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

Diabetes Res Clin Pract. 1991 Apr;12(1):53-9. doi: 10.1016/0168-8227(91)90130-6.

Abstract

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.

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Cyclohexanes / pharmacology*
  • Cyclohexanes / therapeutic use
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / drug therapy*
  • Dogs
  • Glucose Tolerance Test
  • Glyburide / pharmacology
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Male
  • Mice
  • Mice, Mutant Strains
  • Nateglinide
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacology
  • Phenylalanine / therapeutic use
  • Rats
  • Rats, Inbred Strains
  • Tolbutamide / pharmacology

Substances

  • Blood Glucose
  • Cyclohexanes
  • Hypoglycemic Agents
  • Insulin
  • Nateglinide
  • Phenylalanine
  • Tolbutamide
  • Glyburide