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Insulin lispro reduces insulin antibodies in a patient with type 2 diabetes with immunological insulin resistance
Diabetes Research and Clinical Practice 61 (2003) 89 /92 www.elsevier.com/locate/diabres
Insulin lispro reduces insulin antibodies in a patient with type 2 diabetes with immunological insulin resistance Mahito Asai a,*, Tutomu Kodera b, Kanaki Ishizeki a, Seiji Uebori a, Tagui Kashiwaya a, Hiroshi Itoh a, Isao Makino a b
a The Second Department of Internal Medicine, Asahikawa Medical College, 078-8510 Hokkaido, Japan The Third Department of Internal Medicine, National Defense Medical College, 359-8510 Saitama, Japan
Received 25 November 2002; received in revised form 27 January 2003; accepted 11 April 2003
Abstract We describe a 54-year-old Japanese female with type 2 diabetes admitted to our hospital with poor metabolic control. On admission the patient’s HbA1c was 9.1% despite having taken over 60 U of human insulin per day for the previous 10 years. A high titer of antibodies to insulin was detected in the serum, and therefore, we decided to introduce insulin lispro with the aim of minimizing immunogenicity. Over the next 2 months, the dosage of insulin required to achieve reasonable blood glucose control was reduced, with the HbA1c level decreasing significantly to 6.8%. The patient was subsequently withdrawn from insulin and discharged on diet therapy only. This case demonstrates that insulin lispro may ameliorate resistance to insulin therapy even in the presence of human insulin antibodies. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Insulin lispro; Insulin antibodies; Immunological insulin resistance
1. Introduction Insulin lispro is a human insulin analog in which the primary sequence has been altered by the inversion of the amino acids at positions 28 and 29 of the beta chain. This inversion impairs insulin dimerization and formation of hexamers while maintaining receptor binding properties and biological activity. Insulin lispro injected subcutaneously has a faster rate of absorption, higher * Corresponding author. Tel.: /81-166-68-2454; fax: /81166-68-2459. E-mail address: [email protected] (M. Asai).
peak serum concentration, and a shorter duration of action than regular human insulin. Although human insulin and insulin lispro have common epitopes that bind to insulin antibodies [1 /3], two case reports found the analog was less immunogenic due to its lower dimerization potential [4,5]. In both cases, this reduction in the number of hexamers led to a decline in the level of insulin binding antibodies and a concomitant reduction in the units of insulin required daily. We report a patient who required a large dose of human insulin as a consequence of antibodies acquired during 10 years of insulin therapy. This patient was treated with insulin lispro, resulting in
0168-8227/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0168-8227(03)00105-0
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M. Asai et al. / Diabetes Research and Clinical Practice 61 (2003) 89 /92
improved metabolic control, a significant reduction in daily insulin requirements and a decrease in insulin antibody levels.
traction assay according to the method described by Fineberg et al. [2]. The latter antibody binds to both human- and lispro-insulin.
2. Case
3. Results
The patient was a 54-year-old Japanese female with a 21-year history of type 2 diabetes and associated complications of retinopathy, neuropathy and nephropathy. Three years previously she had undergone annuloplasty for mitral insufficiency but had no history of any other serious physical or psychological disorders. Diet therapy was initiated and included an intake of 1400 kcal, 40 g of protein and 5 g of salt per day. Subcutaneous insulin was self-injected three times daily before each meal (Penfil R† , Novo-Nordisk, Bagsvaerd, Denmark) with NPH insulin (Penfil N† ) being administered at bedtime. This regime was continued for 10 years during which time mean insulin requirements were 60 /80 U/day (corresponding to 0.8 /1.1 U/kg body weight) with the HbA1c level ranging from 7.6 to 9.1%. The patient was hospitalized in late December 2001 for the purpose of converting to insulin lispro therapy (Humalog† , Eli Lilly, Indianapolis, USA). On admission she was receiving 66 U of human insulin per day and had an HbA1c level of 9.1% and a body mass index (BMI) of 29.9 kg/m2. Fasting plasma C-peptide concentration was 5.9 ng/ml and a glucagon tolerance test resulted in a 3.9 ng/ml increase 6 min after injection of 1 mg of glucagon. Islet cell antibodies (ICA) and glutamic acid decarboxylase (GAD) antibodies were not detected. Insulin lispro treatment (28 U/day corresponding to 0.38 U/kg body weight) was started 2 weeks later with the units injected before each meal being determined by the pre-prandial blood glucose level. Blood samples were collected before insulin lispro was started and then at monthly intervals and stored frozen for measurements of antibody levels. The samples were sent to LINCO Research Inc., Missouri, USA and the percentage binding capacity of insulin specific antibody (ISA), lispro specific antibody (LSA), and cross reactive antibody (CRA) determined using a self-blank sub-
Fig. 1 summarizes the patient’s mean blood glucose levels, insulin requirements and insulin antibody levels. The patient had a rapid response to the insulin lispro injections resulting in a marked decrease in blood glucose concentration within 2 weeks. The number of units of insulin lispro in this therapy initiation was approximately half of the human insulin units administered previously. The number of units required to maintain this degree of blood glucose control continued to be gradually reduced from 28 U/ day until eventually being withdrawn 2 months later. Post-prandial mean blood glucose levels were 7.3 mmol/l with insulin lispro therapy compared with 9.8 mmol/l with human insulin therapy. During this time mean blood glucose concentration was 7.9 mmol/l and mean HbA1c was 7.4%. The binding capacity of both ISA and CRA decreased during the 6 months after insulin lispro therapy from 2.7 to 0.7% and from 44.4 to 16.2%, respectively (Fig. 1). While LSAs were detected before administration of insulin lispro, the change in treatment regime did not result in an increase in antibody levels during the observation period.
4. Discussion This case demonstrates insulin lispro is effective for achieving blood glucose control in a patient with long-standing resistance to insulin therapy caused by high titers of insulin antibodies. Six weeks after the introduction of insulin lispro, metabolic control was maintained without insulin lispro injections, and approximately 2 weeks later the patient was discharged on diet therapy only. Over the following 3 months the HbA1c remained constant between 6.8 and 7.0%, while BMI decreased from 29.9 to 27.1 kg/m2 in the 6 months after withdrawal of human insulin (data not shown). We consider there are several possible
M. Asai et al. / Diabetes Research and Clinical Practice 61 (2003) 89 /92
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Fig. 1. Decrease in mean blood glucose levels and insulin requirements, and sequential analysis of circulating insulin antibodies.
explanations why insulin lispro was effective in our patient. Firstly, insulin lispro was less immunogenic than human insulin as evidenced by the decrease in ISA and CRA levels after the introduction of the analog. Our data also indicate that insulin lispro maintains its efficacy in the presence of relatively high levels of circulating antibodies. Secondly, a decline in insulin antibody titer was associated with a decrease in immunological insulin resistance. There was also a reduction in obesity in our patient that had probably been a consequence of hyperinsulinemia during high dose human insulin therapy. Furthermore, we observed a reduction in post-prandial blood glucose levels with increasing duration of insulin lispro therapy
[6]. This combination of a decrease in insulin resistance, insulin antibody titer and obesity, with the improvement in post-prandial blood glucose levels, led us to withdraw the patient from insulin treatment. We conclude that insulin lispro is suitable for the treatment of patients with immunogenic insulin therapy resistance.
Acknowledgements We thank Liz Rinehart (LINCO Reseach, Inc., St. Charles, MO, USA) for the measurement of antibodies.
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M. Asai et al. / Diabetes Research and Clinical Practice 61 (2003) 89 /92
References [1] D.L. Bakaysa, J. Radziuk, H.A. Havel, et al., Physicochemical basis for the rapid time-action of LysB28 ProB29insulin: dissociation of a protein /ligand complex, Protein Science 5 (1996) 2521 /2531. [2] N.S. Fineberg, S.E. Fineberg, J.H. Anderson, M.A. Birkett, R.G. Gibson, S. Hufferd, Immunologic effects of insulin lispro [Lys (B28), Pro (B29) human insulin] in IDDM and NIDDM patients previously treated with insulin, Diabetes 45 (1996) 1750 /1754.
[3] L. Jovanovic, S. Ilic, D.J. Pettitt, et al., Metabolic and immunologic effects of insulin lispro in gestational diabetes, Diabetes Care 22 (1999) 1422 /1427. [4] J.T. Lahatela, M. Knip, R. Paul, J. Antonen, J. Salmi, Severe antibody-mediated human insulin resistance: successful treatment with the insulin analog lispro, Diabetes Care 20 (1997) 71 /73. [5] D. Kumar, Lispro analog for treatment of generalized allergy to human insulin, Diabetes Care 20 (1997) 1357 / 1359. [6] J. Plank, B. Semlitsch, A. Wutte, et al., A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes, Diabetes Care 25 (2002) 2053 /2057.
Insulin lispro reduces insulin antibodies in a patient with type 2 diabetes with immunological insulin resistance Mahito Asai a,*, Tutomu Kodera b, Kanaki Ishizeki a, Seiji Uebori a, Tagui Kashiwaya a, Hiroshi Itoh a, Isao Makino a b
a The Second Department of Internal Medicine, Asahikawa Medical College, 078-8510 Hokkaido, Japan The Third Department of Internal Medicine, National Defense Medical College, 359-8510 Saitama, Japan
Received 25 November 2002; received in revised form 27 January 2003; accepted 11 April 2003
Abstract We describe a 54-year-old Japanese female with type 2 diabetes admitted to our hospital with poor metabolic control. On admission the patient’s HbA1c was 9.1% despite having taken over 60 U of human insulin per day for the previous 10 years. A high titer of antibodies to insulin was detected in the serum, and therefore, we decided to introduce insulin lispro with the aim of minimizing immunogenicity. Over the next 2 months, the dosage of insulin required to achieve reasonable blood glucose control was reduced, with the HbA1c level decreasing significantly to 6.8%. The patient was subsequently withdrawn from insulin and discharged on diet therapy only. This case demonstrates that insulin lispro may ameliorate resistance to insulin therapy even in the presence of human insulin antibodies. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Insulin lispro; Insulin antibodies; Immunological insulin resistance
1. Introduction Insulin lispro is a human insulin analog in which the primary sequence has been altered by the inversion of the amino acids at positions 28 and 29 of the beta chain. This inversion impairs insulin dimerization and formation of hexamers while maintaining receptor binding properties and biological activity. Insulin lispro injected subcutaneously has a faster rate of absorption, higher * Corresponding author. Tel.: /81-166-68-2454; fax: /81166-68-2459. E-mail address: [email protected] (M. Asai).
peak serum concentration, and a shorter duration of action than regular human insulin. Although human insulin and insulin lispro have common epitopes that bind to insulin antibodies [1 /3], two case reports found the analog was less immunogenic due to its lower dimerization potential [4,5]. In both cases, this reduction in the number of hexamers led to a decline in the level of insulin binding antibodies and a concomitant reduction in the units of insulin required daily. We report a patient who required a large dose of human insulin as a consequence of antibodies acquired during 10 years of insulin therapy. This patient was treated with insulin lispro, resulting in
0168-8227/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0168-8227(03)00105-0
90
M. Asai et al. / Diabetes Research and Clinical Practice 61 (2003) 89 /92
improved metabolic control, a significant reduction in daily insulin requirements and a decrease in insulin antibody levels.
traction assay according to the method described by Fineberg et al. [2]. The latter antibody binds to both human- and lispro-insulin.
2. Case
3. Results
The patient was a 54-year-old Japanese female with a 21-year history of type 2 diabetes and associated complications of retinopathy, neuropathy and nephropathy. Three years previously she had undergone annuloplasty for mitral insufficiency but had no history of any other serious physical or psychological disorders. Diet therapy was initiated and included an intake of 1400 kcal, 40 g of protein and 5 g of salt per day. Subcutaneous insulin was self-injected three times daily before each meal (Penfil R† , Novo-Nordisk, Bagsvaerd, Denmark) with NPH insulin (Penfil N† ) being administered at bedtime. This regime was continued for 10 years during which time mean insulin requirements were 60 /80 U/day (corresponding to 0.8 /1.1 U/kg body weight) with the HbA1c level ranging from 7.6 to 9.1%. The patient was hospitalized in late December 2001 for the purpose of converting to insulin lispro therapy (Humalog† , Eli Lilly, Indianapolis, USA). On admission she was receiving 66 U of human insulin per day and had an HbA1c level of 9.1% and a body mass index (BMI) of 29.9 kg/m2. Fasting plasma C-peptide concentration was 5.9 ng/ml and a glucagon tolerance test resulted in a 3.9 ng/ml increase 6 min after injection of 1 mg of glucagon. Islet cell antibodies (ICA) and glutamic acid decarboxylase (GAD) antibodies were not detected. Insulin lispro treatment (28 U/day corresponding to 0.38 U/kg body weight) was started 2 weeks later with the units injected before each meal being determined by the pre-prandial blood glucose level. Blood samples were collected before insulin lispro was started and then at monthly intervals and stored frozen for measurements of antibody levels. The samples were sent to LINCO Research Inc., Missouri, USA and the percentage binding capacity of insulin specific antibody (ISA), lispro specific antibody (LSA), and cross reactive antibody (CRA) determined using a self-blank sub-
Fig. 1 summarizes the patient’s mean blood glucose levels, insulin requirements and insulin antibody levels. The patient had a rapid response to the insulin lispro injections resulting in a marked decrease in blood glucose concentration within 2 weeks. The number of units of insulin lispro in this therapy initiation was approximately half of the human insulin units administered previously. The number of units required to maintain this degree of blood glucose control continued to be gradually reduced from 28 U/ day until eventually being withdrawn 2 months later. Post-prandial mean blood glucose levels were 7.3 mmol/l with insulin lispro therapy compared with 9.8 mmol/l with human insulin therapy. During this time mean blood glucose concentration was 7.9 mmol/l and mean HbA1c was 7.4%. The binding capacity of both ISA and CRA decreased during the 6 months after insulin lispro therapy from 2.7 to 0.7% and from 44.4 to 16.2%, respectively (Fig. 1). While LSAs were detected before administration of insulin lispro, the change in treatment regime did not result in an increase in antibody levels during the observation period.
4. Discussion This case demonstrates insulin lispro is effective for achieving blood glucose control in a patient with long-standing resistance to insulin therapy caused by high titers of insulin antibodies. Six weeks after the introduction of insulin lispro, metabolic control was maintained without insulin lispro injections, and approximately 2 weeks later the patient was discharged on diet therapy only. Over the following 3 months the HbA1c remained constant between 6.8 and 7.0%, while BMI decreased from 29.9 to 27.1 kg/m2 in the 6 months after withdrawal of human insulin (data not shown). We consider there are several possible
M. Asai et al. / Diabetes Research and Clinical Practice 61 (2003) 89 /92
91
Fig. 1. Decrease in mean blood glucose levels and insulin requirements, and sequential analysis of circulating insulin antibodies.
explanations why insulin lispro was effective in our patient. Firstly, insulin lispro was less immunogenic than human insulin as evidenced by the decrease in ISA and CRA levels after the introduction of the analog. Our data also indicate that insulin lispro maintains its efficacy in the presence of relatively high levels of circulating antibodies. Secondly, a decline in insulin antibody titer was associated with a decrease in immunological insulin resistance. There was also a reduction in obesity in our patient that had probably been a consequence of hyperinsulinemia during high dose human insulin therapy. Furthermore, we observed a reduction in post-prandial blood glucose levels with increasing duration of insulin lispro therapy
[6]. This combination of a decrease in insulin resistance, insulin antibody titer and obesity, with the improvement in post-prandial blood glucose levels, led us to withdraw the patient from insulin treatment. We conclude that insulin lispro is suitable for the treatment of patients with immunogenic insulin therapy resistance.
Acknowledgements We thank Liz Rinehart (LINCO Reseach, Inc., St. Charles, MO, USA) for the measurement of antibodies.
92
M. Asai et al. / Diabetes Research and Clinical Practice 61 (2003) 89 /92
References [1] D.L. Bakaysa, J. Radziuk, H.A. Havel, et al., Physicochemical basis for the rapid time-action of LysB28 ProB29insulin: dissociation of a protein /ligand complex, Protein Science 5 (1996) 2521 /2531. [2] N.S. Fineberg, S.E. Fineberg, J.H. Anderson, M.A. Birkett, R.G. Gibson, S. Hufferd, Immunologic effects of insulin lispro [Lys (B28), Pro (B29) human insulin] in IDDM and NIDDM patients previously treated with insulin, Diabetes 45 (1996) 1750 /1754.
[3] L. Jovanovic, S. Ilic, D.J. Pettitt, et al., Metabolic and immunologic effects of insulin lispro in gestational diabetes, Diabetes Care 22 (1999) 1422 /1427. [4] J.T. Lahatela, M. Knip, R. Paul, J. Antonen, J. Salmi, Severe antibody-mediated human insulin resistance: successful treatment with the insulin analog lispro, Diabetes Care 20 (1997) 71 /73. [5] D. Kumar, Lispro analog for treatment of generalized allergy to human insulin, Diabetes Care 20 (1997) 1357 / 1359. [6] J. Plank, B. Semlitsch, A. Wutte, et al., A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes, Diabetes Care 25 (2002) 2053 /2057.