An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice.

ABSTRACT:

Aims/hypothesis

Glucose-dependent insulinotropic polypeptide (GIP) and xenin, regulatory gut hormones secreted from enteroendocrine K cells, exert important effects on metabolism. In addition, xenin potentiates the biological actions of GIP. The present study assessed the actions and therapeutic utility of a (DAla²)GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla²)GIP and xenin-8-Gln.

Methods

Following confirmation of enzymatic stability, insulin secretory activity of (DAla²)GIP/xenin-8-Gln was assessed in BRIN-BD11 beta cells. Acute and persistent glucose-lowering and insulin-releasing effects were then examined in vivo. Finally, the metabolic benefits of twice daily injection of (DAla²)GIP/xenin-8-Gln was determined in high-fat-fed mice.

Results

All peptides significantly (p?2)GIP or (DAla²)GIP/xenin-8-Gln in combination with glucose significantly (p?2)GIP/xenin-8-Gln and xenin-8-Gln at elevated doses of 250 nmol/kg. Twice-daily administration of (DAla²)GIP/xenin-8-Gln or (DAla²)GIP for 21 days to high-fat-fed mice returned circulating blood glucose to lean control levels. In addition, (DAla²)GIP/xenin-8-Gln treatment significantly (p?2)GIP and (DAla²)GIP/xenin-8-Gln treatment. Pancreatic islet and beta cell area (p?2)GIP/xenin-8-Gln-treated mice, related to enhanced proliferation and decreased apoptosis of beta cells, whereas (DAla²)GIP evoked increases (p?Conclusions/interpretationThese studies highlight the clear potential of GIP/xenin hybrids for the treatment of type 2 diabetes.

SUBMITTER: Hasib A 

PROVIDER: S-EPMC6518372 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature