Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJ db/db mice

V Pathak, Srividya Vasu, Victor Gault, Peter Flatt, Nigel Irwin

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

AIMS/HYPOTHESIS: GIP(6-30)Cex-K(40)[Pal] has been characterised as a fatty-acid-derived gastric inhibitory polypeptide (GIP) inhibitor that can induce pancreatic beta cell rest by diminishing the incretin effect. We investigated its therapeutic efficacy with and without the glucagon-like peptide-1 (GLP-1) beta cell cytotropic agent liraglutide.METHODS: The therapeutic efficacy of GIP(6-30)Cex-K(40)[Pal] alone, and in combination with liraglutide, was determined in C57BL/KsJ db/db mice using a sequential 12 h administration schedule.RESULTS: GIP(6-30)Cex-K(40)[Pal] was devoid of cAMP-generating or insulin-secretory activity, and inhibited GIP-induced cAMP production and insulin secretion. GIP(6-30)Cex-K(40)[Pal] also inhibited GIP-induced glucose-lowering and insulin-releasing actions in mice. Dose- and time-dependent studies in mice revealed that 2.5 nmol/kg GIP(6-30)Cex-K(40)[Pal], and 0.25 nmol/kg liraglutide, imparted distinct biological effects for 8-12 h post administration. When GIP(6-30)Cex-K(40)[Pal] (2.5 nmol/kg) and liraglutide (0.25 nmol/kg) were administered sequentially at 12 h intervals (at 08:00 and 20:00 hours) to db/db mice for 28 days, mice treated with GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours) displayed pronounced reductions in circulating glucose and insulin. Both oral and intraperitoneal glucose tolerance and glucose-stimulated plasma insulin concentrations were improved together with enhanced insulin sensitivity. The expression of genes involved in adipocyte lipid deposition was generally decreased. The other treatment modalities, including GIP(6-30)Cex-K(40)[Pal] (08:00 and 20:00 hours), liraglutide (08:00 and 20:00 hours) and liraglutide (08:00 hours) combined with GIP(6-30)Cex-K(40)[Pal] (20:00 hours), also imparted beneficial effects but these were not as prominent as those of GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours).CONCLUSION/INTERPRETATION: These data demonstrate that periods of beta cell rest combined with intervals of beta cell stimulation benefit diabetes control and should be further evaluated as a potential treatment option for type 2 diabetes.
LanguageEnglish
Pages2144-2153
Number of pages10
JournalDiabetologia
Volume58
Issue number9
Early online date6 Jun 2015
DOIs
Publication statusPublished - 1 Sep 2015

Fingerprint

Gastric Inhibitory Polypeptide
Glucagon-Like Peptide 1
Peptides
Insulin
Glucose
Liraglutide
Incretins
Insulin-Secreting Cells
Glucose Tolerance Test
Adipocytes
Type 2 Diabetes Mellitus

Keywords

  • db/db mice
  • Diabetes
  • GIP
  • GLP-1
  • Glucose homeostasis
  • Insulin secretion
  • Obesity

Cite this

@article{4df54269d7f1488fac06f5810fbef218,
title = "Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJ db/db mice",
abstract = "AIMS/HYPOTHESIS: GIP(6-30)Cex-K(40)[Pal] has been characterised as a fatty-acid-derived gastric inhibitory polypeptide (GIP) inhibitor that can induce pancreatic beta cell rest by diminishing the incretin effect. We investigated its therapeutic efficacy with and without the glucagon-like peptide-1 (GLP-1) beta cell cytotropic agent liraglutide.METHODS: The therapeutic efficacy of GIP(6-30)Cex-K(40)[Pal] alone, and in combination with liraglutide, was determined in C57BL/KsJ db/db mice using a sequential 12 h administration schedule.RESULTS: GIP(6-30)Cex-K(40)[Pal] was devoid of cAMP-generating or insulin-secretory activity, and inhibited GIP-induced cAMP production and insulin secretion. GIP(6-30)Cex-K(40)[Pal] also inhibited GIP-induced glucose-lowering and insulin-releasing actions in mice. Dose- and time-dependent studies in mice revealed that 2.5 nmol/kg GIP(6-30)Cex-K(40)[Pal], and 0.25 nmol/kg liraglutide, imparted distinct biological effects for 8-12 h post administration. When GIP(6-30)Cex-K(40)[Pal] (2.5 nmol/kg) and liraglutide (0.25 nmol/kg) were administered sequentially at 12 h intervals (at 08:00 and 20:00 hours) to db/db mice for 28 days, mice treated with GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours) displayed pronounced reductions in circulating glucose and insulin. Both oral and intraperitoneal glucose tolerance and glucose-stimulated plasma insulin concentrations were improved together with enhanced insulin sensitivity. The expression of genes involved in adipocyte lipid deposition was generally decreased. The other treatment modalities, including GIP(6-30)Cex-K(40)[Pal] (08:00 and 20:00 hours), liraglutide (08:00 and 20:00 hours) and liraglutide (08:00 hours) combined with GIP(6-30)Cex-K(40)[Pal] (20:00 hours), also imparted beneficial effects but these were not as prominent as those of GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours).CONCLUSION/INTERPRETATION: These data demonstrate that periods of beta cell rest combined with intervals of beta cell stimulation benefit diabetes control and should be further evaluated as a potential treatment option for type 2 diabetes.",
keywords = "db/db mice, Diabetes, GIP, GLP-1, Glucose homeostasis, Insulin secretion, Obesity",
author = "V Pathak and Srividya Vasu and Victor Gault and Peter Flatt and Nigel Irwin",
year = "2015",
month = "9",
day = "1",
doi = "10.1007/s00125-015-3653-1",
language = "English",
volume = "58",
pages = "2144--2153",
journal = "Diabetologia",
issn = "0012-186X",
number = "9",

}

TY - JOUR

T1 - Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJ db/db mice

AU - Pathak, V

AU - Vasu, Srividya

AU - Gault, Victor

AU - Flatt, Peter

AU - Irwin, Nigel

PY - 2015/9/1

Y1 - 2015/9/1

N2 - AIMS/HYPOTHESIS: GIP(6-30)Cex-K(40)[Pal] has been characterised as a fatty-acid-derived gastric inhibitory polypeptide (GIP) inhibitor that can induce pancreatic beta cell rest by diminishing the incretin effect. We investigated its therapeutic efficacy with and without the glucagon-like peptide-1 (GLP-1) beta cell cytotropic agent liraglutide.METHODS: The therapeutic efficacy of GIP(6-30)Cex-K(40)[Pal] alone, and in combination with liraglutide, was determined in C57BL/KsJ db/db mice using a sequential 12 h administration schedule.RESULTS: GIP(6-30)Cex-K(40)[Pal] was devoid of cAMP-generating or insulin-secretory activity, and inhibited GIP-induced cAMP production and insulin secretion. GIP(6-30)Cex-K(40)[Pal] also inhibited GIP-induced glucose-lowering and insulin-releasing actions in mice. Dose- and time-dependent studies in mice revealed that 2.5 nmol/kg GIP(6-30)Cex-K(40)[Pal], and 0.25 nmol/kg liraglutide, imparted distinct biological effects for 8-12 h post administration. When GIP(6-30)Cex-K(40)[Pal] (2.5 nmol/kg) and liraglutide (0.25 nmol/kg) were administered sequentially at 12 h intervals (at 08:00 and 20:00 hours) to db/db mice for 28 days, mice treated with GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours) displayed pronounced reductions in circulating glucose and insulin. Both oral and intraperitoneal glucose tolerance and glucose-stimulated plasma insulin concentrations were improved together with enhanced insulin sensitivity. The expression of genes involved in adipocyte lipid deposition was generally decreased. The other treatment modalities, including GIP(6-30)Cex-K(40)[Pal] (08:00 and 20:00 hours), liraglutide (08:00 and 20:00 hours) and liraglutide (08:00 hours) combined with GIP(6-30)Cex-K(40)[Pal] (20:00 hours), also imparted beneficial effects but these were not as prominent as those of GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours).CONCLUSION/INTERPRETATION: These data demonstrate that periods of beta cell rest combined with intervals of beta cell stimulation benefit diabetes control and should be further evaluated as a potential treatment option for type 2 diabetes.

AB - AIMS/HYPOTHESIS: GIP(6-30)Cex-K(40)[Pal] has been characterised as a fatty-acid-derived gastric inhibitory polypeptide (GIP) inhibitor that can induce pancreatic beta cell rest by diminishing the incretin effect. We investigated its therapeutic efficacy with and without the glucagon-like peptide-1 (GLP-1) beta cell cytotropic agent liraglutide.METHODS: The therapeutic efficacy of GIP(6-30)Cex-K(40)[Pal] alone, and in combination with liraglutide, was determined in C57BL/KsJ db/db mice using a sequential 12 h administration schedule.RESULTS: GIP(6-30)Cex-K(40)[Pal] was devoid of cAMP-generating or insulin-secretory activity, and inhibited GIP-induced cAMP production and insulin secretion. GIP(6-30)Cex-K(40)[Pal] also inhibited GIP-induced glucose-lowering and insulin-releasing actions in mice. Dose- and time-dependent studies in mice revealed that 2.5 nmol/kg GIP(6-30)Cex-K(40)[Pal], and 0.25 nmol/kg liraglutide, imparted distinct biological effects for 8-12 h post administration. When GIP(6-30)Cex-K(40)[Pal] (2.5 nmol/kg) and liraglutide (0.25 nmol/kg) were administered sequentially at 12 h intervals (at 08:00 and 20:00 hours) to db/db mice for 28 days, mice treated with GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours) displayed pronounced reductions in circulating glucose and insulin. Both oral and intraperitoneal glucose tolerance and glucose-stimulated plasma insulin concentrations were improved together with enhanced insulin sensitivity. The expression of genes involved in adipocyte lipid deposition was generally decreased. The other treatment modalities, including GIP(6-30)Cex-K(40)[Pal] (08:00 and 20:00 hours), liraglutide (08:00 and 20:00 hours) and liraglutide (08:00 hours) combined with GIP(6-30)Cex-K(40)[Pal] (20:00 hours), also imparted beneficial effects but these were not as prominent as those of GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours).CONCLUSION/INTERPRETATION: These data demonstrate that periods of beta cell rest combined with intervals of beta cell stimulation benefit diabetes control and should be further evaluated as a potential treatment option for type 2 diabetes.

KW - db/db mice

KW - Diabetes

KW - GIP

KW - GLP-1

KW - Glucose homeostasis

KW - Insulin secretion

KW - Obesity

UR - https://pure.ulster.ac.uk/en/publications/sequential-induction-of-beta-cell-rest-and-stimulation-using-stab-3

U2 - 10.1007/s00125-015-3653-1

DO - 10.1007/s00125-015-3653-1

M3 - Article

VL - 58

SP - 2144

EP - 2153

JO - Diabetologia

T2 - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -