title: Effects of combination therapy with vildagliptin and valsartan in a mouse model of type 2 diabetes.
abstract: BACKGROUND
  Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate incretin hormones and exert anti-diabetic effects in type 2 diabetes mellitus. Treatment with angiotensin II type 1 receptor blockers (ARB) is a proven successful intervention for hypertension with type 2 diabetes. The present study investigated the combined effects of the DPP-4 inhibitor vildagliptin and the ARB valsartan in a mouse model of type 2 diabetes.
  
  
  METHODS
  C57BL/6 J mice fed with high-fat diet (HFD) or db/db mice were treated with placebo, phloridzin (PHZ), vildagliptin alone (ViL), valsartan alone (VaL) or ViL with VaL (ViLVaL) for 8 weeks.
  
  
  RESULTS
  Glucose metabolism was improved in response to PHZ, ViL and ViLVaL in both HFD and db/db mice. Upon glucose challenge, ViLVaL showed the greatest suppression of blood glucose excursions, with increased insulin secretion, in db/db mice. ViLVaL treatment also showed an improvement of insulin sensitivity in db/db mice. Serum inflammatory cytokines were significantly decreased, and adiponectin was highest, in the ViLVaL group. ViLVaL improved insulin signaling and attenuated stress signaling in liver with amelioration of hepatic steatosis due to activated fatty acid oxidation in db/db mice. Furthermore, immunohistochemical analysis of the pancreas revealed that the combination treatment resulted in an increased expression of insulin and PDX-1, and increased insulin content.
  
  
  CONCLUSIONS
  The combination therapy of ViL and VaL improves both pancreatic beta-cell function and insulin sensitivity, with a reduction of the inflammatory and cell stress milieu in mouse models of T2DM. Our results suggest that this combination therapy exerts additive or even synergistic benefits to treat T2DM.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Miyagawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kondo
authors.forename: Rieko
authors.initials: R
authors.lastname: Goto
authors.forename: Rina
authors.initials: R
authors.lastname: Matsuyama
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ono
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kitano
authors.forename: Shuji
authors.initials: S
authors.lastname: Kawasaki
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Igata
authors.forename: Junji
authors.initials: J
authors.lastname: Kawashima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsumura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Motoshima
authors.affiliation: Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo Ward, Kumamoto 860-8556, Japan. earaki@gpo.kumamoto-u.ac.jp.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Araki
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D052242:Adiponectin / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005234:Fatty Liver; D018398:Homeodomain Proteins / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D010695:Phlorhizin / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000068756:Valsartan; D000077597:Vildagliptin
chemical_list: D052242:Adiponectin; D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D018398:Homeodomain Proteins; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; D013777:Tetrazoles; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D000068756:Valsartan; D010695:Phlorhizin; D014633:Valine; D000077597:Vildagliptin; D000218:Adamantane