A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties.

Vadivel Parthsarathy, Nigel Irwin, A Hasib, CM Martin, Stephen McClean, VK Bhat, Tony NG, Peter Flatt, Victor A Gault

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

BACKGROUND: Xenin-25 is a K-cell derived gut peptide with insulin-releasing activity which is rapidly degraded following release into the circulation. We hypothesized that substitution of all naturally-occurring Lys and Arg residues with Gln would lead to prolonged enzyme resistance and enhanced biological efficacy.METHODS: Peptide stability was assessed using murine plasma, in vitro insulin-releasing actions evaluated in BRIN-BD11 cells and acute glucose-lowering and insulin-releasing actions examined in high fat fed mice. For sub-chronic studies, a range of metabolic parameters and pancreatic histology were assessed in high fat fed mice which had received saline vehicle or xenin-25(gln) twice-daily for 21days.RESULTS: In contrast to native xenin-25, xenin-25(gln) was resistant to plasma-mediated degradation and significantly stimulated insulin secretion in BRIN-BD11 cells. Acute administration of xenin-25(gln) in high fat fed mice significantly reduced blood glucose and increased plasma insulin concentrations. Twice-daily administration of xenin-25(gln) in high fat fed mice did not affect food intake, body weight or circulating insulin concentrations but significantly decreased blood glucose from day 9 onwards. Furthermore, glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity and GIP-stimulated insulin-release were significantly enhanced in xenin-25(gln)-treated mice. Pancreatic immunohistochemistry revealed decreased alpha cell area with increased beta cell area and beta-to-alpha cell ratio in xenin-25(gln)-treated mice. In addition, xenin-25(gln) exerted similar beneficial actions in ob/ob mice as demonstrated by reduced blood glucose, superior glycaemic response and glucose-mediated insulin release.CONCLUSIONS: Xenin-25(gln) is resistant to plasma-mediated degradation and exerts sustained and beneficial metabolic actions in high fat fed and ob/ob mice.GENERAL SIGNIFICANCE: Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.
LanguageEnglish
Pages757-764
JournalBIOCHIMICA ET BIOPHYSICA ACTA
Volume1860
Issue number4
Early online date21 Jan 2016
DOIs
Publication statusE-pub ahead of print - 21 Jan 2016

Fingerprint

Glutamine
Insulin
Glucose
Fats
Plasmas
Blood Glucose
xenin 25
Degradation
Peptides
Histology
Medical problems
Type 2 Diabetes Mellitus
Insulin Resistance
Substitution reactions
Eating
Immunohistochemistry
Body Weight
Enzymes

Keywords

  • Glucose homeostasis
  • Gut hormone
  • Insulin secretion
  • Type 2 diabetes
  • Xenin-25

Cite this

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title = "A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties.",
abstract = "BACKGROUND: Xenin-25 is a K-cell derived gut peptide with insulin-releasing activity which is rapidly degraded following release into the circulation. We hypothesized that substitution of all naturally-occurring Lys and Arg residues with Gln would lead to prolonged enzyme resistance and enhanced biological efficacy.METHODS: Peptide stability was assessed using murine plasma, in vitro insulin-releasing actions evaluated in BRIN-BD11 cells and acute glucose-lowering and insulin-releasing actions examined in high fat fed mice. For sub-chronic studies, a range of metabolic parameters and pancreatic histology were assessed in high fat fed mice which had received saline vehicle or xenin-25(gln) twice-daily for 21days.RESULTS: In contrast to native xenin-25, xenin-25(gln) was resistant to plasma-mediated degradation and significantly stimulated insulin secretion in BRIN-BD11 cells. Acute administration of xenin-25(gln) in high fat fed mice significantly reduced blood glucose and increased plasma insulin concentrations. Twice-daily administration of xenin-25(gln) in high fat fed mice did not affect food intake, body weight or circulating insulin concentrations but significantly decreased blood glucose from day 9 onwards. Furthermore, glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity and GIP-stimulated insulin-release were significantly enhanced in xenin-25(gln)-treated mice. Pancreatic immunohistochemistry revealed decreased alpha cell area with increased beta cell area and beta-to-alpha cell ratio in xenin-25(gln)-treated mice. In addition, xenin-25(gln) exerted similar beneficial actions in ob/ob mice as demonstrated by reduced blood glucose, superior glycaemic response and glucose-mediated insulin release.CONCLUSIONS: Xenin-25(gln) is resistant to plasma-mediated degradation and exerts sustained and beneficial metabolic actions in high fat fed and ob/ob mice.GENERAL SIGNIFICANCE: Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.",
keywords = "Glucose homeostasis, Gut hormone, Insulin secretion, Type 2 diabetes, Xenin-25",
author = "Vadivel Parthsarathy and Nigel Irwin and A Hasib and CM Martin and Stephen McClean and VK Bhat and Tony NG and Peter Flatt and Gault, {Victor A}",
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language = "English",
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A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties. / Parthsarathy, Vadivel; Irwin, Nigel; Hasib, A; Martin, CM; McClean, Stephen; Bhat, VK; NG, Tony; Flatt, Peter; Gault, Victor A.

Vol. 1860, No. 4, 21.01.2016, p. 757-764.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties.

AU - Parthsarathy, Vadivel

AU - Irwin, Nigel

AU - Hasib, A

AU - Martin, CM

AU - McClean, Stephen

AU - Bhat, VK

AU - NG, Tony

AU - Flatt, Peter

AU - Gault, Victor A

PY - 2016/1/21

Y1 - 2016/1/21

N2 - BACKGROUND: Xenin-25 is a K-cell derived gut peptide with insulin-releasing activity which is rapidly degraded following release into the circulation. We hypothesized that substitution of all naturally-occurring Lys and Arg residues with Gln would lead to prolonged enzyme resistance and enhanced biological efficacy.METHODS: Peptide stability was assessed using murine plasma, in vitro insulin-releasing actions evaluated in BRIN-BD11 cells and acute glucose-lowering and insulin-releasing actions examined in high fat fed mice. For sub-chronic studies, a range of metabolic parameters and pancreatic histology were assessed in high fat fed mice which had received saline vehicle or xenin-25(gln) twice-daily for 21days.RESULTS: In contrast to native xenin-25, xenin-25(gln) was resistant to plasma-mediated degradation and significantly stimulated insulin secretion in BRIN-BD11 cells. Acute administration of xenin-25(gln) in high fat fed mice significantly reduced blood glucose and increased plasma insulin concentrations. Twice-daily administration of xenin-25(gln) in high fat fed mice did not affect food intake, body weight or circulating insulin concentrations but significantly decreased blood glucose from day 9 onwards. Furthermore, glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity and GIP-stimulated insulin-release were significantly enhanced in xenin-25(gln)-treated mice. Pancreatic immunohistochemistry revealed decreased alpha cell area with increased beta cell area and beta-to-alpha cell ratio in xenin-25(gln)-treated mice. In addition, xenin-25(gln) exerted similar beneficial actions in ob/ob mice as demonstrated by reduced blood glucose, superior glycaemic response and glucose-mediated insulin release.CONCLUSIONS: Xenin-25(gln) is resistant to plasma-mediated degradation and exerts sustained and beneficial metabolic actions in high fat fed and ob/ob mice.GENERAL SIGNIFICANCE: Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.

AB - BACKGROUND: Xenin-25 is a K-cell derived gut peptide with insulin-releasing activity which is rapidly degraded following release into the circulation. We hypothesized that substitution of all naturally-occurring Lys and Arg residues with Gln would lead to prolonged enzyme resistance and enhanced biological efficacy.METHODS: Peptide stability was assessed using murine plasma, in vitro insulin-releasing actions evaluated in BRIN-BD11 cells and acute glucose-lowering and insulin-releasing actions examined in high fat fed mice. For sub-chronic studies, a range of metabolic parameters and pancreatic histology were assessed in high fat fed mice which had received saline vehicle or xenin-25(gln) twice-daily for 21days.RESULTS: In contrast to native xenin-25, xenin-25(gln) was resistant to plasma-mediated degradation and significantly stimulated insulin secretion in BRIN-BD11 cells. Acute administration of xenin-25(gln) in high fat fed mice significantly reduced blood glucose and increased plasma insulin concentrations. Twice-daily administration of xenin-25(gln) in high fat fed mice did not affect food intake, body weight or circulating insulin concentrations but significantly decreased blood glucose from day 9 onwards. Furthermore, glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity and GIP-stimulated insulin-release were significantly enhanced in xenin-25(gln)-treated mice. Pancreatic immunohistochemistry revealed decreased alpha cell area with increased beta cell area and beta-to-alpha cell ratio in xenin-25(gln)-treated mice. In addition, xenin-25(gln) exerted similar beneficial actions in ob/ob mice as demonstrated by reduced blood glucose, superior glycaemic response and glucose-mediated insulin release.CONCLUSIONS: Xenin-25(gln) is resistant to plasma-mediated degradation and exerts sustained and beneficial metabolic actions in high fat fed and ob/ob mice.GENERAL SIGNIFICANCE: Glutamine (gln)-modified analogues of xenin may represent an attractive therapeutic approach for type 2 diabetes.

KW - Glucose homeostasis

KW - Gut hormone

KW - Insulin secretion

KW - Type 2 diabetes

KW - Xenin-25

U2 - 10.1016/j.bbagen.2016.01.015

DO - 10.1016/j.bbagen.2016.01.015

M3 - Article

VL - 1860

SP - 757

EP - 764

IS - 4

ER -