Enzymatic Stability and Comparative Effects of Kisspeptin-14, Kisspeptin-13 and Kisspeptin-10 on Beta-Cell Function, Glucose Homeostasis and Appetite Regulation.

Background/Objective: Kisspeptin peptides are being increasingly recognised as regulators of metabolism, but whether these actions differ depending on peptide isoform remains unclear. Methods: The current study compared the enzymatic stability and biological effects of kisspeptin-14 (KP-14), kisspeptin-13 (KP-13) and kisspeptin-10 (KP-10) on beta-cell health and function, glucose homeostasis and appetite. Peptide stability was assessed in murine plasma and, following confirmation of KISS1R expression in BRIN-BD11 beta-cells, actions on insulin secretion, beta-cell proliferation and apoptosis were investigated, with additional secretory studies in isolated murine islets. Metabolic effects of KP-14, KP-13 and KP-10 were subsequently evaluated in healthy male and female mice. Results: KP-14 was resistant to plasma degradation, whereas KP-13 and KP-10 underwent N-terminal proteolysis, with KP-13 degradation generating KP-10 amongst other fragment peptides. The kisspeptin peptides exerted modest direct effects on insulin secretion from BRIN-BD11 cells, with KP-13 being the most efficacious, a bioactivity profile that was confirmed in islets. In addition, KP-13 significantly enhanced beta-cell proliferation and protected against cytokine-induced apoptosis, producing superior beta-cell proliferative effects compared to exenatide. Acute administration of all kisspeptin peptides elevated circulating glucose concentrations, and while KP-14 and KP-10 impaired glucose tolerance, KP-13 did not. Interestingly, KP-14 enhanced glucose-stimulated insulin secretion, with KP-13 and KP-10 being devoid of such actions. All kisspeptin isoforms suppressed food intake, although only KP-13, and especially KP-10 administration, led to an inhibition of feeding. Conclusions: Taken together, these data identify KP-13 as possessing the most favourable overall metabolic actions, based on a combination of beneficial actions on beta-cell health and function together with inhibition of feeding and lack of prominent glucose-elevating actions, suggesting possible therapeutic application for type 2 diabetes.