title: Antidiabetic effects of sub-chronic activation of the GIP receptor alone and in combination with background exendin-4 therapy in high fat fed mice.
abstract: GLP-1 and GIP are the two key incretin hormones that regulate post-prandial glucose homeostasis. Furthermore, potent enzyme-resistant GIP and GLP-1 receptor agonists such as N-AcGIP and exendin-4 have now been developed. In the present study the effects of stable incretins, exendin-4 and N-AcGIP alone and in combination were examined in mice with high fat feeding induced glucose intolerance. Daily s.c. injections of exendin-4 (50 nmol/kg bw) for 12 days restored glycaemic control and significantly (P<0.05) decreased glucose intolerance compared to saline-treated controls. Food intake was transiently decreased (P<0.05) without effect on body weight. In the following 12 day period, mice either continued the original treatment or were administered an additional dose of N-AcGIP (50 nmol/kg body weight; s.c.). Under these circumstances sub-chronic administration of exendin-4 alone or particularly when combined with N-AcGIP significantly (P<0.05) reduced body weight. Exendin-4, N-AcGIP and combined treatment groups displayed significantly (P<0.05) decreased plasma glucose levels and less severe glucose intolerance. Non-fasting 24-h glycaemic profiles revealed marked (P<0.05 to P<0.01) beneficial effects of all treatment regimes. Insulin resistance was also reduced (P<0.01 to P<0.001) in all exendin-4 treated mice compared to saline controls. Adipose tissue mRNA levels of adiponectin, leptin, resistin, GIP-R, LPL and DGAT-1 were not significantly altered. These results illustrate efficacy of enzyme resistant GIP and GLP-1 analogues for treatment of glucose intolerance induced by high fat feeding.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, United Kingdom. n.irwin@ulster.ac.uk
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Kerry
authors.initials: K
authors.lastname: Hunter
authors.forename: Norma
authors.initials: N
authors.lastname: Frizzell
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004041:Dietary Fats; D004435:Eating; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D018149:Glucose Intolerance; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D010455:Peptides / Q000627:therapeutic use*; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D004041:Dietary Fats; D007004:Hypoglycemic Agents; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; C041086:gastric inhibitory polypeptide receptor