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

Diabetologia
F Shojaee-MoradieR H Jones

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 glucos...Continue Reading

References

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Citations

Jun 1, 2005·Archives of Medical Research·Francisco J Gómez-Pérez, Juan A Rull
Sep 12, 2001·Lancet·D R OwensG B Bolli
May 18, 2013·Diabetes, Obesity & Metabolism·R HerringD L Russell-Jones
Oct 6, 2001·Endocrine Reviews·Z VajoW C Duckworth

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