Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion
ABSTRACT Type 1 diabetes (T1D) is associated with low IGF-I and altered levels of IGF-binding proteins (IGFBPs) in plasma. This may be of importance for insulin sensitivity and the risk of developing diabetic complications. We hypothesized that IGF-I-bioactivity is affected by the route of insulin administration and that intraperitoneal insulin infusion (CIPII) has a more pronounced effect than subcutaneous insulin infusion (CSII).
We compared 10 patients with T1D on CIPII to 20 age-and sex matched patients on CSII. Blood sampling was done 7 to 9 am after an overnight fast. All patients were C-peptide negative. IGF-I bioactivity was measured in vitro using a specific IGF-I kinase receptor activation (KIRA) assay. IGF-I was also measured by immunoassay together with IGF-II, IGFBP-1 and IGFBP-2.
When compared to subcutaneous insulin, intraperitoneal insulin resulted in (CIPII vs. CSII) higher IGF-I bioactivity (1.83±0.76 vs. 1.16±0.24 μg/l; p=0.02), IGF-I (120±35 vs. 81±19 μg/l; p=0.01), and IGF-II (1050±136 vs. 879±110 μg/l; p=0.02). By contrast, log transformed IGFBP-1 was reduced (p=0.013), whereas log transformed IGFBP-2 was not different (p=0.12). There was a positive correlation between IGF-bioactivity and IGF-I (r=0.69; p<0.001) and an inverse correlation between IGF-bioactivity and lnBP-1 (r=-0.68, p<0.001).
The in vitro IGF-I bioactivity was higher in patients treated CIPII compared to CSII supporting the theory that the route of insulin administration is of importance for the activity of the IGF-system. Intraperitoneal insulin administration may therefore be beneficial by correcting the alterations of the IGF-system in T1D. This article is protected by copyright. All rights reserved.
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ABSTRACT: 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.This article is protected by copyright. All rights reserved.Clinical Endocrinology 07/2014; 81(4). DOI:10.1111/cen.12546 · 3.35 Impact Factor
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ABSTRACT: Growth hormone/insulin-like growth factor (IGF) axis may play a role in maintaining glucose homeostasis in synergism with insulin. IGF-1 can directly stimulate glucose transport into the muscle through either IGF-1 or insulin/IGF-1 hybrid receptors. In severely decompensated diabetes including diabetic ketoacidosis, plasma levels of IGF-1 are low and insulin delivery into the portal system is required to normalize IGF-1 synthesis and bioavailability. Normalization of serum IGF-1 correlated with the improvement of glucose homeostasis during insulin therapy providing evidence for the use of IGF-1 as biomarker of metabolic control in diabetes. Taking apart the inherent mitogenic discussion, diabetes treatment using insulins with high affinity for the IGF-1 receptor may act as an endocrine pacer exerting a cardioprotective effect by restoring the right level of IGF-1 in bloodstream and target tissues, whereas insulins with low affinity for the IGF-1 receptor may lack this positive effect. An excessive and indirect stimulation of IGF-1 receptor due to sustained and chronic hyperinsulinemia over the therapeutic level required to overtake acute/chronic insulin resistance may act as endocrine disruptor as it may possibly increase the cardiovascular risk in the short and medium term and mitogenic/proliferative action in the long term. In conclusion, normal IGF-1 may be hypothesized to be a good marker of appropriate insulin treatment of the subject with diabetes and may integrate and make more robust the message coming from HbA1c in terms of prediction of cardiovascular risk.Acta Diabetologica 08/2014; 52(3). DOI:10.1007/s00592-014-0635-6 · 3.68 Impact Factor
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ABSTRACT: Intraperitoneal insulin allows physiological portal insulin administration and first-pass hepatic insulin extraction but the impact on liver metabolism and inflammation is unknown. Our objective was to compare the impact, on metabolic control and liver function, of the same dose of insulin administered either intraperitoneally or subcutaneously during continuous infusion in diabetic rats. Wistar rats were randomly divided into 4 groups: control (C); untreated diabetic (streptozotocin, 100 mg/kg); and diabetic rats treated by continual subcutaneous Insuplant(®) infusion (CSII) or continual intraperitoneal Insuplant(®) infusion (CPII) of 2 UI/200 g/day (via an osmotic mini-pump for 1 to 4 weeks). Insulin signalling pathways were analysed through hepatic expression of growth hormone receptor and phosphorylated insulin receptor substrate 1. Metabolic control was determined by measurement of body weight, blood glucose, and fructosamine. Liver function was assessed by measuring insulin growth factor-1 (IGF-1), with global inflammation assessed by levels of alpha-2-macroglobulin (α2M) and lipid peroxidation in plasma. Liver inflammation was evaluated by quantification of hepatic macrophage infiltration and reactive oxygen species production. CPII induced a better improvement in metabolic control and liver function than CSII, producing a significant decrease in blood glucose and fructosamine, coupled with increased IGF-1 and hepatic glycogen storage. Moreover, liver oxidative stress and inflammation was reduced. Such observations indicate that the same insulin level in CPII improves glucose control and hepatic glucose metabolism and function, attenuating the hepatic inflammatory response to diabetes. These data demonstrate the importance of focusing on therapeutics to allow first-pass hepatic insulin extraction or prevent diabetic complications. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Fundamental and Clinical Pharmacology 06/2015; DOI:10.1111/fcp.12129 · 2.08 Impact Factor