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

Annie Hasib, Tony Ng, Victor A Gault, Dawood Khan, Vadivel Parthsarathy, Peter Flatt, Nigel Irwin

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10 Citations (Scopus)

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.
LanguageEnglish
Pages541-552
JournalDiabetologia
Volume60
Issue number3
Early online date21 Dec 2016
DOIs
Publication statusE-pub ahead of print - 21 Dec 2016

Fingerprint

Gastric Inhibitory Polypeptide
Homeostasis
Fats
Glucose
Peptides
Insulin
xenin 25
Islets of Langerhans
Therapeutics
Blood Glucose
xenin-8

Keywords

  • GIP
  • Glucose
  • Glucose homeostasis
  • Glucose-dependent insulinotropic polypeptide
  • High-fat feeding
  • Hybrid
  • Insulin secretion
  • Xenin

Cite this

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title = "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.",
keywords = "GIP, Glucose, Glucose homeostasis, Glucose-dependent insulinotropic polypeptide, High-fat feeding, Hybrid, Insulin secretion, Xenin",
author = "Annie Hasib and Tony Ng and Gault, {Victor A} and Dawood Khan and Vadivel Parthsarathy and Peter Flatt and Nigel Irwin",
year = "2016",
month = "12",
day = "21",
doi = "10.1007/s00125-016-4186-y",
language = "English",
volume = "60",
pages = "541--552",
journal = "Diabetologia",
issn = "0012-186X",
number = "3",

}

TY - JOUR

T1 - An enzymatically stable GIP/xenin hybrid peptide restores GIP sensitivity, enhances beta cell function and improves glucose homeostasis in high-fat-fed mice

AU - Hasib, Annie

AU - Ng, Tony

AU - Gault, Victor A

AU - Khan, Dawood

AU - Parthsarathy, Vadivel

AU - Flatt, Peter

AU - Irwin, Nigel

PY - 2016/12/21

Y1 - 2016/12/21

N2 - 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.

AB - 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.

KW - GIP

KW - Glucose

KW - Glucose homeostasis

KW - Glucose-dependent insulinotropic polypeptide

KW - High-fat feeding

KW - Hybrid

KW - Insulin secretion

KW - Xenin

U2 - 10.1007/s00125-016-4186-y

DO - 10.1007/s00125-016-4186-y

M3 - Article

VL - 60

SP - 541

EP - 552

JO - Diabetologia

T2 - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 3

ER -