A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

Abstract

Glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) exert important complementary beneficial metabolic effects. This study assessed the biological actions and therapeutic utility of a novel (pGlu-Gln)-CCK-8/exendin-4 hybrid peptide compared with the stable GLP-1 and CCK mimetics exendin-4 and (pGlu-Gln)-CCK-8, respectively. All peptides significantly enhanced in vitro insulin secretion. Administration of the peptides, except (pGlu-Gln)-CCK-8 alone, in combination with glucose significantly lowered plasma glucose and increased plasma insulin in mice. All treatments elicited appetite-suppressive effects. Twice-daily administration of the novel (pGlu-Gln)-CCK-8/exendin-4 hybrid, (pGlu-Gln)-CCK-8 alone, or (pGlu-Gln)-CCK-8 in combination with exendin-4 for 21 days to high-fat–fed mice significantly decreased energy intake, body weight, and circulating plasma glucose. HbA1c was reduced in the (pGlu-Gln)-CCK-8/exendin-4 hybrid and combined parent peptide treatment groups. Glucose tolerance and insulin sensitivity also were improved by all treatment modalities. Interestingly, locomotor activity was decreased in the hybrid peptide group, and these mice also exhibited reductions in circulating triglyceride and cholesterol levels. Pancreatic islet number and area, as well β-cell area and insulinotropic responsiveness, were dramatically improved by all treatments. These studies highlight the clear potential of dual activation of GLP-1 and CCK1 receptors for the treatment of type 2 diabetes.

An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

“…Immunohistochemistry Pancreas tissue was excised, divided longitudinally and either snap frozen for extraction of insulin using acid ethanol (5 ml/g), as described previously [22], or processed for immunohistochemical examination. Immunohistochemistry was performed as described previously [33].…”

“…Successful generation of hybrid peptides has been achieved through fusion of the key bioactive amino acid sequences of the parent peptides [19][20][21][22]. This increases the therapeutic applicability of gut-hormone-based drugs by facilitating formulation and dosing with a single molecule, rather than coinjection of separate parent peptide forms.…”

“…As such, therapeutic interventions that combine the biological actions of xenin and GIP, and potentially restore GIP action in type 2 diabetes, would have particularly exciting potential. There has been a recent upsurge in interest focused on generating designer hybrid peptides that can modulate multiple regulatory peptide hormone receptor pathways [19][20][21][22].…”

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Indeed, combined administration of long-acting GLP-1R and CCK1-R agonists has shown pronounced synergistic metabolic benefits in rodent models of type 2 diabetes, including improved glycaemic control and loss of body weight (Irwin et al 2013, Trevaskis et al 2015. As such, a novel CCK/GLP-1 hybrid peptide based on the chemical structures of the CCK1-R agonist, (pGlu-Gln)-CCK-8, and exenatide has recently been described and shown to have significant therapeutic potential in high-fat-fed mice (Irwin et al 2015). This molecule clearly warrants further study as a potential new treatment option for type 2 diabetes.…”

“…Furthermore, 8 weeks of treatment with the bile acid sequestrant, colesevelam, improves glycaemic control in humans with impaired glucose tolerance through a mechanism dependent on prevention of bile acid absorption and increased local CCK secretion (Marina et al 2012), suggesting this aforementioned CCK gut-brain-liver axis could be of therapeutic relevance. Additionally, cotreatment of a CCK receptor agonist with a GLP-1R agonist has demonstrated initial therapeutic promise (Irwin et al 2015; see section below).…”