Summary
Intraperitoneal insulin infusion using implantable devices in insulin-dependent diabetic (IDDM) patients is promising since it improves diabetic control and decreases frequency of hypoglycaemia. However, preliminary data show a striking increase in plasma levels of anti-insulin antibodies with this therapy. In order to more precisely evaluate the immunogenicity and its consequences, anti-insulin antibody levels in 62 IDDM patients were assessed every 3 months during a 2-year period following pump implantation. At the same time, diabetes control was evaluated with HbA1c, mean blood glucose levels, standard deviation of the daily blood glucose levels and the frequency of low blood glucose (<3.58 mmol/l). Factors involved in antibody formation such as age, gender, HLA typing, and complement C4 alleles were also studied. After implantation, anti-insulin antibody levels increased significantly from 3.14% (range 0–26%) to 8.34% (0–49%) after 1 year and remained elevated. Patients were divided into two groups: responders able to show at least one antiinsulin antibody titre higher than 15% and non-responders whose titres were always lower than 6%. None of the factors studied was shown to statistically influence the anti-insulin antibody titres. Non-responders had significantly better metabolic results than the responders. Severe hypoglycaemic episodes decreased dramatically in both groups. Insulin requirements were comparable at time 0 and decreased initially in both groups. They remained low for the non-responders but returned to pre-implantation values for responders. Intraperitoneal insulin infusion led to a high immunogenetic response towards insulin in about half of the patients, leading to only moderately deleterious effects on metabolic control. Further studies are necessary to document other consequences (such as the role of circulating immune complexes).
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Abbreviations
- IDDM:
-
Insulin-dependent diabetes mellitus
- AIA:
-
anti-insulin antibodies
- MI:
-
multiple injections
- CSII:
-
continuous subcutaneous insulin injection
References
Saudek CD, Selam JL, Pitt THA et al. (1989) A preliminary trial of the programmable implantable medication system for insulin delivery. N Engl J Med 321: 574–579
Broussolle C, Jeandidier N, Hanaire-Broutin H (1994) French multicentre experience of implantable insulin pumps. Lancet 343: 514–515
Selam JL, Raccah D, Jeandidier N, Lozano J, Waxman K, Charles MA (1992) Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care 15: 53–58
Olsen CL, Liu G, Iravani M, Nguyen S et al. (1993) Long term safety and efficacy of programmable implantable insulin delivery systems. Int J Artif Organs 16: 847–854
Olsen CL, Chan E, Turner D et al. (1994) Insulin antibody responses after long-term intraperitoneal insulin administration via implantable programmable insulin delivery systems. Diabetes Care 17: 169–176
Boivin S, Jeandidier N, Buckenmeyer V, Sapin R, Derdour H, Pinget M (1994) Effect of immunogenicity of long term continuous peritoneal insulin infusion (CPII) on metabolic parameters in type I diabetic patients. Horm Metab Res 26: A7 (Abstract)
Bousquet-Rouaud R, Chante MA, Orsetto A, Mirouze J (1990) Increase in anti-insulin antibody titer during continuous peritoneal insulin infusion. Artficial Organs 14 [Suppl 3]: 241–244
Charles MA, Dunn F, Nathan D, Scavini M (1993) Insulin antibody levels after 2–3 years of intraperitoneal or intravenous insulin using implantable insulin delivery. Diabetologia 36 [Suppl 1]: A161 (Abstract)
Lassmann-Vague V, Belicar P, Raccah D, Vialettes B, Vague Ph (1993) Immunogenicity of long term intra-peritoneal insulin infusion and relation to metabolic control. Diabetologia 36 [Suppl 1]: A38 (Abstract)
Selam JL, Charles MA (1990) Devices for insulin administration. Diabetes Care 13: 955–959
Delahunty T (1990) Convenient screening for hemoglobin variants by using the Diamat HPLC system Clin Chem 36: 903–905
Vartdal F, Gaudernack G, Funderud S et al. (1986) HLA class I and class II typing using cells positively selected from blood by immunomagnetic isolation: a fast and reliable technique. Tissue Antigens 28: 301
The DCCT Study 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 (14): 977–986
Ushigata Y, Kuwata S et al. (1992) Strong association of insulin autoimmune syndrome with HLA DR4. Lancet 339–394
Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann New York Acad. Sci. 51: 660–672
Sodoyez JC, Koch M, Sodoyez-Goffaux F (1991) Anticorps anti-insuline: méthodologie et implications cliniques. Diabète et Métabolisme 17: 255–269
Roitt I (1989) In: Pradel (ed) Immunologie. Editions Pradel no first name Initials. City Paris 75001 France. Publisher Jouve (18 rue Saint Denis 75001 Paris) p 122
Kahn CR, Mann D, Rosenthal AS, Galloway JA, Johnson AH, Mendell N (1982) The immune response to insulin in man. Interaction of HLA alloantigens and the development of the immune response. Diabetes 31: 716–723
Reeves WG, Barr D, Douglas CA et al. (1984) Factors governing the human immune response to injected insulin. Diabetologia 26: 266–271
Andersen O (1972) Insulin antibody formation. The influence of age, sex, infections, insulin dosage and regulation of diabetes. Acta Endocrinol 71: 126–140
Chute EP, Rupp WM, Barbosa JJ et al. (1985) Anti-insulin antibody titers after one year of intravenous insulin infusion by implantable pump. Surgical Forum 36: 189–191
Overkamp D, Mohammed Ali S, Cartledge C, Landon J (1988) Production of polyclonal antibodies in ascitic fluid of mice: technique and appolications. J Immunoassay 9 (1): 51–58
Lalor P, Mora G (1990) The peritoneal Ly (CD5) B cell repertoire is unique among murine B cell repertoire. Eur J Immunol 20: 485–492
Fineberg SE, Galloway JA, Fineberg NS, Goldman J (1983) Effects of species of origin, purification levels, and formulation on insulin immunogenicity. Diabetes 32: 592–599
Heding LG, Larsson Y, Ludvigsson J (1980) The immunogenicity of insulin preparations: antibody levels before and after transfer to highly purified porcine insulin. Diabetologia 19: 511–515
Kurtz AB, Matthews JA, Mustaffa BE, Daggett PR, Nabarro JDN (1980) Decrease of antibodies to insulin, proinsulin and contaminating hormones after changing treatment from conventional beef to purified pork insulin. Diabetologia 18: 147–150
Grau U (1985) Chemical stability of insulin in a delivery system environment. Diabetologia 28: 458–463
Kasama T, Iwata Y et al. (1981) Antigenicity of desamidoinsulin and monocomponent insulin. Diabetologia 21: 65–69
Grau U, Saudek C (1987) Stable insulin preparation for implanted insulin pumps. Diabetes 36: 1453–1459
Robbins DC, Cooper SM, Fineberg SE, Mead PM (1987) Antibodies to covalent aggregates of insulin in blood of insulin-using diabetic patients. Diabetes 36: 838–841
Chantelau E, Sonnenberg GE, Heding LG, Berger M (1984) Impaired metabolic response to regular insulin in the presence of high level of circulating insulin-binding immunoglobulin G. Diabetes Care 7: 403
Van Haeften TW, Heiling VJ, Gerich JE (1987) Adverse effects of insulin antibodies on postprandial plasma glucose and insulin profiles in diabetic patients without immune insulin resistance. Implications for intensive insulin regimens. Diabetes 36: 305–309
Van Haeften TW (1989) Clinical significance of insulin antibodies in insulin-treated diabetic patients. Diabetes Care 12: 641–648
Waldhausl W, Bratusch-Marrain P, Kruse V, Jensen I, Nowotny P, Vierhapper H (1985) Effect of insulin antibodies on insulin pharmacokinetics and glucose utilization in insulin-dependent diabetic patients. Diabetes 34: 166–173
De Pirro R, Fusco A, Spallone L, Magnatta R, Lauro R (1980) Insulin antibodies prevent insulin-receptor interactions. Diabetologia 19: 118–122
Koch M, Sodoyez JC, Sodoyez-Goffaux F, Dozio N, Di Silvio LS, Kurtz AB (1989) Is quantitative assessment of insulin-antibodies and autoantibodies feasible? Diabetologia 32: 774–778
Davidson JK, Fineberg SE, De Meyts P, Fineberg N, Galloway JA (1992) Immunological and metabolic responses of patients with history of antibody-induced beef insulin resistance to treatment with beef, pork, human, and sulfated beef insulin. Diabetes Care 15: 702–704
Koch M, FranÇois-Gerard C, Sodoyez-Goffaux F, Sodoyez JC (1986) Semi-quantitative assessment of anti-insulin total IgG subclasses in insulin immunised patients using a highly sensitive immunochemical micromethod. Diabetologia 29: 720–726
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Jeandidier, N., Boivin, S., Sapin, R. et al. Immunogenicity of intraperitoneal insulin infusion using programmable implantable devices. Diabetologia 38, 577–584 (1995). https://doi.org/10.1007/BF00400727
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DOI: https://doi.org/10.1007/BF00400727