent peptide alone. These effects were linked to increases (p<0.001) in GLUT2 and glucokinase beta-cell gene expression, with decreased (p<0.05-p<0.001) expression of NF kappa B and BAX. [Lys(12)Pal]Ex-4/CCK exhibited prominent insulinotropic actions in vitro, coupled with beneficial (p<0.001) satiety and glucose homeostatic effects in the mice, with bioactivity evident 24 h after administration. Following twice daily injection of [Lys(12)Pal]Ex-4/CCK for 28 days in diabetic high fat fed (HFF) mice with streptozotocin (STZ)-induced compromised beta-cells, there were clear reductions (p<0.05-p<0.001) in energy intake and body weight. Circulating glucose was returned to lean control concentrations, with associated increases (p<0.001) in plasma and pancreatic insulin levels. Glucose tolerance and insulin secretory responsiveness were significantly (p<0.05-p<0.001) improved by hybrid peptide therapy. In keeping with this, evaluation of pancreatic histology revealed restoration of normal islet alpha- to beta-cell ratios and reduction (p<0.01) in centralised islet glucagon staining. Improvements in pancreatic islet morphology were associated with increased (p<0.05) proliferation and reduced (p<0.001) apoptosis of beta-cells. Together, these data highlight the effectiveness of sustained dual GLP-1 and CCK1 receptor activation by [Lys(12)Pal]Ex-4/CCK for the treatment of obesity-related diabetes.

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