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Cited by 93Pancreatic function and diabetesDiabetes Treatment and ManagementDiabetes Management and Research

Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (−)‐N‐(trans‐4‐isopropylcyclohexane‐carbonyl)‐d‐phenylalanine (A‐4166)

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Ikenoue, Takao, Akiyoshi, Megumi, Fujitani, Shoji, Okazaki, Kyoko, Kondo, Nobuo, Maki, Toshio·1997·British Journal of Pharmacology
DOI 10.1038/sj.bjp.0700875PMC PMC1564350
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Abstract

(−)‐N‐(trans‐4‐isopropylcyclohexanecarbonyl)‐d‐phenylalanine (A‐4166), a novel oral hypoglycaemic agent is a non‐sulphonylurea insulin secretagogue. We investigated the insulin‐releasing action and hypoglycaemic effect of A‐4166 compared to sulphonylureas in vitro and in vivo. A‐4166 stimulated insulin secretion from rat freshly isolated pancreatic islets at concentrations from 3×10‐6m to 3×10‐4m in the presence of 2.8 m m glucose. There was no obvious difference in glucose dependency between the insulinotropic effect of A‐4166 and that of glibenclamide, and no additive or synergistic effect was observed between these two drugs. A‐4166 displaced [3 H]‐glibenclamide bound to intact HIT‐T15 cells in a concentration‐dependent manner. The Ki value was 4.34±0.04×10−7m, and the displacement potency of A‐4166 was between that of glibenclamide and tolbutamide, being similar to that of gliclazide. In fasted beagle dogs, A‐4166 showed a dose‐dependent hypoglycaemic effect after oral administration over the range 1 to 10 mg kg−1. The hypoglycaemic action of A‐4166 showed an earlier onset and a shorter duration than that of sulphonylureas. Simultaneous measurement of plasma insulin levels revealed that the hypoglycaemic effect of A‐4166 was caused by a rapid‐onset and brief burst of insulin secretion. The pharmacokinetic profile of A‐4166 was consistent with the changes of the blood glucose and plasma insulin levels. Although the in vitro insulin‐releasing effect of A‐4166 was similar to that of sulphonylureas, its hypoglycaemic effect was more rapid and shorter‐lasting, associated with rapid absorption and clearance. Thus, A‐4166 may be useful in suppressing postprandial hyperglycaemia in patients with non‐insulin‐dependent diabetes mellitus. British Journal of Pharmacology (1997) 120, 177–186; doi:10.1038/sj.bjp.0700875

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  • Nateglinide has earlier onset and faster dissociation from sulfonylurea receptor, resulting in diminished risk of hypoglycemia.

    “Despite the possible disadvantage of this generalized binding that may cause undesirable effects on other KATP-channel types, for example, those in the heart,312 meglitinides, namely nateglinide, have an earlier onset of action and a faster dissociation rate from the sulfonylurea receptor,313, 314, 315 resulting in a diminished risk of hypoglycemia.316”

    From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [315]

    The Discussion (page not provided) reports that A-4166 has an earlier onset than sulphonylureas and suggests its short duration may reduce hypoglycaemic episodes. It does not establish faster dissociation from the sulphonylurea receptor; instead, it attributes the drug’s early, short-lived action to rapid absorption and clearance. The reported binding dissociation constant is not a dissociation rate. (LLM, conf=0.88)

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Research works printed but not linked: 1

  1. Bailey, C.J. & Flatt, P.R. pp. 93 ± 106. London: Smith-Gordon and Co.

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Authors
Ikenoue, T., Akiyoshi, M., Fujitani, S., Okazaki, K., Kondo, N., & Maki, T.
Affiliations
Ajinomoto (Japan) (JP)
Corresponding author
Ikenoue, Takao
ORCID
Kondo, Nobuo
Venue
British Journal of Pharmacology
Publisher
Wiley
Published
1997-01
Volume
120
Issue
1
Pages
137-145
ISSN
  • 0007-1188 (ISSN-L)
  • 1476-5381
DOI
10.1038/sj.bjp.0700875
PMC
PMC1564350
OpenAlex
W2011750387
Cited by
93
References
38
Citations by year
2026: 1 · 2024: 1 · 2022: 1 · 2020: 1 · 2018: 2 · 2016: 1 · 2014: 1 · 2013: 1
FWCI
13.05
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 4416 d)
Locations
  • British Journal of Pharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Kagoshima University
  • Keio University
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
oral antidiabetic drugs, insulin secretagogues, sulfonylureas, hypoglycemic effect, insulin secretion, pancreatic islets, glibenclamide, HIT-T15 cells, pharmacokinetics, postprandial blood glucose, type 2 diabetes, beagle dogs
MeSH terms
Nateglinide, Insulin Secretion, Animals, Binding, Competitive, Blood Glucose, Calcium, Cell Line, Cyclohexanes, Diazoxide, Diuretics, Dogs, Glyburide, Hypoglycemic Agents, Insulin, Islets of Langerhans, Male, Phenylalanine, Stimulation, Chemical, Rats, Wistar, Sodium Chloride Symporter Inhibitors, Rats, In Vitro Techniques

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