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Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs.

Shojaee-Moradie, F, Jackson, NC, Boroujerdi, M, Brandenburg, D, Sönksen, PH and Jones, RH (1995) Demonstration of a relatively hepatoselective effect of covalent insulin dimers on glucose metabolism in dogs. Diabetologia, 38 (9). pp. 1007-1013.

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Abstract

Insulin analogues with relatively greater effect on hepatic glucose production than peripheral glucose disposal could offer a more physiological approach to the treatment of diabetes mellitus. The fact that proinsulin exhibits this property to a minor degree may suggest that analogues with increased molecular size may be less able than insulin to obtain access to peripheral receptor sites. Covalent insulin dimers have previously been shown to possess lower hypoglycaemic potencies than predicted by their in vivo receptor binding affinities. Reduced rates of diffusion to peripheral target tissues might be an explanation for the lower in vivo potency compared to insulin. To test the relative hepatic and peripheral effects of covalent insulin dimers, glucose clamp procedures with D-[3-3H]glucose tracer infusions were used in anaesthetised greyhounds to establish dose-response curves for rates of hepatic glucose production and glucose disposal with insulin, N alpha B1, N alpha B'1,-suberoyl-insulin dimer, and N epsilon B29, N epsilon B'29,-suberoyl-insulin dimer. With N alpha B1, N alpha B'1,-suberoyl-insulin dimer molar potencies relative to insulin were 68%, (34-133) (mean and 95% fiducial limits), for inhibition of hepatic glucose production and 14.7%, (10.3-20.9) for glucose disposal. With N epsilon B29,N epsilon B'29,-suberoyl-insulin dimer potencies were 75%, (31-184) and 2.5%. (1.5-4.3), for inhibition of hepatic glucose production and for glucose disposal, respectively. The demonstration that both dimers exhibit a significantly greater effect on glucose production than on glucose disposal supports the suggestion that analogues with increased molecular size may exhibit reduced ability to gain access to peripheral target cells.

Item Type: Article
Authors :
NameEmailORCID
Shojaee-Moradie, Ff.shojaee-moradie@surrey.ac.ukUNSPECIFIED
Jackson, NCUNSPECIFIEDUNSPECIFIED
Boroujerdi, MUNSPECIFIEDUNSPECIFIED
Brandenburg, DUNSPECIFIEDUNSPECIFIED
Sönksen, PHUNSPECIFIEDUNSPECIFIED
Jones, RHUNSPECIFIEDUNSPECIFIED
Date : September 1995
Uncontrolled Keywords : Analysis of Variance, Animals, Blood Glucose, Dogs, Glucose, Glucose Clamp Technique, Humans, Insulin, Kinetics, Liver, Metabolic Clearance Rate, Radioisotope Dilution Technique, Recombinant Proteins, Structure-Activity Relationship, Tritium
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:32
Last Modified : 17 May 2017 09:32
URI: http://epubs.surrey.ac.uk/id/eprint/824110

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