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

Abstract

SummaryInsulin 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 ~m, N~S'l,-suberoyl-insulin dimer, and N ~B29, N~B'29,-suberoyl-insulin dimer. With N ~B1, N~B'l,-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~B29,N~S'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 glu: cose disposal supports the suggestion that analogues with increased molecular size may exhibit reduced ability to gain access to peripheral target cells. [Diabetologia (1995[Diabetologia ( ) 38: 1007[Diabetologia ( -1013 Key words Insulin, insulin analogues, glucose metabolism, euglycaemic clamp, insulin action, hepatoselectivity, glucose production.Insulin influences glucose metabolism in vivo by inhibiting hepatic glucose production (Ra) and by stimulating peripheral glucose disposal (Rd) mostly in skeletal muscle [1]. There have been suggestions that

Hepatoselectivity and the evolution of insulin

“…Covalent insulin dimers N_B1, N_B 1-suberoylinsulin and N_B29, N_S 29-suberoylinsulin were prepared to increase molecular size and compared with human insulin. They exhibited a greater effect on hepatic glucose output than peripheral uptake showing relative hepatoselectivity, but the lower hypoglycaemic potency than that predicted by in vivo receptor-binding affinities limits their use in clinical practice [38].…”

Basal insulin peglispro: Overview of a novel long‐acting insulin with reduced peripheral effect resulting in a hepato‐preferential action

“…Subsequently, BIL was shown to have a reduced peripheral effect producing a hepatopreferential activity profile in a dog model of insulinopenic diabetes, 20 healthy men 21 and patients with T1D. 22 Previously, a minimal hepato-preferential activity profile had been demonstrated with proinsulin, 23,24 insulin dimers, 25 thyroxyl-insulin 26 and insulin detemir. 27,28 The protein binding of thyroxyl-insulin to thyroxine-binding protein and of detemir to albumin results in high molecular weight entities.…”

Novel hepatoselective insulin analog: studies with a covalently linked thyroxyl-insulin complex in humans.

“…Previous studies with insulin analogs have led us to suggest that the molecular size of covalent insulin dimers and proinsulin could influence access of these substances to peripheral tissues when compared with insulin (9,10). In contrast, the open sinusoids in the liver allow free access of all plasma constituents to the hepatocyte cell surface (11).…”