Daily inhibition of postprandial hyperglycaemia with JTT-608, a novel oral antidiabetic agent, ameliorates pancreatic function in neonatally streptozotocin-treated rats.
OBJECTIVE
Chronic glycaemic control, in particular, the control of postprandial hyperglycaemia, is essential for preventing the development of diabetic complications. We therefore evaluated the chronic treatment effect of a new antidiabetic agent, JTT-608 [trans-4-(methylcyclohexyl)-4-oxobutyric acid], in neonatally streptozotocin-treated rats.


METHODS
The rats were maintained with liquid meal three times a day and treated orally with JTT-608 10 min before each meal for 12 weeks. Haemoglobin A1C (HbA1C) and fasting blood glucose levels were measured at 4-week intervals, and effects of JTT-608 on pancreatic function and diabetic complications were examined after dosing period.


RESULTS
The postprandial hyperglycaemia was suppressed by JTT-608 administration, and both HbA1C levels and fasting blood glucose levels were reduced during the experimental period. After the treatment period of 12 weeks, JTT-608 further improved the early insulin secretion and the impaired glucose tolerance after meal loading in the diabetic rats. Also, pathological examination revealed that JTT-608 reduced the incidence of the decrease in immunoreactivity of insulin. In examination of other diabetic complications, JTT-608 ameliorated the reduced motor nerve conduction velocities observed in diabetic rats and inhibited the incidence of cataracts with diabetes.


CONCLUSIONS
We conclude that a newly developed antidiabetic agent, JTT-608, improves the pancreatic function and prevents the development of diabetic complications by inhibition of daily postprandial hyperglycaemia and could be useful for the treatment of diabetic subjects with impaired insulin secretion.
Ohta
T
T
Japan Tobacco, Central Pharmaceutical Research Institute, 1-1, Murasaki-cho, Takatsuki, Osaka, Japan. takeshi.ota@ims.jti.co.jp
Sasase
T
T
Miyajima
K
K
Matsui
K
K
Matsushita
M
M
Furukawa
N
N
Yonemori
F
F
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002087:Butyrates / Q000627:therapeutic use*; D003510:Cyclohexanes / Q000627:therapeutic use*; D048909:Diabetes Complications / Q000473:pathology / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006943:Hyperglycemia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects* / Q000503:physiopathology; D019518:Postprandial Period; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D002087:Butyrates; D003510:Cyclohexanes; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; C116719:4-(4-methylcyclohexyl)-4-oxobutyric acid