Possibility of ideal blood glucose control by a new oral hypoglycemic agent, N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166), and its stimulatory effect on insulin secretion in animals.
N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) revealed a new mode of hypoglycemic action with a more rapid onset and a shorter duration of action than the sulfonylureas (SUs). Hypoglycemic mechanisms and glycemic control benefits were demonstrated in laboratory animals. The stimulatory effect of A-4166 on insulin release, in fasting dogs with a cannula into the portal vein, was more rapid than that of tolbutamide after oral administration. A-4166 stopped the stimulation of insulin secretion very quickly, whereas tolbutamide maintained an elevation in plasma insulin levels for at least 6 hours. In the case of A-4166, a counter-regulatory glucagon response was observed during recovery from hypoglycemia, but it was significantly inhibited by tolbutamide. Hyperglycemia induced by glucose loading was rapidly inhibited by A-4166 in normal rats, in genetically diabetic KK mice and in STZ-induced non-insulin-dependent diabetes mellitus (NIDDM) rats. Also, repeated administration of A-4166 for 2 weeks enhanced insulin secretion in the same manner as a single administration in normal rats. In conclusion, A-4166 is a new type of oral hypoglycemic agent, having a rapid and short-term insulin secretory effect and no suppressive effect on the hypoglycemia-induced glucagon response. Oral therapy with A-4166 would be beneficial in supplementing endogenous insulin secretion and would exert ideal glycemic control in NIDDM patients.
Sato
Y
Y
Central Research Laboratories, Ajinomoto Co., Inc., Life Science Laboratories, Yokohama, Japan.
Nishikawa
M
M
Shinkai
H
H
Sukegawa
E
E
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D004285:Dogs; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D014044:Tolbutamide / Q000494:pharmacology
D001786:Blood Glucose; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D000077715:Nateglinide; D010649:Phenylalanine; D014044:Tolbutamide; D005905:Glyburide