Effect of storage temperature of insulin on pharmacokinetics and pharmacodynamics of insulin mixtures injected subcutaneously in subjects with Type 1 (insulin-dependent) diabetes mellitus

Summary

These studies were undertaken to assess the influence of storage temperature of insulin vials on pharmacokinetics and pharmacodynamics of a mixture of lente insulin (Monotard HM) and regular insulin (Actrapid HM) injected subcutaneously. Seven subjects with Type 1 (insulin-dependent) diabetes mellitus were studied twice after overnight normalization of plasma glucose. A mixture of lente insulin (0.22 U/kg) and regular insulin (0.11 U/kg) was prepared from insulin vials kept either refrigerated (∼4 °C) or at room temperature (∼18 °C) and injected subcutaneoulsy (abdomen). Euglycaemia was maintained for the following 16 h by glucose infusion at variable rate. With refrigerated insulin, the plasma free insulin peak was greater (53±5 versus 45±6 mU/l) and occurred earlier (2.5±0.2 versus 6±0.3 h), and the glucose infusion rate showed a greater (16.5±1.2 versus 14.5±0.9 μmol·kg−1·min−1) and earlier peak (3.2±0.2 versus 6±0.4 h) as compared to that occurring with the non-refrigerated insulin (p<0.05). However, 6 h after insulin injection, both plasma free insulin and glucose infusion rate were 30% lower with the mixture of refrigerated as compared to that of non-refrigerated insulin (p<0.05). In contrast, when NPH-insulin (Protaphane HM) was mixed with regular insulin and injected in 4 out of the 7 diabetic patients, the storage temperature of insulin vials had no effect on the pharmacokinetics and pharmacodynamics of the mixture. Thus, the storage temperature of insulin vials profoundly influences the effects of the mixture lente/regular insulin, but does not affect the pharmacokinetics and pharmacodynamics of the mixture NPH/regular insulin.

References

  1. 1.

    Schlichtkrull J (1977) The absorption of insulin. Acta Paediatr Scand 270 (Suppl): 97–102

    Google Scholar 

  2. 2.

    Galloway JA, Spradlin CT, Nelson RL, Wentworth SM, Davidson JA, Swarner JL (1981) Factors influencing the absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures. Diabetes Care 4: 366–376

    Google Scholar 

  3. 3.

    Berger M, Cuppers HJ, Hegner H, Jorgens V, Berchtold P (1982) Absorption kinetics and biological effects of subcutaneously injected insulin preparations. Diabetes Care 5: 77–91

    Google Scholar 

  4. 4.

    Heine RJ, Bilo HJG, Fonk T, van der Veen EA, von der Mer J (1984) Absorption kinetics and action profiles of mixtures of short and intermediate-acting insulins. Diabetologia 27: 558–562

    Google Scholar 

  5. 5.

    Colagiuri S, Villabolos S (1986) Assessing effect of mixing insulins by glucose clamp technique in subjects with diabetes mellitus. Diabetes Care 9: 579–586

    Google Scholar 

  6. 6.

    Forlani G, Santacroce G, Ciavarella A, Capelli M, Mattioli L, Vannini P (1986) Effects of mixing short- and intermediate-acting insulins on absorption course and biologic effect of short-acting preparation. Diabetes Care 9: 587–590

    Google Scholar 

  7. 7.

    Olsson PO, Arnqvist H, von Schenck H (1987) Miscibility of human semisynthetic regular and lente insulin and human biosynthetic regular and NPH insulin. Diabetes Care 10: 473–477

    Google Scholar 

  8. 8.

    Muhlhauser I, Broermann C, Tsotsalas M, Berger M (1984) Miscibility of human and bovine ultralente insulin with soluble insulin. Br Med J 289: 1656–1657

    Google Scholar 

  9. 9.

    Heine RJ, Bilo HJG, Sikkenk AC, van der Veen EA (1985) Mixing short and intermediate acting insulins in the syringe: effect on postprandial blood glucose concentrations in type 1 diabetics. Br Med J 290: 204–205

    Google Scholar 

  10. 10.

    Goicolea I, Quiroga A, Vazquez JA (1987) The effect of insulin mixtures in type 1 diabetics: influence of the intermediate acting insulin on the action of short acting insulin. Diabete Metabolisme 13: 467–470

    Google Scholar 

  11. 11.

    Best JD, Ley CJ, Strauss BJG, Alford FP, Aitken PM (1987) The clinical effects of mixing short- and intermediate-acting insulins in the treatment of non-insulin-dependent diabetes. Med J Austr 146: 621–627

    Google Scholar 

  12. 12.

    Kolendorf K, Boisen J, Deckert T (1983) Absorption and miscibility of regular porcine insulin after subcutaneous injection in insulin-treated diabetic patients. Diabetes Care 6: 6–9

    Google Scholar 

  13. 13.

    Deckert T (1980) Intermediate acting insulin preparations: NPH and Lente. Diabetes Care 3: 623–626

    Google Scholar 

  14. 14.

    Binder C, Lauritzen T, Faber O, Pramming S (1984) Insulin pharmacokinetics. Diabetes Care 3: 188–199

    Google Scholar 

  15. 15.

    Faber O, Binder C (1977) C-peptide response to glucagon: a test for the residual B-cell function in diabetes mellitus. Diabetes 26: 605–610

    Google Scholar 

  16. 16.

    Naka K, Yamazaki K, Yamamoto H (1981) Development of glycosylated hemoglobin A1c Auto-Analyzer. Jpn J Clin Lab Automation 6 [Suppl]: 1–2

    Google Scholar 

  17. 17.

    McGuire E, Helderman J, Tobin R, Andres R, Berman M (1976) Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol 41: 565–573

    Google Scholar 

  18. 18.

    De Feo P, Perriello G, Ventura MM, Calcinaro F, Basta G, Lolli C, Cruciani C, Dell'Olio A, Santeusanio F, Brunetti P, Bolli GB (1986) Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon. Diabetologia 29: 475–480

    Google Scholar 

  19. 19.

    Bolli G, De Feo P, Perriello G, De Cosmo S, Compagnucci P, Santeusanio F, Brunetti P, Unger RH (1984) Mechanisms of glucagon secretion during insulin-induced hypoglycemia in man: role of the betacell and arterial hyperinsulinemia. J Clin Invest 73: 917–922

    Google Scholar 

  20. 20.

    Kuzuya H, Blix PM, Horwitz DL, Steiner DF, Rubenstein AH (1977) Determination of free and total insulin and C-peptide in insulin-treated diabetics. Diabetes 26: 22–29

    Google Scholar 

  21. 21.

    Faber O, Binder C, Markussen J, Heding L, Naithani V, Kuzuya H, Blix P, Horwitz D, Rubenstein A (1978) Characterization of seven C-peptide antisera. Diabetes 27 [Suppl. 1]: 170–177

    Google Scholar 

  22. 22.

    Zar J (1984) Biostatistic Analysis. Prentice Hall, Englewood Cliffs, NJ

    Google Scholar 

  23. 23.

    Grootendorst BC, Jonkers JR, Kruit I (1983) The miscibility of short acting insulins with depot insulins. An in vitro study Pharm Week 118: 746–751

    Google Scholar 

  24. 24.

    Galloway JA, Spradlin T, Jackson RL, Otto CD, Bechte LD (1982) Mixtures of intermediate-acting insulin (NPH and lente) with regular insulin: a update. In: Skyler J (ed) Insulin update. Excerpta Medica, Amsterdam, p 11–120

    Google Scholar 

  25. 25.

    Nolle MS, Poon V, Grodsky GM, Forsham PH, Karam JH (1983) Reduced solubility of short-acting soluble insulins when mixed with longer-acting insulins. Diabetes 32: 1177–1181

    Google Scholar 

  26. 26.

    Tsotsalas M, Muhlhauser I (1985) Miscibility of human lente insulin with soluble insulin. Diabetologia 28: 252

    Google Scholar 

  27. 27.

    Berger M (1985) Pharmacokinetics of subcutaneously injected insulin: the miscibility of short and long-acting insulin preparations. In: Crepaldi G, Tiengo A, Baggio G (eds) Diabetes, Obesity and Hyperlipemias, Vol 3. Excerpta Medica, Amsterdam, p 427–431

    Google Scholar 

  28. 28.

    Bilo HJ, Sikkenk AC, van der Meer J, van der Veen EA (1987) Absorption kinetics and action profiles after sequential subcutaneous administration of human soluble and lente insulin through one needle. Diabetes Care 10: 466–469

    Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perriello, G., Torlone, E., Di Santo, S. et al. Effect of storage temperature of insulin on pharmacokinetics and pharmacodynamics of insulin mixtures injected subcutaneously in subjects with Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 31, 811–815 (1988). https://doi.org/10.1007/BF00277482

Download citation

Key words

  • Insulin pharmacokinetics
  • insulin pharmacodynamics
  • insulin mixtures
  • glucose clamp
  • insulin absorption
  • regular insulin
  • lente insulin
  • NPH insulin