Administration of an acylated GLP-1 and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity

Abstract

The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys37Myr) (N-acetylGIP with myristic acid conjugated at Lys37), a simple combination of both peptides and a Lira–AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys37Myr)] were incubated with DPP-IV (dipeptidyl peptidase-IV) to assess peptide stability, and BRIN–BD11 cells were used to evaluate cAMP production and insulin secretion. Acute glucose-lowering and insulinotropic actions were evaluated in Swiss TO mice. Subchronic studies on glucose homoeostasis, insulin secretion, food intake and bodyweight were evaluated in ob/ob mice. Liraglutide, N-AcGIP(Lys37Myr), a simple combination of both peptides and the Lira–AcGIP preparation demonstrated improved DPP-IV resistance (P<0.001), while stimulating cAMP production and insulin secretion (1.4–2-fold; P<0.001). The Lira–AcGIP preparation was more potent at lowering plasma glucose (20–51% reduction; P<0.05–P<0.001) and stimulating insulin secretion (1.5–1.8-fold; P<0.05–P<0.001) compared with Liraglutide and N-AcGIP(Lys37Myr) or a simple peptide combination. Daily administration of the Lira–AcGIP preparation to ob/ob mice lowered bodyweight (7–9%; P<0.05), food intake (23%; P<0.05) and plasma glucose (46% reduction; P<0.001), while increasing plasma insulin (1.5–1.6-fold; P<0.001). The Lira–AcGIP preparation enhanced glucose tolerance, insulin response to glucose and insulin content (P<0.05–P<0.001). These findings demonstrate that a combined preparation of the acylated GLP-1 and GIP peptides Liraglutide and N-AcGIP(Lys37Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.