Combination treatment with alogliptin and voglibose increases active GLP-1 circulation, prevents the development of diabetes and preserves pancreatic beta-cells in prediabetic db/db mice.
OBJECTIVE
Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and voglibose, an alpha-glucosidase inhibitor, have different but complementary mechanisms of action on glucagon-like peptide-1 (GLP-1) regulation and glucose-lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice.


METHODS
Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice.


RESULTS
After 3 weeks, voglibose treatment increased GLP-1 secretion (voglibose alone, 1.6-fold; alogliptin plus voglibose, 1.5-fold), while it decreased plasma glucose-dependent insulinotropic polypeptide (GIP) (voglibose alone, -30%; alogliptin plus voglibose, -29%). Alogliptin, voglibose and combination treatment decreased plasma DPP-4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP-1 levels by 4.5-, 1.8- and synergistically by 9.1-fold respectively. Combination treatment increased plasma insulin by 3.6-fold (alogliptin alone, 1.3-fold; voglibose alone, 1.8-fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6-, 3.4- and synergistically by 8.5-fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha-cell distribution in the pancreatic islet.


CONCLUSIONS
Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP-1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta-cells and islet structure in prediabetic db/db mice.
Moritoh
Y
Y
Pharmacology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. moritou_yuusuke@takeda.co.jp
Takeuchi
K
K
Hazama
M
M
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D004359:Drug Therapy, Combination / Q000379:methods; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007294:Inositol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000008:administration & dosage*; D011236:Prediabetic State / Q000188:drug therapy*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000187:drug effects; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives*
C118642:Hexim1 protein, mouse; D007004:Hypoglycemic Agents; D010880:Piperidines; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D007294:Inositol; D014498:Uracil; C520853:alogliptin; C102817:voglibose