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Cited by 39Diabetes Management and ResearchIntravenous Infusion Technology and SafetySkin Diseases and Diabetes

Detailed Analysis of Insulin Absorption Variability and the Tissue Response to Continuous Subcutaneous Insulin Infusion Catheter Implantation in Swine

Open access
Hauzenberger, Jasmin R., Hipszer, Brian R., Loeum, Channy, McCue, Peter A., DeStefano, Mark, Torjman, Marc C., Kaner, Mahmut T., Dinesen, Alek R. +3 more·2017·Diabetes Technology & Therapeutics
DOI 10.1089/dia.2017.0175PMC PMC5689134
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Abstract

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: 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.

AI snapshot

Written from the paper’s full text.

TL;DR

In a 5-day swine study, insulin absorption from a commercial CSII catheter was fastest and highest on day 5, while an investigational catheter caused more tissue trauma and more variable absorption. The surrounding inflammatory tissue layer is proposed as a mechanical barrier contributing to day-to-day insulin absorption variability.

Key findings

  • Commercial catheters (CCs) produced the fastest insulin absorption on day 5: tmax = 12.0 ± 4.5 min, highest Cmax = 114.7 ± 30.1 mU/L, and highest AUC60 = 54.9 ± 20.8 mU/L·h.
  • Both catheter types showed high intra- and intersubject day-to-day variability; for example, IC intersubject CV for AUC was 52.5% on day 1, 82.1% on day 3, and 93.8% on day 5.
  • Investigational catheters (ICs) caused significantly more tissue disruption: larger debris field (4.9 ± 1.4 mm vs 3.2 ± 1.1 mm for CCs), more irregular topography, and more reticular fiber disruption, fat necrosis, and hemorrhage at the tip base (P < 0.001 for several comparisons).
  • Both catheter types were surrounded by an inflammatory tissue layer that varied in thickness, density, composition, and continuity; the paper concludes this layer may act as a mechanical barrier to insulin flow into adjacent vascular tissue.

Methods

  • Observational study in six nondiabetic ambulatory female swine (68.5 ± 3.6 kg); 72 CSII catheters were implanted for 5 days: 36 commercial CSII catheters and 36 investigational CSII catheters.
  • Insulin lispro (U-100 Humalog) was infused via pumps; 5-U boluses were given on days 1, 3, and 5, with PK measured as Cmax, tmax, AUC, and AUC60.
  • Tissue surrounding catheters was excised after euthanasia, stained with hematoxylin and eosin, Masson’s trichrome, and reticulin, and graded by a blinded surgical pathologist for hemorrhage, reticular fiber disruption, fibrin deposition, fat necrosis, and collagen deposition.

Limitations

  • Stated: small sample size; difficulty controlling variables in awake swine such as temperature, activity level, and food intake; many catheters had occlusion alarms or dye/insulin leakage; histology sometimes did not fully localize the insertion channel; no lispro-specific ELISA was commercially available, so insulin was calculated indirectly by subtracting porcine insulin from total insulin, adding to variability.
  • Stated: PK data could not be analyzed for statistical significance due to the small number of studies.
  • Evident from text: the swine model may not fully represent human inflammatory responses, although the authors argue swine is an adequate model for human wound healing.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1089/dia.2017.0175

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

19 of 50 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    When a CSII catheter is inserted, it causes an acute inflammatory response of the adipose tissue.

    “When a CSII catheter is inserted, it causes an acute inflammatory response of the adipose tissue.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] source

      The Introduction (page not provided) says implantation of biomaterials is followed by acute inflammation and that the response depends partly on the tissue implanted. It does not specifically address CSII catheters or establish an acute response in adipose tissue. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    The degree of inflammation may influence insulin absorption.

    “The degree of inflammation is dependent on catheter material, shape, and wear-time and may influence insulin absorption.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [14] source

      The Introduction describes inflammation following biomaterial implantation, and §2.1 describes how biomaterial surfaces affect inflammatory responses. Neither addresses whether inflammation influences insulin absorption; searches for “insulin absorption” and insulin-delivery catheters found no relevant passage. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [17] source
  • Premisecitation

    Catheter insertion and maintenance damage capillaries, lymphatics, cells, and connective tissue, leading to an acute inflammatory response.

    “Catheter insertion and maintenance damage capillaries, lymphatics, cells, and connective tissue leading to an acute inflammatory response.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] source

      The Introduction (page unavailable) says that injury to vascularized connective tissue during biomaterial implantation initiates inflammation, including an acute response. It does not specifically address catheter maintenance or say that capillaries, lymphatics, and cells are damaged. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Patients routinely insert a new CSII catheter every 2-3 days because insulin absorption into the circulation becomes more variable and less reliable over time.

    “Patients routinely insert a new catheter every 2–3 days due to increasing variability of insulin absorption over time.”
    • Also stated in: § Introduction · plain
      “Patients are instructed to insert a new CSII set every 2 to 3 days because insulin absorption into the circulation becomes more variable and less reliable over time.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] source

      The Introduction recommends changing infusion sets every 48–72 hours, and the Discussion says prolonged use appeared to change insulin absorption and reduce glycemic control. But the study measured blood glucose, not variability in insulin absorption, and does not establish that increasing absorption variability is why patients routinely change catheters. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [8] Shetty G, 2010, Diabetes Technol Ther source
    • cites [9] source

      The Discussion recommends changing infusion sets every 2–3 days, and the introductory passage under Abstract says longer use appeared to change insulin absorption and worsen glycemic control. The paper does not establish increasing variability of absorption as the reason patients routinely change catheters; it also gives skin reactions and other adverse effects as reasons for the recommended interval. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Despite recent improvements in CSII catheter design and insertion method, the CSII catheter remains the weak link of an insulin infusion system for the management of type 1 diabetes.

    “Despite recent improvements in CSII catheter design and method of insertion, the CSII catheter remains the weak link of an insulin infusion system for the management of type 1 diabetes.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [5] source
    • cites [6] source

      The Abstract (page unavailable) reports that infusion-set and injection-site problems began to occur in measurable amounts on day 3 in patients with type 1 diabetes. The Discussion (page unavailable) also describes catheter-related disruptions to insulin delivery. Our copy does not establish that catheter design or insertion methods had recently improved, or compare the catheter with other components to call it the system’s weak link. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [7] source

      The Abstract and Conclusion describe infusion sets as essential to pump therapy and implicated in many pump-related adverse events, supporting the claim that the catheter remains a vulnerable component. The Conclusion discusses a newer cannula design, but the passages on insertion in “Site Selection and Rotation” describe available techniques rather than establishing that insertion methods have recently improved. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • May combine two claims. 25
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Premisecitation

    Patients commonly experience an insulin bolus that fails to produce the expected glucose lowering effect, leading to persistent hyperglycemia.

    “Patients commonly experience an insulin bolus that fails to produce the expected glucose lowering effect, leading to persistent hyperglycemia.6,19”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [6] source

      The Discussion (page unavailable) says disrupted pump delivery or prolonged catheter use can impair insulin absorption, and reports rising mean blood glucose with longer catheter use. It does not establish that a bolus commonly fails to lower glucose as expected or that this leads to persistent hyperglycemia. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [19] Patel PJ, 2013, Diabetes Technol Ther source

  • May combine two claims.

    Interpretationcitation

    This observation is consistent with published animal studies, human clinical trials, and routine clinical care.

    “This observation is consistent with published animal studies, human clinical trials, and routine clinical care.5,6,22,23”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [5] source
    • cites [6] source
    • cites [22] Plum A, 2000, Drug Metab Dispos source
    • cites [23] source

  • May combine two claims.

    Interpretationcitation

    Insulin may flow into the connective tissue septa that surround the adipose cells, remain within the surrounding layer of inflammatory tissue, and/or flow upward along the cannula shaft onto the skin surface.

    “Insulin may flow into the connective tissue septa that surround the adipose cells, remain within the surrounding layer of inflammatory tissue, and/or flow upward along the cannula shaft onto the skin surface.30,31”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [30] source

      The Results (page not available) say injected insulin distributes between fat lobules, and the Introduction describes connective tissue separating those lobules. The Discussion mentions back-flow through the injection channel. The paper does not describe insulin remaining in a surrounding layer of inflammatory tissue or flowing along a cannula shaft onto the skin surface. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [31] source

  • May combine two claims.

    Interpretationcitation

    The acute inflammatory response and the infusion of insulin may directly increase local blood flow, which may contribute to increased insulin uptake on day 5 of catheter wear-time.

    “Furthermore, the acute inflammatory response and the infusion of insulin may directly increase local blood flow,33–38 which may contribute to increased insulin uptake on day 5 of catheter wear-time.”
    Quote in the paperNot a substantial claim2 of 6 sources checked
    • cites [33] source
    • cites [34] source
    • cites [35] source
    • cites [36] source

      The Abstract (page unavailable) reports that inserting a dermal microdialysis probe significantly increased skin blood flow, supporting the proposed link between insertion trauma and local perfusion. It does not address insulin infusion, insulin uptake, or day 5 of catheter wear-time. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [37] source

      The Conclusions propose that increased blood flow around an aging infusion site could explain earlier peak insulin action. They do not identify an acute inflammatory response or insulin infusion as the direct causes of that blood flow. The Methods and Results compare day 1 with day 4, not day 5; however, the day-5 uptake finding appears to be the citing authors’ application of the proposed mechanism, rather than a finding attributed to this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [38] source

  • May combine two claims.

    Interpretationcitation

    Slow increases and abrupt decreases in insulin pump back pressure suggest that a bolus dose of insulin may accumulate within the layer of inflammatory tissue, distend the tissue, and then abruptly travel into adjacent tissue through a pathway with lower resistance.

    “Slow increases and abrupt decreases in insulin pump back pressure suggest that a bolus dose of insulin may accumulate within the layer of inflammatory tissue, distend the tissue, and then abruptly travel into adjacent tissue through a pathway with lower resistance.30”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [30] source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The CC had the highest Cmax and fastest tmax values on day 5 of catheter wear-time.

    “Insulin absorption was better when infused through a CC with highest Cmax and fastest tmax values on day 5 of catheter wear-time.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Insulin absorption was better when infused through a CC than through an IC.

    “Insulin absorption was better when infused through a CC with highest Cmax and fastest tmax values on day 5 of catheter wear-time.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Insulin absorption from the CCs was least variable on day 5 and most variable on days 1 and 3.

    “Insulin absorption from the CCs was least variable on day 5 and most variable on days 1 and 3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Many of the specimens had a continuous or near-continuous layer of inflammatory tissue surrounding the CSII cannula, while other specimens had a discontinuous layer with normal adipose tissue adjacent to the CSII cannula.

    “Many of the specimens had a continuous or near-continuous layer of inflammatory tissue surrounding the CSII cannula, while other specimens had a discontinuous layer with normal adipose tissue adjacent to the CSII cannula.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The IC of swine 1, 2, and 6 leaked dye into the CSII hub and produced limited insulin absorption on days 3 and/or 5.

    “The IC of swine 1, 2, and 6 leaked dye into the CSII hub and produced limited insulin absorption on days 3 and/or 5 (Fig. 2D).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Five CCs leaked a small amount of dye into the hub (14%).

    “One of the CCs leaked a large amount of dye into the hub (3%), five CCs leaked a small amount into the hub (14%), and four CCs had a pump occlusion alarm (11%).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    Many CCs and ICs produced one or more pump occlusion alarms, leaked dye/insulin into the hub or onto the skin surface.

    “Many CCs and ICs produced one or more pump occlusion alarms, leaked dye/insulin into the hub or onto the skin surface.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The CC of swine 1 used for the PK study did not insert fully into the subcutaneous tissue, kinked, leaked a large amount of dye onto the skin surface, and produced very limited insulin absorption into the circulation.

    “The CC of swine 1 used for the PK study did not insert fully into the subcutaneous tissue, kinked, leaked a large amount of dye onto the skin surface, and produced very limited insulin absorption into the circulation (Fig. 2B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Compared with the tissue response to IC implantation, the tissue layer surrounding the Teflon cannula had more regular connective tissue topography, more regular reservoir geometry, a smaller debris field, less reticular fiber disruption, less fat necrosis, and less hemorrhage within the reservoir.

    “Compared with the tissue response to IC implantation, the tissue layer surrounding the Teflon cannula had more regular connective tissue topography, more regular reservoir geometry, a smaller debris field, less reticular fiber disruption, less fat necrosis, and less hemorrhage within the reservoir.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The CC of swine 2 used for the PK study produced a pump occlusion alarm on day 3 only.

    “The CC of swine 2 used for the PK study produced a pump occlusion alarm on day 3 only.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No difference in tissue response was observed between infusion types, except for increased fibrin when insulin was infused.

    “We did not observe a difference in tissue response between infusion types, except for increased fibrin when insulin was infused.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    There was no statistically significant difference in fibrin or collagen deposition at the cannula tip between CCs and ICs.

    “There was no statistically significant difference in fibrin or collagen deposition at the cannula tip.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The ICs produced the highest AUC, AUC60, and Cmax on day 1, the fastest tmax on day 3, and the lowest AUC, AUC60, and Cmax on day 5.

    “In contrast, the ICs produced the highest AUC, AUC60, and Cmax on day 1, the fastest tmax on day 3, and the lowest AUC, AUC60, and Cmax on day 5.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The CCs produced the fastest insulin absorption, the highest plasma insulin concentration, and the greatest AUC60 on day 5 of implantation.

    “Of interest, the CCs produced the fastest insulin absorption, the highest plasma insulin concentration, and the greatest AUC60 on day 5 of implantation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The three ICs that produced low insulin absorption on day 5 had a pump occlusion alarm and/or leaked dye into the hub.

    “The three ICs that produced low insulin absorption on day 5 had a pump occlusion alarm and/or leaked dye into the hub.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    One of the CCs leaked a large amount of dye into the hub (3%).

    “One of the CCs leaked a large amount of dye into the hub (3%), five CCs leaked a small amount into the hub (14%), and four CCs had a pump occlusion alarm (11%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Results from this study indicate faster and better absorption of insulin on day 5, with a fairly high interindividual CV of 41% for the AUC of the commercial and 94% for the investigational catheter.

    “Results from this study indicate faster and better absorption of insulin on day 5, however, with a fairly high interindividual CV of 41% for the AUC of the commercial and 94% for the investigational catheter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Maximum insulin plasma concentration levels did not change or increased with wear-time.

    “Maximum insulin plasma concentration levels did not change or increased with wear-time.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    AUC for the CC in swine 6 could not be calculated because blood samples 20 min after bolus administration could not be collected for a period of 1.5 h in this animal.

    “We furthermore could not calculate the AUC for the CC in swine 6, as we were unable to collect blood samples 20 min after bolus administration for a period of 1.5 h in this animal.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The order of catheter type for the 5-U insulin bolus was randomized.

    “We then infused a 5-U bolus of insulin into a CC or an IC in a randomized order.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The pathologist remained blinded throughout the study.

    “The pathologist remained blinded throughout the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Blood glucose concentration was measured in duplicate using the YSI analyzer.

    “The concentration of blood glucose (BG) was measured in duplicate using the YSI analyzer.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The tissue histology grading system was newly established by the lead pathologist, who predefined the criteria before analyzing all samples.

    “This grading system was newly established by the lead pathologist of this study who predefined these criteria before analyzing all samples.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Subcutaneous tissue glucose sensors were calibrated using CVC blood samples and a reference glucose analyzer.

    “The subcutaneous tissue glucose concentration was monitored using commercial glucose sensors (SEVEN PLUS; Dexcom, Inc.) calibrated using CVC blood samples and a reference glucose analyzer (YSI-2300STAT Plus™; Yellow Springs Instruments).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    CSII catheters were carefully inspected to confirm correct insertion through the skin and into the subcutaneous tissue.

    “CSII catheters were carefully inspected to confirm correct insertion through the skin and into the subcutaneous tissue.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study protocol was approved by the Institutional Animal Care & Use Committee of Thomas Jefferson University.

    “The protocol was approved by the Institutional Animal Care & Use Committee of Thomas Jefferson University.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    A surgical pathologist analyzed the tissue specimens using an objective grading system with each swine acting as its own control.

    “A surgical pathologist analyzed the tissue specimens using an objective grading system with each swine acting as its own control.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Lysed adipose cells would have released their contents (cytoplasm, nucleus, organelles, and triglycerides) into the wound.

    “Although not visualized, lysed adipose cells would have released their contents (cytoplasm, nucleus, organelles, and triglycerides) into the wound.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Round, soft shapes are known to be better tolerated than sharp edges.

    “Round, soft shapes are known to be better tolerated that sharp edges.17,25”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] source
    • cites [25] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Histology did not always provide a complete picture of the tissue surrounding the CSII cannula, as localization of the full insertion channel was sometimes difficult.

    “In addition, histology did not always provide a complete picture of the tissue surrounding the CSII cannula, as localization of the full insertion channel was sometimes difficult.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    At the time of plasma insulin measurement, no lispro-specific ELISA was commercially available and insulin concentrations were calculated indirectly by subtracting porcine insulin from total insulin content.

    “At the time of plasma insulin measurement, no lispro-specific ELISA was commercially available and insulin concentrations were calculated indirectly by subtracting porcine insulin from total insulin content.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some patients successfully wear CSII catheters up to 7 days.

    “Studies have shown that some patients indeed successfully wear CSII catheters up to 7 days.19,24”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Patel PJ, 2013, Diabetes Technol Ther

      Not checked in the free run.

    • cites [24] source

  • May combine two claims.

    Study design and conductnone given

    The study was limited by the small sample size and the difficulty in controlling variables that may affect insulin absorption into the subcutaneous vascular tissue in awake swine, such as temperature, activity level, and food intake.

    “The study was limited by the small sample size and the difficulty in controlling variables that may affect insulin absorption into the subcutaneous vascular tissue in awake swine, such as temperature, activity level, and food intake.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Like humans, swine has a thick epidermis (70-150 μm), sparse body hair, and a similar composition of the skin lipid layer.

    “Like humans it has a thick epidermis (70–150 μm), sparse body hair, and a similar composition of the skin lipid layer.26,29”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] source
    • cites [29] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Insulin absorption can further be negatively influenced by insulin traveling upward onto the skin due to an obstruction of insulin flow into the adjacent tissue.

    “Insulin absorption can further be negatively influenced by insulin traveling upward onto the skin due to an obstruction of insulin flow into the adjacent tissue.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The clam-shell mechanism of the IC was sometimes difficult to handle and the insertion angle of the cannula was not consistent among samples.

    “The clam-shell mechanism of the IC was sometimes difficult to handle and the insertion angle of the cannula was not consistent among samples.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    When unnoticed by the patient, blood glucose control may become challenging.

    “When unnoticed by the patient, blood glucose control may become challenging.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The subcutaneous adipose tissue of the swine has a similarly high elastic and collagen fiber content and the animals show a healing mechanism comparable to humans.

    “The subcutaneous adipose tissue of the swine has a similarly high elastic and collagen fiber content and the animals show a healing mechanism comparable to humans.26,27,29”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [26] source
    • cites [27] Wang JF, 2001, Comp Med
    • cites [29] source
43 of 43

  • The paper relies on this without support.

    The tissue response and insulin absorption pharmacokinetics observed in nondiabetic swine are representative of those in humans with type 1 diabetes using CSII.

    “Detailed Analysis of Insulin Absorption Variability and the Tissue Response to Continuous Subcutaneous Insulin Infusion Catheter Implantation in Swine”
    “The study was performed in six nondiabetic ambulatory female swine (68.5 ± 3.6 kg).”

  • The paper relies on this without support.

    The differences in tissue trauma and insulin absorption variability between the IC and CC are attributable to the catheter insertion method (manual sharp tip vs 90° Teflon cannula with automated insertion) rather than to other differences in catheter material, shape, or design.

    “The CC had a stable plastic platform with an adhesive base for attachment to the skin. The 6 mm Teflon cannula was inserted at a 90° angle through the skin and subcutaneous tissue over a sharp 27-gauge steel needle. Insertion force was applied to the catheter using a spring-loaded introducer.”
    “The IC had a stable plastic platform with an adhesive base for attachment to the skin. The platform was an open clam-shell design with a side hinge. Closing the platform manually guided the curved cannula through the skin and into the subcutaneous tissue at an insertion angle of ∼60°.”

  • The paper relies on this without support.

    Patients are currently educated to replace their CCs every 2 to 3 days to minimize the risk of infection and because insulin absorption from the subcutaneous tissue into the circulation becomes more variable and less reliable over time.

    “Patients are currently educated to replace their CCs every 2 to 3 days to minimize the risk of infection and because insulin absorption from the subcutaneous tissue into the circulation becomes more variable and less reliable over time.”

  • The paper relies on this without support.

    Current recommendations do not recommend the patient to wear a CSII set until day 5.

    “The day 5 observations are of interest, as current recommendations do not recommend the patient to wear a CSII set until day 5, when insulin absorption may recover.”

  • The paper relies on this without support.

    Both manual and supported insertions are prone to insertion failure and the optimal insertion angle is not always achieved.

    “Both manual and supported insertions are prone to insertion failure and the optimal insertion angle is not always achieved.”

  • The paper relies on this without support.

    When insulin is infused, an insulin pump produces a hydrostatic pressure differential between the inside of the CSII cannula and the adjacent subcutaneous tissue, causing insulin to flow into the tissue along the path of least resistance.

    “When insulin is infused, an insulin pump produces a hydrostatic pressure differential between the inside of the CSII cannula and the adjacent subcutaneous tissue, causing insulin to flow into the tissue along the path of least resistance.”
6 of 6

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Overall Cmax comparison is reversed

    Major

    The mean of the three reported daily Cmax values is 93.1 mU/L for CCs and about 113.4 mU/L for ICs. Thus, the reported Cmax values do not support the statement that mean Cmax was higher for CCs.

  • IC variability is assigned to the wrong day

    Major

    The text calls day 3 the most variable for IC AUC and gives a CV of 93.8%, but Table 4 assigns 82.1% to day 3 and 93.8% to day 5.

  • Incorrect percentage for seven specimens in Table 2

    Minor

    The 'None' infusion group has 24 specimens, so seven specimens are 29.2%, not 29.7%.

    Reported 29.7 · recomputed 29.166667

  • Table 2 percentage denominator is misstated

    Minor

    Table 2 reports percentages within each 24-catheter infusion group: for example, 9 insulin-infused specimens are listed as 37.5%. Its note instead says the percentages are of the 36 CCs and 36 ICs total.

  • CC variability was not generally greatest on day 1

    Minor

    Table 4 shows higher between-animal CVs on day 3 than on day 1 for CC AUC60, Cmax, and tmax. Only the AUC CV is greatest on day 1.

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Patel PJ, 2013, Diabetes Technol Ther, 16, 1
  2. Wang JF, 2001, Comp Med, 51, 341

Cited by

Sorted by citations

Related

Authors
Hauzenberger, J. R., Hipszer, B. R., Loeum, C., McCue, P. A., DeStefano, M., Torjman, M. C., Kaner, M. T., Dinesen, A. R., Chervoneva, I., Pieber, T. R., & Joseph, J. I.
Affiliations
  • Thomas Jefferson University (US)
  • Chester County Historical Society (US)
  • Medical University of Graz (AT)
Corresponding author
Joseph, Jeffrey I
ORCID
Venue
Diabetes Technology & Therapeutics
Publisher
SAGE Publications
Published
2017-11
Volume
19
Issue
11
Pages
641-650
ISSN
  • 1520-9156 (ISSN-L)
  • 1557-8593
DOI
10.1089/dia.2017.0175
PMC
PMC5689134
OpenAlex
W2762466554
Semantic Scholar
b04efe0b92d5a1cd334def512745195a82f869ab
Cited by
39
References
41
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 7 · 2020: 4 · 2019: 4 · 2018: 1
FWCI
1.68
Type
journal article
Language
en
Open access
Licence
www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations
  • Diabetes Technology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • Thomas Jefferson University
  • Bosch-Forschungsstiftung
  • Austrian Science Fund (W1241)
  • Karl-Franzens-Universität Graz
  • Medizinische Universität Graz (W1241)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Physical Sciences › Engineering › Biomedical Engineering › Intravenous Infusion Technology and Safety
  • Health Sciences › Medicine › Dermatology › Skin Diseases and Diabetes
Keywords
insulin pump therapy, type 1 diabetes, insulin pharmacokinetics, catheter design, porcine model
MeSH terms
Animals, Catheters, Indwelling, Female, Hypoglycemic Agents, Inflammation, Insulin, Insulin Infusion Systems, Swine, Subcutaneous Tissue

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-13.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-13.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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