Summary
The biological properties of three covalently-linked insulin dimers were studied in greyhounds. Constant infusions showed that the plasma distribution kinetics were slower for the dimers than for insulin. The metabolic clearance rates of the three dimers (10.3±0.4, 8.8±0.5, 8.2±0.5 ml· min-1· kg-1; mean ± SEM) were significantly lower than that of insulin (19±0.8 ml · min-1 · kg-1), and their hypoglycaemic effects (11.2%, 3% and 0.3%) were markedly reduced compared with their lipogenic potencies in vitro (80%, 30% and 13%, respectively). A low dose infusion of insulin or an equipotent dose of one of the dimers significantly prolonged the effects of an insulin bolus on plasma glucose but not on non-esterified fatty acids. The apparent distribution space (106.4±11.9 ml/kg) and clearance rate (14.7±0.5 ml · min-1 · kg-1) of an insulin bolus were significantly reduced by one dimer (44.5±8.4 ml/ kg and 10.7±2.8ml·min-1·kg-1) but not by the equipotent insulin infusion (102.7±8.2ml/kg and 16.4±0.07ml· min-1 · kg-1). The apparent partial competitive antagonism of insulin by the dimers that has been reported in vitro can be observed in vivo, in that antagonism of insulin metabolism was directly demonstrated with one of the dimers.
Article PDF
Similar content being viewed by others
References
Jones RH, Dron DI, Ellis MJ, Sönksen PH, Brandenburg D (1976) Biological properties of chemically modified insulins. I. Biological activity of proinsulin and insulin modified at A1-glycine and B29-lysine. Diabetologia 12: 601–608
The Peking Insulin Structure Research Group (1974) Studies on the insulin crystal structure: the molecule at 1.8 A resolution. Sci Sin 17: 752–778
Pullen RA, Lindsay DG, Wood SP, Tickle IJ, Blundell TL, Wollmer A, Krail G, Brandenburg D, Zahn H, Gliemann J, Gammeltoft S (1976) Receptor-binding region of insulin. Nature 259: 369–373
Jones RH, Quine KH, Tatnell MA, Dron DI, Brandenburg D, Lindsay D (1977) Chemically modified insulins: the relationship between biological activity and metabolism. Diabetologia 13: 405 (Abstract)
Willey KP, Tatnell MA, Jones RH, Schüttler A, Brandenburg D (1980) Biological properties of covalent insulin dimers. In: Brandenburg D, Wollmer A (eds) Insulin chemistry, structure, and function of insulin and related hormones. deGruyter, Berlin New York, pp 425–431
Thomas SL, Wisher MH, Brandenburg D, Sönksen PH (1979) Insulin action on adipocytes. Biochem J 184: 355–360
Schüttler A, Brandenburg D (1982) Preparation and properties of covalently-linked insulin dimers. Hoppe-Seyler's Z Physiol Chem 363: 317–330
Dole VP, Meinertz H (1960) Microdetermination of long-chain fatty acids in plasma and tissues. J Biol Chem 235: 2595–2599
Sönksen PH, Tompkins CVT, Srivastava MC, Nabarro JDN (1973) A comparative study on the metabolism of human insulin and porcine proinsulin in man. Clin Sci Mol Med 45: 633–654
Morgan CR, Lazarow A (1963) Immunoassay of insulin. Two antibody system plasma insulin levels of normal, subdiabetic and diabetic rats. Diabetes 12: 115–126
Tatnell MA, Jones RH (1981) Effects of pH and NaCl concentrations on binding of covalently-linked insulin dimers to liver plasma membranes. Hoppe-Seyler's Z Physiol Chem 362: 1315–1321
Wick AN, Drury DR (1958) Effects of superimposed native insulin on disposal of iodoinsulin in the body. Proc Soc Exp Biol Med 97: 514–416
Schade DS, Eaton RP (1977) Dose response to insulin in man: differential effects on glucose and ketone body regulation. J Clin En-docrinol Metab 44: 1038–1053
Cheng JS, Kalant K (1970) Effects of insulin and growth hormone on the flux rates of plasma glucose and free fatty acids in man. J Clin Endocrinol 31: 647–653
Brown PM, Tompkins CV, Juul S, Sönksen PH (1978) Mechanism of the action insulin in diabetic patients: a dose related effect on glucose production and utilisation. Br Med J 1: 1239–1242
Tompkins CV, Brandenburg D, Jones RH, Sönksen PH (1981) Mechanism of action of insulin and insulin analogues. Diabetologia 20: 94–101
Cherrington AD, Vranic M (1974) Effect of interaction between insulin and glucagon on glucose turnover and FFA concentration in normal and depancreatised dogs. Metabolism 23: 729–744
Cryer PE (1981) Glucose counterregulation in man. Diabetes 30: 261–266
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tatnell, M.A., Jones, R.H. & Sönksen, P.H. Covalently-linked insulin dimers: their metabolism and biological effects in vivo as partial competitive antagonists of insulin clearance. Diabetologia 27, 27–31 (1984). https://doi.org/10.1007/BF00253497
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00253497