Chronic administration of voglibose, an alpha-glucosidase inhibitor, increases active glucagon-like peptide-1 levels by increasing its secretion and decreasing dipeptidyl peptidase-4 activity in ob/ob mice.
Administration of an alpha-glucosidase inhibitor, voglibose, increases the secretion of glucagon-like peptide (GLP)-1, a key modulator of pancreatic islet hormone secretion and glucose homeostasis. In the present study, novel mechanisms by which voglibose increases active GLP-1 circulation were evaluated. Voglibose (0.001 and 0.005%) was administered in the diet to ob/ob mice for 1 day or 3 to 4 weeks to determine effects on incretin profiles and plasma activity of dipeptidyl peptidase-4 (DPP-4), an enzyme responsible for GLP-1 degradation. Voglibose showed no direct inhibitory effect against DPP-4 in vitro (DPP-4 inhibitor alogliptin, IC(50) < 10 nM). Likewise, 1-day treatment with voglibose did not change plasma DPP-4 activity; however, it increased plasma active GLP-1 by 1.6- to 3.4-fold. After chronic treatment, voglibose stimulated GLP-1 secretion, as evidenced by the 1.3- to 1.5-fold increase in plasma active plus inactive amidated GLP-1 levels. Plasma DPP-4 activity was decreased unexpectedly by 40 to 51%, resulting from reduced plasma DPP-4 concentrations in voglibose-treated mice. Voglibose increased GLP-1 content by 1.5- to 1.6-fold and 1.4- to 1.6-fold in the lower intestine and colon, respectively. The increased GLP-1 content in the colon was associated with elevated expression of gut glucagon gene. Chronic treatment with voglibose resulted in 1.9- to 4.1-fold increase in active GLP-1 circulation, which was higher than 1-day treatment. A similar treatment with pioglitazone (0.03%), an insulin sensitizer, did not affect plasma DPP-4 activity or GLP-1 levels. These results suggest that increased GLP-1 secretion, decreased DPP-4 activity, and increased gut GLP-1 content may have contributed to increased active GLP-1 circulation after chronic treatment with voglibose in a glucose control-independent manner in ob/ob mice.
Moritoh
Yusuke
Y
Pharmacology Research Laboratories I, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka, Japan. moritou_yuusuke@takeda.co.jp
Takeuchi
Koji
K
Hazama
Masatoshi
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005934:Glucagon / Q000235:genetics; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism*; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007294:Inositol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000097:blood / Q000150:complications / Q000378:metabolism; D013997:Time Factors
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D007294:Inositol; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; C102817:voglibose