title: Beneficial metabolic actions of a stable GIP agonist following pre-treatment with a SGLT2 inhibitor in high fat fed diabetic mice.
abstract: The purpose of the present study was to examine if a stable glucose-dependent insulinotropic polypeptide (GIP) agonist could exert beneficial metabolic control in diabetic mice which had been pre-treated with sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA). High fat fed mice administered low dose streptozotocin (STZ) received vehicle, DAPA once-daily over 28 days, or DAPA once-daily for 14 days followed by (DAla(2))GIP once-daily for 14 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin tolerance test, dual-energy X-ray absorptiometry (DEXA) and pancreatic histology were examined. Once-daily administration of (DAla(2))GIP for 14 days in high fat fed diabetic mice pre-treated with DAPA demonstrated significant decrease in body weight, blood glucose and increased insulin concentrations which were independent of changes in energy intake. Similarly, glucose tolerance, glucose-stimulated insulin secretion, insulin sensitivity and HOMA-β were significantly enhanced in (DAla(2))GIP-treated mice. DEXA analysis revealed sustained percentage body fat loss with no changes in lean mass, bone mineral content and density. Pancreatic immunohistochemical analysis revealed decreased islet number and increases in islet area, beta cell area and pancreatic insulin content. The DAPA-induced increase in alpha cell area was also reversed. Additional acute in vitro and in vivo experiments confirmed that the impaired action of (DAla(2))GIP under hyperglycaemic-induced conditions was significantly reversed by DAPA treatment. These data demonstrate that (DAla(2))GIP can exert beneficial metabolic control in high fat fed diabetic mice pre-treated with DAPA. The results highlight possibility of a targeted and personalized approach using a GIP agonist and SGLT2 inhibitor for the treatment of type 2 diabetes.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: P J B
authors.initials: PJ
authors.lastname: Millar
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: V
authors.initials: V
authors.lastname: Pathak
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Moffett
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Pathak
authors.affiliation: Northern Ireland Centre for Stratified Medicine, University of Ulster, C-TRIC Building, Altnagelvin Hospital, Londonderry BT47 6SB, Northern Ireland, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bjourson
authors.affiliation: Northern Ireland Centre for Stratified Medicine, University of Ulster, C-TRIC Building, Altnagelvin Hospital, Londonderry BT47 6SB, Northern Ireland, UK; Clinical Chemistry Laboratory, Western Health and Social Care Trust, Altnagelvin Hospital, Londonderry BT47 6SB, Northern Ireland, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: O'Kane
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. Electronic address: va.gault@ulster.ac.uk.
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D005215:Fasting / Q000097:blood; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage / Q000819:agonists* / Q000494:pharmacology / Q000627:therapeutic use; D005960:Glucosides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007328:Insulin; D012333:RNA, Messenger; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C557888:glucose-dependent insulinotropic polypeptide, Ala(2)-; C529054:dapagliflozin; D005749:Gastric Inhibitory Polypeptide
keywords: Dapagliflozin; Diabetes; Glucose-dependent insulinotropic polypeptide (GIP); Insulin secretion; SGLT2 inhibitor