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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
Article first published online: 22 SEP 2009
DOI: 10.1111/j.1463-1326.2009.01156.x
© 2010 Blackwell Publishing Ltd
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How to Cite
Moritoh, Y., Takeuchi, K. and Hazama, M. (2010), 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. Diabetes, Obesity and Metabolism, 12: 224–233. doi: 10.1111/j.1463-1326.2009.01156.x
Publication History
- Issue published online: 31 JAN 2010
- Article first published online: 22 SEP 2009
- Date submitted 2 June 2009; date of first decision 10 August 2009; date of final acceptance 16 August 2009
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Keywords:
- alogliptin;
- dipeptidyl peptidase-4;
- glucagon-like peptide-1;
- prediabetes;
- voglibose
Aim: 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.