A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents

Abstract

AimGlucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794.MethodsAC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala2]GIP(1–42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F β-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu14] exenatide. Human GIP or [d-Ala2]GIP(1–42) were used for comparison.ResultsAC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala2]GIP(1–42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala2]GIP(1–42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174.ConclusionsThese studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes.

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

“…Although we do not have an assay for (D-Ser 2 )glucagon-exe with which to determine pharmacokinetics, bioactivity studies revealed that the glucose-lowering actions of (D-Ser 2 )glucagon-exe were sustained for up to 12 h after administration. This is consistent with other regulatory peptides that possess similar amino acid substitutions [14,31,32]. Further studies were performed to determine which receptors were activated by (D-Ser 2 )glucagon-exe.…”

“…Thus, (D-Ser 2 )glucagon-exe, which consists of the entire glucagon sequence, with a nine amino acid C-terminal extension, may have improved therapeutic use over OXM, similar to exendin(1-39). The C-terminal extension employed for (D-Ser 2 )glucagon-exe has previously been shown to stabilise peptides, reduce clearance and significantly enhance in vivo potency [30,31]. Although we do not have an assay for (D-Ser 2 )glucagon-exe with which to determine pharmacokinetics, bioactivity studies revealed that the glucose-lowering actions of (D-Ser 2 )glucagon-exe were sustained for up to 12 h after administration.…”

Palmitoylated PrRP analog decreases body weight in DIO rats but not in ZDF rats

“…Infusion of a combination of another GLP1 analog, exenatide, and a peptide YY 3-36 analog caused a reduction in food intake and body weight in DIO rats (Reidelberger et al 2011). In the ZDF diabetic rat model, a combination of exenatide and gastrin treatment (Skarbaliene et al 2015), as well as glucose-dependent insulinotropic peptide treatment (Tatarkiewicz et al 2014), Palm-PrRP analog in rat models of obesity caused a prolonged glucose-lowering effect rather than a body weight-decreasing effect. Finally, a study by Fosgerau et al (2014) described that the biological effect of a novel selective lipidized analog of α-melanocyte-stimulating hormone (α-MSH) with a strong central anorexigenic effect caused a significant decrease in food intake and body weight in DIO rats after repeated peripheral administration.…”

Internalization and desensitization of the human glucose-dependent-insulinotropic receptor is affected by N-terminal acetylation of the agonist

“…Moreover, very promising preclinical data were obtained in rodents, monkeys and humans showing that a single peptidic molecule having dual agonist activity at GIP and GLP1 receptors exhibits enhanced insulinotropic and anti-hyperglycemic efficacy relative to GLP1 alone (Finan et al, 2013). As a consequence, a renewed interest in developing pharmacological strategies to target GIPR has emerged (Finan et al, 2013;Irwin et al, 2010;Tatarkiewicz et al, 2013).…”