Evaluation of metabolic and cardiovascular actions of [Pyr1]apelin-13 in patients with Type 2 diabetes mellitus

Name: Dr Petra Sulentic Thesis title: Evaluation of metabolic and cardiovascular actions of [Pyr1]apelin-13 in patients with Type 2 diabetes mellitus Type 2 diabetes mellitus (T2DM) is common, long term metabolic disorder characterised by hyperglycaemia (high blood glucose) resulting from insulin resistance (IR) and insulin insufficiency. Type 2 diabetes mellitus and related complications present a significant cause of morbidity and mortality and there is an urgent need to identify novel pathways that may ultimately lead to the development of new therapies to improve blood glucose control and prevent development of diabetic complications. Apelin is a naturally occurring peptide investigated in animal models and humans showing beneficial cardiovascular and metabolic properties. Apelin reduces peripheral vascular resistance (PVR) and increases cardiac index (CI) in healthy volunteers and heart failure patients, and also increases insulin sensitivity in overweight participants. Besides health risks connected to hyperglycaemia, T2DM patients have increased cardiovascular risk, therefore modulation of the apelin signalling pathway may provide a novel cardiometabolic therapeutic approach. Systemic studies were planned to investigate the effects of prolonged intravenous apelin infusions on CI, blood glucose and IR for the first time in patients with T2DM, following hypothesis that apelin would induce beneficial cardiovascular and metabolic effects in that patient group. Firstly, the tolerability and safety of apelin in increasing doses were tested in a pilot study including healthy volunteers. Subsequently, eighteen participants with increased body mass index (BMI) 25–34.9 kg/m2 who served as a model of IR and nine T2DM patients underwent a series of randomised, double blind, saline controlled, prolonged infusion studies. [Pyr1]apelin-13 was infused systemically for two hours with measurements of cardiovascular and metabolic parameters. Results showed that in participants with increased BMI, compared to saline control, [Pyr1]apelin-13 in dose 30 nmol/min caused a significant rise in CI and stroke volume index (SVI), whilst reducing peripheral vascular resistance (PVR) and mean arterial pressure (MAP). After a mixed meal, [Pyr1]apelin-13 also significantly reduced plasma C peptide without inducing significant changes in glucose or insulin plasma level. In patients with T2DM, [Pyr1]apelin-13 in the equivalent [Pyr1]apelin-13 dose of 30 nmol/min and compared to saline control, also increased SVI and CI and reduced PVR without affecting MAP and levels of insulin, glucose or C-peptide. In T2DM group a possible delay in gastric emptying was observed, representing a novel finding in this condition and requiring further investigations. In summary, following these pilot studies results, there is a reason to believe that patients with T2DM have the potential to benefit from apelin mediated vasodilation, increased CI and better glucose homeostasis combined with possible delay in gastric emptying. Therefore, targeting apelin signalling represents novel pathways yet to be explored and developed therapeutically with further studies required to investigate those effects.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Sulentic, Petra

Advisor dc:contributor.advisor

• Davenport, Anthony

• apelin
• metabolic
• cardiovascular
• diabetes
• glucose
• insulin resistance
• T2D

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.92011

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/344590