Dataset Information

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 < 0.05 to p < 0.001) enhanced in vitro insulin secretion from pancreatic clonal BRIN-BD11 cells, with xenin (and particularly GIP)-related signalling pathways, being important for this action. Administration of (DAla²)GIP or (DAla²)GIP/xenin-8-Gln in combination with glucose significantly (p < 0.05) lowered blood glucose and increased plasma insulin in mice, with a protracted response of up to 4 h. All treatments elicited appetite-suppressive effects (p < 0.05), particularly (DAla²)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 < 0.05) reduced glycaemic levels during a 24 h glucose profile assessment. Neither of the treatment regimens had an effect on body weight, energy intake or circulating insulin concentrations. However, insulin sensitivity was significantly (p < 0.001) improved by both treatments. Interestingly, GIP-mediated glucose-lowering (p < 0.05) and insulin-releasing (p < 0.05 to p < 0.01) effects were substantially improved by (DAla²)GIP and (DAla²)GIP/xenin-8-Gln treatment. Pancreatic islet and beta cell area (p < 0.001), as well as pancreatic insulin content (p < 0.05), were augmented in (DAla²)GIP/xenin-8-Gln-treated mice, related to enhanced proliferation and decreased apoptosis of beta cells, whereas (DAla²)GIP evoked increases (p < 0.05 to p < 0.01) in islet number.

Conclusions/interpretation

These 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

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Publications

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

Hasib Annie A Ng Ming T MT Gault Victor A VA Khan Dawood D Parthsarathy Vadivel V Flatt Peter R PR Irwin Nigel N

Diabetologia 20161221 3

<h4>Aims/hypothesis</h4>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 (DAla<sup>2</sup>)GIP/xenin-8-Gln hybrid peptide, in comparison with the parent peptides (DAla<sup>2</sup>)GIP and xenin-8-Gln.<h4>Methods</h4>Following confirmation of enzymatic sta ...[more]

PMID: 28004148

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Dataset Information

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

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Publications

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

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