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

Abstract

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 [Lys12Pal]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 NFκB and BAX. [Lys12Pal]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 [Lys12Pal]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 [Lys12Pal]Ex-4/CCK for the treatment of obesity-related diabetes.

The Association between Peptide Hormones with Obesity and Insulin Resistance Markers in Lean and Obese Individuals in the United Arab Emirates

“…CCK-resistance in obesity is evident, making obese individuals less sensitive to CCK’s satiety effect [ 58 ]. The biological action profile of CCK has strong parallels with those of GLP-1 [ 56 ], and a combined activation of their receptors induces body-weight reduction and blood-glucose control [ 59 ].…”

Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

“…In this regard, administration of the beta-cell toxin, streptozotocin (STZ), can counter beta-cell compensation and prevent such innate adaptations ( Furman 2015 ). Thus, HFF mice with STZ-induced compromised beta-cells are characterised by obstruction of the classical beta-cell hypertrophy in response to prolonged high-fat feeding ( Tanday et al 2021 ). Therefore, this HFF-STZ murine model represents an ideal tool to fully explore the positive effects of peptide-based GCGR antagonists in obesity-driven forms of diabetes, where restoration of functional beta-cell mass would be highly advantageous.…”

“…Therefore, this HFF-STZ murine model represents an ideal tool to fully explore the positive effects of peptide-based GCGR antagonists in obesity-driven forms of diabetes, where restoration of functional beta-cell mass would be highly advantageous. Notably, the benefits of GCGR blockade are believed to require at least some residual beta-cell function ( Damond et al 2016 ), which would be the case for HFF-STZ mice ( Tanday et al 2021 ).…”

“…It has been well established that abnormal elevation in circulating glucagon leads to an increase in hepatic glucose production and glycogen metabolism that contribute to hyperglycaemia in diabetes (Unger 1978). For this reason, blockade of glucagon receptor (GCGR) signalling has been widely regarded as a potential therapeutic option to help control blood glucose levels for the treatment of diabetes (Patil et al 2020;Lafferty et al 2021). In addition, some recent observations (Wang et al 2021), coupled with earlier work (Okamoto et al 2015;, suggest that GCGR blockade can also promote recovery of functional beta-cell mass, with obvious additional benefits for diabetes.…”

Stearic acid induces CCK and GLP-1 upregulation via GPR120/PLC-β, leading to reduced appetite in Hu sheep fed with rice straw

“…Study has confirmed that peripherally administered physiological doses of Frontiers in Veterinary Science frontiersin.org GLP-1 can reduce meal size in rodents and humans, and that postprandial plasma concentrations of GLP-1 can cause satiety in rodents and humans (19). The combined injection of GLP-1 and CCK (20) or coadministration of a glucagon-like peptile-1 receptor (GLP-1R) agonist with a cholecystokinin Receptor-1 (CCKR1) agonist (21)(22)(23) can inhibit appetite and reduce body weight. Our results were similar, we found that Hu sheep fed with RS exhibited significantly reduced feed intake, which was associated with high CCK and GLP-1 levels in their blood.…”