Beneficial metabolic effects of recurrent periods of beta‐cell rest and stimulation using stable NPY1 and GLP ‐1 receptor agonists

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Abstract

Aim
The current study examines whether sequential administration of (d-Arg35)-sea lamprey PYY(1-36) (SL-PYY) and the GLP-1 mimetic, liraglutide, has beneficial effects in diabetes.

Methods
SL-PYY is an enzymatically stable neuropeptide Y1 receptor (NPY1R) agonist known to induce pancreatic beta-cell rest and improve overall beta-cell health. We have employed SL-PYY and liraglutide to induce appropriate recurrent periods of beta-cell rest and stimulation, to assess therapeutic benefits in high fat fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF-STZ mice.

Results
Previous studies confirm that at a dose of 0.25 nmol/kg liraglutide exerts bioactivity over 8-12 h period in mice. Initial pharmacokinetic analysis revealed that 75 nmol/kg SL-PYY yielded a similar plasma drug time profile. When SL-PYY (75 nmol/kg) and liraglutide (0.25 nmol/kg) were administered sequentially at 08:00 h and 20:00 h respectively, to HFF-STZ mice for 28 days reductions in energy intake, body weight, circulating glucose, insulin and glucagon were noted. Similarly positive, but slightly less striking, effects were also apparent with twice daily liraglutide only therapy. The sequential SL-PYY and liraglutide treatment also improved insulin sensitivity and glucose-induced insulin secretory responses, that was not apparent with liraglutide treatment although benefits on glucose tolerance were mild. Interestingly, combined therapy also elevated pancreatic insulin, decreased pancreatic glucagon and enhanced plasma insulin/glucagon ratio when compared to liraglutide alone. This was not associated with enhancement of beneficial changes in islet cell areas, proliferation or apoptosis when compared to liraglutide alone, but numbers of centrally stained glucagon-positive islet cells were reduced by sequential combination therapy.

Conclusion
These data demonstrate that NPY1R induced intervals of beta-cell rest, combined with GLP-1R stimulated periods of beta-cell stimulation, should be further evaluated as an effective treatment option for obesity-driven forms of diabetes.

This article is protected by copyright. All rights reserved.
Original languageEnglish
JournalDiabetes, Obesity and Metabolism
Early online date18 Jul 2022
DOIs
Publication statusE-pub ahead of print - 18 Jul 2022

Keywords

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

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