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: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: Varun
authors.initials: V
authors.lastname: Pathak
authors.forename: Srividya
authors.initials: S
authors.lastname: Vasu
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D005227:Fatty Acids / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D054795:Incretins / Q000378:metabolism; D007263:Infusions, Parenteral; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology*; D000069450:Liraglutide / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D054795:Incretins; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP