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: Katsutoshi Miyagawa, Tatsuya Kondo, Rieko Goto, Rina Matsuyama, Kaoru Ono, Sayaka Kitano, Shuji Kawasaki, Motoyuki Igata, Junji Kawashima, Takeshi Matsumura, Hiroyuki Motoshima, Eiichi Araki
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 12 Pg. 160 (Nov 04 2013) ISSN: 1475-2840 [Electronic] England
• PMID: 24188631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adiponectin
• Angiotensin II Type 1 Receptor Blockers
• Blood Glucose
• Cytokines
• Dipeptidyl-Peptidase IV Inhibitors
• Homeodomain Proteins
• Insulin
• Nitriles
• Pyrrolidines
• Tetrazoles
• Trans-Activators
• pancreatic and duodenal homeobox 1 protein
• Valsartan
• Phlorhizin
• Valine
• Vildagliptin
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology, therapeutic use)
• Adiponectin (metabolism)
• Angiotensin II Type 1 Receptor Blockers (pharmacology, therapeutic use)
• Animals
• Blood Glucose (drug effects, metabolism)
• Cytokines (drug effects)
• Diabetes Mellitus, Experimental (drug therapy)
• Diabetes Mellitus, Type 2 (drug therapy)
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Therapy, Combination
• Fatty Liver
• Homeodomain Proteins (drug effects, metabolism)
• Inflammation
• Insulin (metabolism)
• Insulin Resistance
• Insulin Secretion
• Insulin-Secreting Cells (drug effects)
• Mice
• Mice, Inbred C57BL
• Nitriles (pharmacology, therapeutic use)
• Phlorhizin (pharmacology)
• Pyrrolidines (pharmacology, therapeutic use)
• Tetrazoles (pharmacology, therapeutic use)
• Trans-Activators (drug effects, metabolism)
• Valine (analogs & derivatives, pharmacology, therapeutic use)
• Valsartan
• Vildagliptin