TY - JOUR
T1 - Chronic apelin analogue administration is more effective than established incretin therapies for alleviating metabolic dysfunction in diabetic db/db mice
AU - O'Harte, Finbarr
AU - V, Parthsarathy
AU - Flatt, PR
N1 - Funding Information:
This work was supported by Invest Northern Ireland , Proof of Concept, Phase III, [ PoC518 ] and the Irish Endocrine Society [small grant 2016], Ireland. Appendix A
Funding Information:
This work was supported by Invest Northern Ireland, Proof of Concept, Phase III, [PoC518] and the Irish Endocrine Society [small grant 2016], Ireland.
Publisher Copyright:
© 2020 Elsevier B.V.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - Stable apelin-13 peptide analogues have shown promising acute antidiabetic effects in mice with diet-induced obesity diabetes. Here the efficacy of (pGlu)apelin-13 amide (apelin amide) and the acylated analogue (pGlu)(Lys
8GluPAL)apelin-13 amide (apelin FA), were examined following chronic administration in db/db mice, a genetic model of degenerative diabetes. Groups of 9-week old male db/db mice (n = 8) received twice daily injections (09:00 and 17:00 h; i.p.) or saline vehicle, apelin amide, apelin FA, or the established incretin therapies, exendin-4(1–39) or liraglutide, all at 25 nmol/kg body weight for 21 days. Control C57BL/6J mice were given saline twice daily. No changes in body weight or food intake were observed with either apelin or liraglutide treatments, but exendin-4 showed a reduction in cumulative food intake (p < 0.01) compared with saline-treated db/db mice. Apelin analogues and incretin mimetics induced sustained improvements of glycaemia (p < 0.05 to p < 0.001, from day 9–21), lowered HbA
1c at 21 days (p < 0.05) and raised plasma insulin concentrations. The treatments also improved OGTT and ipGTT with enhanced insulin responses compared with saline-treated control db/db mice (p < 0.05 to p < 0.001). Apelin amide was superior to incretin mimetics in lowering plasma triglycerides by 34% (p < 0.05). Apelin analogues unlike both incretin mimetics reduced pancreatic α-cell area (p < 0.05 to p < 0.01) and all peptide treatments enhanced pancreatic insulin content (p < 0.05 to p < 0.01). In conclusion, longer-term administration of apelin-13 analogues, induced similar and in some respects more effective metabolic improvements than incretin mimetics in db/db mice, providing a viable alternative approach for counteracting metabolic dysfunction for mild and more degenerative forms of the disease.
AB - Stable apelin-13 peptide analogues have shown promising acute antidiabetic effects in mice with diet-induced obesity diabetes. Here the efficacy of (pGlu)apelin-13 amide (apelin amide) and the acylated analogue (pGlu)(Lys
8GluPAL)apelin-13 amide (apelin FA), were examined following chronic administration in db/db mice, a genetic model of degenerative diabetes. Groups of 9-week old male db/db mice (n = 8) received twice daily injections (09:00 and 17:00 h; i.p.) or saline vehicle, apelin amide, apelin FA, or the established incretin therapies, exendin-4(1–39) or liraglutide, all at 25 nmol/kg body weight for 21 days. Control C57BL/6J mice were given saline twice daily. No changes in body weight or food intake were observed with either apelin or liraglutide treatments, but exendin-4 showed a reduction in cumulative food intake (p < 0.01) compared with saline-treated db/db mice. Apelin analogues and incretin mimetics induced sustained improvements of glycaemia (p < 0.05 to p < 0.001, from day 9–21), lowered HbA
1c at 21 days (p < 0.05) and raised plasma insulin concentrations. The treatments also improved OGTT and ipGTT with enhanced insulin responses compared with saline-treated control db/db mice (p < 0.05 to p < 0.001). Apelin amide was superior to incretin mimetics in lowering plasma triglycerides by 34% (p < 0.05). Apelin analogues unlike both incretin mimetics reduced pancreatic α-cell area (p < 0.05 to p < 0.01) and all peptide treatments enhanced pancreatic insulin content (p < 0.05 to p < 0.01). In conclusion, longer-term administration of apelin-13 analogues, induced similar and in some respects more effective metabolic improvements than incretin mimetics in db/db mice, providing a viable alternative approach for counteracting metabolic dysfunction for mild and more degenerative forms of the disease.
KW - Apelin analogues
KW - Diabetes
KW - Incretin mimetics
KW - Pancreas
KW - Therapy
KW - db/db mice
UR - http://www.scopus.com/inward/record.url?scp=85078559670&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2019.110695
DO - 10.1016/j.mce.2019.110695
M3 - Article
C2 - 31904406
VL - 504
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
IS - 110695
M1 - 110695
ER -