, Volume 38, Issue 5, pp 592–598 | Cite as

Long-term comparison of human insulin analogue B10Asp and soluble human insulin in IDDM patients on a basal/bolus insulin regimen

  • F. S. Nielsen
  • L. N. JØrgensen
  • M. Ipsen
  • A. I. Voldsgaard
  • H. -H. Parving


Recombinant DNA technology allows the production of insulin analogues with faster absorption rates from subcutaneous tissue as compared to soluble human insulin. The human insulin analogue B10Asp (mono/dimeric) is absorbed twice as fast as soluble human insulin (hexameric). A double blind, randomised crossover study with a 1-month run-in period and two 2-month treatment periods was performed in 21 male insulin-dependent diabetic (IDDM) patients aged 18–40 years in order to compare the metabolic control obtained with equimolar doses of the analogue B10Asp vs soluble human insulin (Actrapid) given as mealtime insulin and intermediate acting isophane insulin (Protaphane) at bedtime. At the end of each 2-month study period, the patients were admitted to the metabolic ward. We found significantly higher plasma insulin/analogue levels after breakfast, lunch and dinner with B10Asp as compared to Actrapid (p<0.05). The plasma insulin/analogue levels were significantly lower before lunch and dinner with B10Asp as compared to Actrapid (p<0.05). Also, the plasma insulin/analogue level tended to be lower at bedtime when comparing B10Asp to Actrapid. The 24-h blood glucose profiles showed identical fasting blood glucose, significantly lower blood glucose after breakfast with the analogue (p<0.05), no differences in blood glucose after lunch and dinner but a significantly higher blood glucose at midnight using the analogue (p<0.05). The overall 24-h mean blood glucose concentrations, the daily insulin dose, HbA1c, diet, home blood glucose monitoring and frequency of hypoglycaemia were almost identical in the two treatment periods. In conclusion, the overall glycaemic control remained unchanged and quite good when Actrapid was exchanged dose for dose with the insulin analogue B10Asp in IDDM patients treated with a basal bolus regime.

Key words

IDDM insulin analogues metabolic control 



Insulin-dependent diabetes mellitus




insulin-like growth factor-I


  1. 1.
    Eschewege E, Job D, Guyot-Argenton C, Aubry JP, Tchobroutsky G (1979) Delayed progression of diabetic retinopathy by divided insulin administration: a further follow up. Diabetologia 16: 13–15PubMedGoogle Scholar
  2. 2.
    Deckert T, Lauritzen T, Parving H-H, Christiansen JS (1984) Effect of two years of strict metabolic function in long-term insulin-dependent diabetes. Diabetic Nephropathy 3: 6–10Google Scholar
  3. 3.
    The Kroc Collaborative Study Group (1984) Blood glucose control and the evolution of diabetic retinopathy and albuminuria. N Engl J Med 311: 365–372Google Scholar
  4. 4.
    Beck-Nielsen H, Richelsen B, Mogensen CE (1985) Effect of insulin pump treatment for one year on renal function and retinal morphology in patients with IDDM. Diabetes Care 8: 585–589PubMedGoogle Scholar
  5. 5.
    Olsen T, Richelsen B, Ehlers N, Beck-Nielsen H (1987) Diabetic retinopathy after 3 years treatment with continous subcutaneous insulin infusion (CSII). Acta Ophtalmol 65: 185–189Google Scholar
  6. 6.
    Christensen CK, Sandahl Christiansen J, Schmidt A (1987) Effect of continuous subcutaneous insulin infusion on kidney function and size in IDDM patients: a 2-year controlled study. J Diab Compl 1: 91–95Google Scholar
  7. 7.
    Dahl-JØrgensen J, Hanssen KF, Kierulf P, BjØro T, Sandvik L, Aagenaes Ø (1988) Reduction of urinary albumin excretion after 4 years of continuous subcutaneous insulin infusion in insulin-dependent diabetes mellitus. Acta Endocrinol 117: 19–25PubMedGoogle Scholar
  8. 8.
    Verrillo A, de Teresa A, Martino C, Verrillo L, di Chiara G (1988) Long-term correction of hyperglycemia and progression of retinopathy in insulin dependent diabetes: a five-year randomized prospective study. Diabetes Research 8: 71–76PubMedGoogle Scholar
  9. 9.
    Reichard P, Berglund B, Britz A, Cars I, Nilsson BY, Rosenqvist U (1991) Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years. J Intern Med 230: 101–108PubMedGoogle Scholar
  10. 10.
    Wang PH, Lau J, Chalmers TC (1993) Meta-analysis of effects of intensive blood-glucose control on late complications of type 1 diabetes. Lancet 341: 1306–1309PubMedGoogle Scholar
  11. 11.
    The Diabetes Contact and Complication Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 329: 977–986Google Scholar
  12. 12.
    Small M, MacRury S, Boal A, Paterson KR, MacCuish AC (1988) Comparison of conventional twice daily subcutaneous insulin administration and a multiple injection regimen (using the NovoPen) in insulin-dependent diabetes mellitus. Diabetes Research 8: 85–89PubMedGoogle Scholar
  13. 13.
    Gall M-A, Mathiesen ER, SkØtt P, Musaeus L, Damm S, Beck-Nielsen H et al. (1989) Effect of multiple insulin injections with a pen injector on metabolic control and general well-being in insulin-dependent diabetes mellitus. Diabetes Research 11: 97–101PubMedGoogle Scholar
  14. 14.
    Houtzagers CMG, Berntzen PA, van der Stap H et al. (1989) Efficacy and acceptance of two intensified conventional insulin therapy regimens: a long-term cross-over comparison. Diabet Med 6: 416–421PubMedGoogle Scholar
  15. 15.
    Eaton RP, Allen RC, Schade S, Standefer JC (1980) Normal insulin secretion: the goal of artificial insulin delivery systems? Diabetes Care 3: 270–273PubMedGoogle Scholar
  16. 16.
    Schade DS, Eaton RP, Spencer W (1980) Normalisation of plasma insulin in diabetic subjects with programmed insulin delivery. Diabetes Care 3: 9–14PubMedGoogle Scholar
  17. 17.
    Owens DR (1986) Human insulin: clinical pharmacological studies in normal man. MTP Press Lancaster pp. 46–70Google Scholar
  18. 18.
    Van Haeften TW, Bolli GB, Dimitridias GD, Gottesman IS, Horwitz DL, Gerich JE (1986) Effect of insulin antibodies and their kinetic characteristics on plasma free insulin dynamics in patients with diabetes mellitus. Metabolism 7: 649–656CrossRefGoogle Scholar
  19. 19.
    Home PD, Pickup JC, Keen H, Alberti KGMM, Parson JA, Binder C (1981) Continuous subcutaneous insulin infusion: comparison of plasma insulin profiles after infusion or bolus injection of the mealtime dose. Metabolism 30: 439–442CrossRefPubMedGoogle Scholar
  20. 20.
    Blundell T, Dodson G, Hodgkin D, Mercola D (1972) Insulin: the structure in the crystal and its reflection in chemistry and biology. Adv Protein Chem 26: 279–402Google Scholar
  21. 21.
    Binder C (1969) Absorption of injected insulin. Acta Pharmacol Toxicol 17: 67–87Google Scholar
  22. 22.
    Mosekilde E, Jensen KS, Binder C, Pramming S, Thorsteinsson B (1989) Modeling absorbtion kinetics of subcutaneous injected soluble insulin. J Pharmacokinet Biopharm 17: 67–87PubMedGoogle Scholar
  23. 23.
    Brange J, Ribel U, Hansen JF et al. (1988) Monomeric insulins obtained by protein engineering and their medical implications. Nature 333: 679–682CrossRefPubMedGoogle Scholar
  24. 24.
    Kang S, Brange J, Burch A, VØlund A, Owens DR (1991) Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans. Diabetes Care 14: 942–948PubMedGoogle Scholar
  25. 25.
    Kang S, Creagh FM, Peters JR, Brange J, VØlund A, Owens DR (1991) Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type I diabetic subjects. Diabetes Care 14: 571–577PubMedGoogle Scholar
  26. 26.
    Heinemann L, Starke AA, Heding L, Jensen I, Berger M (1990) Action profiles of fast onset insulin analogues. Diabetologia 33: 384–386PubMedGoogle Scholar
  27. 27.
    Hother-Nielsen O, Faber O, SØrensen NS, Beck-Nielsen H (1988) Classification of newly diagnosed diabetic patients as insulin-requiring or non-insulin-requiring based on clinical and biochemical variables. Diabetes Care 11: 531–537PubMedGoogle Scholar
  28. 28.
    Andersen I, Hannibal S (1983) Analytical and economical optimization of a glucose method with immobilized enzymes. J Automatic Chemistry 4: 188–192Google Scholar
  29. 29.
    Goldstein DE, Peth SB, England JD, Hess RL, Randall LH, DaCosta J (1980) Effects of acute changes in blood glucose on HbA1c. Diabetes 29: 623–628PubMedGoogle Scholar
  30. 30.
    Heding LG (1972) Determination of total serum (IRI) in insulin-treated diabetic patients. Diabetologia 8: 260–266PubMedGoogle Scholar
  31. 31.
    Schlichtkrull J, Munch O, Jersild M (1965) The M-value, an index of blood sugar in diabetes. Acta Med Scand 177: 95–102PubMedGoogle Scholar
  32. 32.
    Friedewald WT, Levy RI, Frederickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifugation. Clin Chem 18: 499–502PubMedGoogle Scholar
  33. 33.
    Christensen C, Ørskov C (1984) Rapid screening PEG radioimmunoassay for quantification of pathological microalbuminuria. Diabetic Nephropathy 3: 92–94Google Scholar
  34. 34.
    Drejer K, Kruse V, Larsen UD (1988) Insulin analogs: binding to the human liver cell line, Hep G2. Diabetes Res Clin Pract 5 [Suppl 2]: 102–103 (Abstract)Google Scholar
  35. 35.
    Jansson PA, Fowelin JP, von Schenck HP, Smith UP, Lönnroth PN (1993) Measurement by microdialysis of the insulin concentration in subcutaneous interstitial fluid. Diabetes 42: 1469–1473PubMedGoogle Scholar
  36. 36.
    JØrgensen LN, Nielsen FS (1990) Timing of pre-meal insulins in diabetic patients on a multiple daily injection regimen. A questionnaire study. Diabetologia 33: A116 (Abstract)Google Scholar
  37. 37.
    Linde B (1986) Dissociation of insulin absorption and blood flow during massage of a subcutaneous injection site. Diabetes Care 6: 570–574Google Scholar
  38. 38.
    Dillon RS (1983) Improved serum insulin profiles in diabetic individuals who massaged their insulin injection sites. Diabetes Care 6: 399–401PubMedGoogle Scholar
  39. 39.
    Taylor R, Home PD, Alberti KGMM (1981) Plasma free insulin profiles after administration of insulin by jet and conventional syringe injections. Diabetes Care 4: 377–379PubMedGoogle Scholar
  40. 40.
    Pehling GB, Gerlich JE (1984) Comparison of plasma insulin profiles after administration of insulin by jet spray and conventional needle in patients with insulin-dependent diabetes mellitus. Mayo Clin Proc 59: 751–754PubMedGoogle Scholar
  41. 41.
    Edsberg B, Herly D, Hildebrandt P, Kühl C (1987) Insulin bolus given by sprinkler needle: effect on absorption and glycaemic responce to a meal. BMJ 294: 1373–1376PubMedGoogle Scholar
  42. 42.
    Linde B, Gunnarsson R (1985) Influence of aprotinin on insulin absorption and subcutaneous blood flow in type 1 (insulin-dependent) diabetes. Diabetologia 28: 645–648PubMedGoogle Scholar
  43. 43.
    Kang S, Brange J, Burch A, VØlund A, Owens DR (1991) Absorption kinetics and action profiles of subcutaneously administered insulin analogues (AspB9, GluB27, AspB10, AspB28) in healthy subjects. Diabetes Care 14: 1057–1065PubMedGoogle Scholar
  44. 44.
    JØrgensen LN, Didriksen LH, Drejer K (1992) Carcinogen effect of the human insulin analogue B10 Asp in female rats. Diabetologia 35 [Suppl 1]: A3 (Abstract)Google Scholar
  45. 45.
    Bornfeldt KE, Gidlof RA, Wasteson A, Lake M, Skottner A, Arnqvist HJ (1991) Binding and biological effects of insulin, insulin analogues and insulin-like growth factors in rat aortic smooth muscle cell. Comparison of maximal growth promoting activities. Diabetologia [Suppl] 34: 307–313Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • F. S. Nielsen
    • 1
  • L. N. JØrgensen
    • 2
  • M. Ipsen
    • 1
  • A. I. Voldsgaard
    • 1
  • H. -H. Parving
    • 1
  1. 1.Steno Diabetes CenterGentofteDenmark
  2. 2.Novo Nordisk A. S.BagsvÆrdDenmark

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