Clinical Endocrinology (2014) 81, 488–497
doi: 10.1111/cen.12546
REVIEW ARTICLE
Intraperitoneal insulin infusion: treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia P.R. van Dijk*, S.J.J. Logtenberg*,†, R.O.B. Gans†, H.J.G. Bilo*,†,‡ and N. Kleefstra*,†,§ *Diabetes Centre, Isala, Zwolle, The Netherlands, †Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, ‡Department of Internal Medicine, Isala, and §Langerhans Medical Research Group, Zwolle, The Netherlands
Summary Continuous intraperitoneal insulin infusion (CIPII) is a treatment option for patients with type 1 diabetes mellitus who fail to reach adequate glycaemic control despite intensive subcutaneous (SC) insulin therapy. CIPII has clear advantages over SC insulin administration in terms of pharmacokinetic and pharmacodynamic properties and has been shown to improve glycaemic regulation. Due to the delivery of insulin predominantly in the portal vein, as opposed to systemically, CIPII offers a unique research model to investigate the effects of insulin on endocrine and metabolic parameters in vivo. The aim of the present article is to provide an overview of the literature with respect to the effects of CIPII on glucose management, quality of life, complications and costs, with additional focus on metabolic and endocrine aspects. Finally, future use and research objectives are discussed. (Received 10 April 2014; returned for revision 11 May 2014; finally revised 27 June 2014; accepted 3 July 2014)
Introduction Type 1 diabetes mellitus (T1DM) is characterized by an (almost) absent production of insulin due to various (autoimmune) mechanisms. In healthy subjects, insulin, together with other hormones, maintains blood glucose concentrations within a narrow range (35–70 mM) despite fluctuations in nutritional intake, physical exercise and other (physical or psychological) influences. In individuals with T1DM, it has been unambiguously proven that the development of micro- and macrovascular complications is linked to the duration and severity of hyperglycaemia
Correspondence: P.R. van Dijk, Diabetes Centre, Isala, P.O. box 10400, 8000 G.K. Zwolle, The Netherlands. Tel.: +31 38 424 79 42; Fax: +31 38 424 76 95; E-mail: [email protected]
488
and can be either prevented or delayed by intensive insulin therapy.1,2 Hence, an ideal insulin replacement regimen should achieve blood glucose levels as close to the physiological state as possible and thus be able to accurately reproduce both the basal and bolus component of insulin secretion. This is the aim of every exogenous insulin replacement modality in T1DM: multiple daily injections (MDI) of insulin in the subcutaneous (SC) tissue and continuous subcutaneous insulin infusion (CSII) with an externally placed pump. With MDI and CSII, deviations from the normal response occur due to pharmacokinetic and pharmacodynamic properties of SC administered insulin. For example, the lag time to insulin action after SC injection varies between 5 and 15 min for the rapidly acting insulin analogues and 6–10 h for the long-acting insulins with an effective duration between 4–6 h (rapid acting analogues) and 20–24 h (long acting analogues).3 Partly due to tissue properties, and partly due to the tendency of insulin molecules to aggregate, the rate of SC absorption of insulin varies within and between individuals. Factors that contribute to the inconsistent pharmacokinetics of insulin are related to the insulin preparation (volume, concentration and additives), differences between injection sites (anatomical region, depth of injection, degree of fibrosis and injection infiltrates) and/or changes to the injection site [local blood flow (temperature), other substances applied]. These combined factors may lead to a pronounced variability of the appearance of insulin in the circulation of up to 35%. Furthermore, intraindividual variability in insulin sensitivity is an additional important parameter determining insulin pharmacodynamics. Not surprisingly, SC administration of insulin may lead to unpredictable fluctuations in blood glucose concentrations. These fluctuations in themselves are associated with elevated HbA1c levels and hypoglycaemic episodes with subsequent stress, anxiety, impaired well-being and reduced quality of life (QoL). This unpredictability is also illustrated by the fact that, despite all efforts,
doi: 10.1111/cen.12546
REVIEW ARTICLE
Intraperitoneal insulin infusion: treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia P.R. van Dijk*, S.J.J. Logtenberg*,†, R.O.B. Gans†, H.J.G. Bilo*,†,‡ and N. Kleefstra*,†,§ *Diabetes Centre, Isala, Zwolle, The Netherlands, †Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, ‡Department of Internal Medicine, Isala, and §Langerhans Medical Research Group, Zwolle, The Netherlands
Summary Continuous intraperitoneal insulin infusion (CIPII) is a treatment option for patients with type 1 diabetes mellitus who fail to reach adequate glycaemic control despite intensive subcutaneous (SC) insulin therapy. CIPII has clear advantages over SC insulin administration in terms of pharmacokinetic and pharmacodynamic properties and has been shown to improve glycaemic regulation. Due to the delivery of insulin predominantly in the portal vein, as opposed to systemically, CIPII offers a unique research model to investigate the effects of insulin on endocrine and metabolic parameters in vivo. The aim of the present article is to provide an overview of the literature with respect to the effects of CIPII on glucose management, quality of life, complications and costs, with additional focus on metabolic and endocrine aspects. Finally, future use and research objectives are discussed. (Received 10 April 2014; returned for revision 11 May 2014; finally revised 27 June 2014; accepted 3 July 2014)
Introduction Type 1 diabetes mellitus (T1DM) is characterized by an (almost) absent production of insulin due to various (autoimmune) mechanisms. In healthy subjects, insulin, together with other hormones, maintains blood glucose concentrations within a narrow range (35–70 mM) despite fluctuations in nutritional intake, physical exercise and other (physical or psychological) influences. In individuals with T1DM, it has been unambiguously proven that the development of micro- and macrovascular complications is linked to the duration and severity of hyperglycaemia
Correspondence: P.R. van Dijk, Diabetes Centre, Isala, P.O. box 10400, 8000 G.K. Zwolle, The Netherlands. Tel.: +31 38 424 79 42; Fax: +31 38 424 76 95; E-mail: [email protected]
488
and can be either prevented or delayed by intensive insulin therapy.1,2 Hence, an ideal insulin replacement regimen should achieve blood glucose levels as close to the physiological state as possible and thus be able to accurately reproduce both the basal and bolus component of insulin secretion. This is the aim of every exogenous insulin replacement modality in T1DM: multiple daily injections (MDI) of insulin in the subcutaneous (SC) tissue and continuous subcutaneous insulin infusion (CSII) with an externally placed pump. With MDI and CSII, deviations from the normal response occur due to pharmacokinetic and pharmacodynamic properties of SC administered insulin. For example, the lag time to insulin action after SC injection varies between 5 and 15 min for the rapidly acting insulin analogues and 6–10 h for the long-acting insulins with an effective duration between 4–6 h (rapid acting analogues) and 20–24 h (long acting analogues).3 Partly due to tissue properties, and partly due to the tendency of insulin molecules to aggregate, the rate of SC absorption of insulin varies within and between individuals. Factors that contribute to the inconsistent pharmacokinetics of insulin are related to the insulin preparation (volume, concentration and additives), differences between injection sites (anatomical region, depth of injection, degree of fibrosis and injection infiltrates) and/or changes to the injection site [local blood flow (temperature), other substances applied]. These combined factors may lead to a pronounced variability of the appearance of insulin in the circulation of up to 35%. Furthermore, intraindividual variability in insulin sensitivity is an additional important parameter determining insulin pharmacodynamics. Not surprisingly, SC administration of insulin may lead to unpredictable fluctuations in blood glucose concentrations. These fluctuations in themselves are associated with elevated HbA1c levels and hypoglycaemic episodes with subsequent stress, anxiety, impaired well-being and reduced quality of life (QoL). This unpredictability is also illustrated by the fact that, despite all efforts,
