Comparison of efficacies of a dipeptidyl peptidase IV inhibitor and alpha-glucosidase inhibitors in oral carbohydrate and meal tolerance tests and the effects of their combination in mice.
E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase IV (DPP-IV) inhibitor. Since the target of both DPP-IV inhibitors and alpha-glucosidase inhibitors is the lowering of postprandial hyperglycemia, we compared antihyperglycemic effects for E3024 and alpha-glucosidase inhibitors in various oral carbohydrate and meal tolerance tests using normal mice. In addition, we investigated the combination effects of E3024 and voglibose on blood glucose levels in a meal tolerance test using mice fed a high-fat diet. ER-235516-15 (the trifluoroacetate salt form of E3024, 1 mg/kg) lowered glucose excursions consistently, regardless of the kind of carbohydrate loaded. However, the efficacy of acarbose (10 mg/kg) and of voglibose (0.1 mg/kg) varied with the type of carbohydrate administered. The combination of E3024 (3 mg/kg) and voglibose (0.3 mg/kg) improved glucose tolerance additively, with the highest plasma active glucagon-like peptide-1 levels. This study shows that compared to alpha-glucosidase inhibitors, DPP-IV inhibitors may have more consistent efficacy to reduce postprandial hyperglycemia, independent of the types of carbohydrate contained in a meal, and that the combination of a DPP-IV inhibitor and an alpha-glucosidase inhibitor is expected to be a promising option for lowering postprandial hyperglycemia.
Yamazaki
Kazuto
K
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan. k5-yamazaki@hhc.eisai.co.jp
Inoue
Takashi
T
Yasuda
Nobuyuki
N
Sato
Yoshiaki
Y
Nagakura
Tadashi
T
Takenaka
Osamu
O
Clark
Richard
R
Saeki
Takao
T
Tanaka
Isao
I
D020909:Acarbose / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D019422:Dietary Sucrose / Q000008:administration & dosage / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005526:Food, Formulated; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test / Q000379:methods; D065089:Glycoside Hydrolase Inhibitors; D006943:Hyperglycemia / Q000097:blood / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D007275:Injections, Intravenous; D007294:Inositol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019518:Postprandial Period; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
C515375:3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo(4,5-d)pyridazin-4-one tosylate; D001786:Blood Glucose; D019422:Dietary Sucrose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007328:Insulin; D011724:Pyridazines; D014105:Tosyl Compounds; C082131:Ensure formulated food; D007294:Inositol; D052216:Glucagon-Like Peptide 1; C102817:voglibose; D020909:Acarbose