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Delayed insulin absorption correlates with alterations in subcutaneous depot kinetics in rats with diet-induced obesity.

ABSTRACT: Objective:Obesity is associated with delayed insulin absorption upon subcutaneous (s.c.) dosing in humans. The aim of this study was to investigate whether alterations in depot structure and kinetics of the s.c. injection depot contribute to this delay. Methods:Rats fed a high-fat diet (HFD) and low-fat diet (LFD) were included in a series of insulin pharmacokinetic and imaging studies. Injection depots were visualized with micro X-ray computed tomography imaging upon s.c. administration of insulin aspart mixed with the contrast agent iomeprol, and insulin aspart exposure was measured by means of luminescent oxygen channelling immunoassay. Results:Body weight and fat mass were increased in rats fed an HFD vs. LFD (p < 0.05), whereas the lean mass was not. The HFD group exhibited delayed insulin absorption from the s.c. tissue (p < 0.001). This delay was associated with smaller injection depots upon s.c. dosing (p < 0.05) and correlated with a slower depot disappearance from the s.c. tissue (p < 0.05) compared with the LFD group. Depot disappearance from the s.c. tissue was inversely correlated with body fat mass (p < 0.05). Conclusions:Alterations in s.c. injection depot structure and kinetics may play a role in the obesity-associated delay in insulin absorption.

SUBMITTER: Gradel AKJ

PROVIDER: S-EPMC6587326 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Delayed insulin absorption correlates with alterations in subcutaneous depot kinetics in rats with diet-induced obesity.

Gradel A K J AKJ Porsgaard T T Brockhoff P B PB Seested T T Lykkesfeldt J J Refsgaard H H F HHF

Obesity science & practice 20190318 3

<h4>Objective</h4>Obesity is associated with delayed insulin absorption upon subcutaneous (s.c.) dosing in humans. The aim of this study was to investigate whether alterations in depot structure and kinetics of the s.c. injection depot contribute to this delay.<h4>Methods</h4>Rats fed a high-fat diet (HFD) and low-fat diet (LFD) were included in a series of insulin pharmacokinetic and imaging studies. Injection depots were visualized with micro X-ray computed tomography imaging upon s.c. adminis ...[more]

PMID: 31275602

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Project description:BACKGROUND:Worldwide, ?1 million people manage their type 1 diabetes with an insulin pump and a continuous subcutaneous insulin infusion (CSII) catheter. Patients routinely insert a new catheter every 2-3 days due to increasing variability of insulin absorption over time. Catheter insertion and maintenance damage capillaries, lymphatics, cells, and connective tissue leading to an acute inflammatory response. METHODS:We compared an investigational CSII catheter (IC) and a commercial CSII catheter (CC) regarding insulin absorption pharmacokinetics (PK) and tissue inflammation. The two different catheter designs were implanted into the subcutaneous tissue of six swine for 5 days. Insulin boluses were given on days 1, 3, and 5 of wear-time to assess PK. Tissue around catheters was excised and stained to visualize inflammation and morphological changes of adjacent tissue. RESULTS:Insulin absorption was better when infused through a CC with highest Cmax and fastest tmax values on day 5 of catheter wear-time. Both catheter types produced high intra- and intersubject day-to-day insulin absorption variability. The IC caused significantly more tissue disruption and lead to irregular changes in tissue morphology. Both catheter types were surrounded by a layer of inflammatory tissue that varied in composition, thickness, and density over time. A catheter that was manually inserted by pushing a sharp tip through the skin caused more trauma and variability than a 90° Teflon cannula with automated insertion. CONCLUSIONS:Insulin absorption variability could be attributed to the layer of inflammatory tissue, which may function as a mechanical barrier to insulin flow into adjacent vascular tissue. The impact of the acute inflammatory tissue response on insulin absorption has to be considered in future catheter designs. A catheter that was manually inserted by pushing a sharp tip through the skin caused more trauma and variability than a 90° Teflon cannula with automated insertion.

Dataset Information

Delayed insulin absorption correlates with alterations in subcutaneous depot kinetics in rats with diet-induced obesity.

Publications

Delayed insulin absorption correlates with alterations in subcutaneous depot kinetics in rats with diet-induced obesity.

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