ISSN:
1432-0428
Keywords:
Key words Insulin
;
insulin analogues
;
glucose metabolism
;
euglycaemic clamp
;
insulin action
;
hepatoselectivity
;
glucose production.
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary 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, NαB1, NαB′ 1,-suberoyl-insulin dimer, and NɛB29, NɛB′ 29,-suberoyl-insulin dimer. With NαB1, NαB′ 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 NɛB29,NɛB′ 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. [Diabetologia (1995) 38: 1007–1013]
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00402169
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