DEMONSTRATION OF A RELATIVELY HEPATOSELECTIVE EFFECT OF COVALENT INSULIN DIMERS ON GLUCOSE-METABOLISM IN DOGS

Insulin analogues with relatively greater effect on hepatic glucose pr oduction than peripheral glucose disposal could offer a more physiolog ical approach to the treatment of diabetes mellitus. The fact that pro insulin exhibits this property to a minor degree may suggest that anal ogues with increased molecular size may be less able than insulin to o btain access to peripheral receptor sites. Covalent insulin dimers hav e 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 he patic and peripheral effects of covalent insulin dimers, glucose clamp procedures with D-[3-H-3]glucose tracer infusions were used in anaest hetised greyhounds to establish dose-response curves for rates of hepa tic 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-insul in dimer molar potencies relative to insulin were 68%, (34-133) (mean and 95 % fiducial limits), for inhibition of hepatic glucose productio n and 14.7 %, (10.3-20.9) for glucose disposal. With N-epsilon B29,N-e psilon 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 g lucose disposal, respectively. The demonstration that both dimers exhi bit a significantly greater effect on glucose production than on gluco se disposal supports the suggestion that analogues with increased mole cular size may exhibit reduced ability to gain access to peripheral ta rget cells.