A small-molecule glucokinase activator lowers blood glucose in the sulfonylurea-desensitized rat.
Glucokinase activators increase insulin release from pancreatic beta-cells and hepatic glucose utilization by modifying the activity of glucokinase, a key enzyme in glucose-sensing and glycemic regulation. Sulfonylureas are antihyperglycemic agents that stimulate insulin secretion via a glucose-independent mechanism that is vulnerable to secondary failure through beta-cell desensitization. The present study determined whether glucokinase activator treatment retains its glucose-lowering efficacy in male, adult, non-diabetic Sprague-Dawley rats desensitized to sulfonylurea treatment and whether glucose-lowering during chronic glucokinase activator treatment is subject to secondary failure. Animals were given food containing either glimepiride (a sulfonylurea), Compound B (3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide, an experimental glucokinase activator), or no drug for up to 5 weeks. Food containing 0.04% of either drug produced acute (within 4-8 h) and significant (P<0.05) reductions in blood glucose to approximately 50% of control levels. Chronic treatment with either 0.01% or 0.04% glimepiride resulted in complete failure of glucose-lowering efficacy within 3 days whereas the efficacy of Compound B was sustained throughout the entire study. Glipizide, also a sulfonylurea, had no glucose-lowering effect when given by gavage (3mg/kg) to glimepiride-desensitized animals whereas Compound B retained full glucose-lowering efficacy in glimepiride-desensitized animals. Oral glucose tolerance was significantly impaired, compared with controls, in animals treated with glimepiride for two weeks but was enhanced to a small extent in animals treated with Compound B. Compound B also significantly increased pancreatic insulin content, compared with controls. These findings suggest that Compound B has sustained glucose-lowering effects in a rat model of sulfonylurea failure.
Ohyama
Sumika
S
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. sumika_ohyama@merck.com
Takano
Hiroki
H
Iino
Tomoharu
T
Nishimura
Teruyuki
T
Zhou
Yun-Ping
YP
Langdon
Ronald B
RB
Zhang
Bei B
BB
Eiki
Jun-ichi
J
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004987:Ethers / Q000737:chemistry / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013997:Time Factors
D001786:Blood Glucose; C118183:CH3OCF2CH(CF3)OCH2F; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D007328:Insulin; D013453:Sulfonylurea Compounds; C057619:glimepiride; D005941:Glucokinase