A pharmacological approach assessing the role of mast cells in insulin infusion site inflammation

Kesserwan, Shereen; Li, Mao; Sharafieh, Roshanak; Kreutzer, Donald L.; Klueh, Ulrike

doi:10.1007/s13346-021-01070-w

Cited by 2 publications

(3 citation statements)

References 30 publications

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“…Notably, two independent MC-deficient mouse strains, the Cpa3-Cre ; Mcl-1 fl/fl and the C57BL/6j-Kit W-Sh/W-sh , demonstrated the same outcome. Thus, we conclude that obtaining the same results using a pharmacological approach [ 11 ] and a genetic approach while utilizing two distinctive different MC-deficient mouse strains establishes an MC role in IPP-induced inflammation.…”

Section: Discussionmentioning

confidence: 56%

“…Of note is the significantly increased total leukocyte count mainly driven by an increased neutrophil influx at 3 days in the air pouch of non-diabetic control mice ( C57BL/ 6J) ( Figure 2 A,B). This was not repeated at day 7 or in the HSD:CD-1 strains [ 6 , 7 , 8 , 10 , 11 ]. Although, reduced PMN chemotaxis [ 38 ], including the reduced leukocyte recruitment in diabetes patients [ 39 ] compared to that in non-diabetic controls, has been demonstrated, the reduced immune response in IPP-induced leukocyte influx in STZ-induced diabetic C57BL/6 J mice over a 3-day period warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Several hypotheses have been proposed regarding the limited insulin infusion set functional lifespan, including inflammation induced by the material–tissue interface [ 2 , 3 , 4 ], insulin aggregate formation [ 5 , 6 ], or the toxicity of insulin phenolic preservatives (IPPs), such as phenol and m-cresol [ 7 , 8 , 9 , 10 ]. Specifically, our laboratory reported that these IPPs lead to unwanted cell and tissue toxicity [ 6 , 7 , 10 ], whereas Cromolyn sodium, an MC membrane stabilizer, significantly minimized IPP-induced inflammation [ 11 ]. These Cromolyn studies targeting MCs highlighted the potential to improve on automated insulin-delivery systems by mitigating the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

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Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation

Kesserwan

Sadagurski

et al. 2023

Biomedicines

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One major obstacle that limits the lifespan of insulin infusion pumps is surmounting the tissue site reaction at the device implantation site. All commercial insulin formulations contain insulin phenolic preservatives (IPPs) designed to ensure insulin protein stability and prolong shelf-life. However, our laboratory demonstrated that these preservatives are cytotoxic and induce inflammation. Mature mast cells (MCs) reside in cutaneous tissue and are one of the first responders to an epidermal breach. Upon activation, MCs release proinflammatory and immunomodulatory prepacked mediators that exacerbate these inflammatory reactions. Thus, we hypothesized that once the epidermis is breached, cutaneous MCs are triggered inciting the inflammatory response to IPP-induced inflammation. This hypothesis was pursued utilizing our modified in vivo mouse air pouch model, including a c-kit dependent (C57BL/6J-kitW-sh/W-sh) and a c-kit independent (Cpa3-Cre; Mcl-1fl/fl) MC-deficient mouse model. Leukocytes were quantified in the mouse air pouch lavage fluid following flow cytometry analysis for IPP infusion under three different states, insulin-containing phenolic preservatives (Humalog®), insulin preservatives alone, and normal saline as a control. The air pouch wall was assessed using histopathological evaluations. Flow cytometry analysis demonstrated a statistically significant difference in inflammatory cell recruitment for both MC-deficient mouse models when compared to the control strain including infused control saline. Significantly less inflammation was observed at the site of infusion for the MC-deficient strains compared to the control strain. Overall, concordant results were obtained in both mouse types, C57Bl6-kitW-sh/W-sh and Cpa3-Cre; Mcl-1fl/fl. These findings in multiple model systems support the conclusion that MCs have important or possible unique roles in IPP-induced inflammation.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation

Kesserwan

Sadagurski

et al. 2023

Biomedicines

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Inflammation at Site of Insulin Infusion Diminishes Glycemic Control

Kesserwan¹,

Lewis²,

Li³

et al. 2022

Journal of Pharmaceutical Sciences

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The approximation of euglycemia is the most effective means of preventing diabetic complications, which is achieved through effective insulin delivery. Recent reports indicate that insulin phenolic preservatives, which are found in all commercial insulin formulations, are cytotoxic, pro-inflammatory and induce secondary fibrosis. Therefore, we hypothesize that these preservatives induce an inflammatory response at the site of insulin infusion leading to diminished glycemic control and adverse pharmacokinetic outcomes. Insulin degradation by inflammatory cell proteases was quantitated following protease treatment in vitro. A modified murine air pouch model was utilized to evaluate the relative inflammatory responses following infusions of saline, insulin preservatives, and insulin, utilizing the adjuvant irritant thioglycolate. Blood glucose levels were monitored in diabetic mice with and without air pouch irritation. A pharmacokinetic analysis evaluated insulin effectiveness for diabetic mice between these two conditions. Inflammatory cells are significantly present in insulin preservative-induced inflammation, which effects diminished blood glucose control by both insulin uptake and degradation. Insulin containing these preservatives resulted in similar degrees of inflammation as observed with the irritant thioglycolate. These studies imply that the preservative agents found in commercial insulin formulations induce an intense localized inflammatory reaction. This inflammatory reaction may be responsible for the premature failure of insulin infusion devices. Future studies directed at reducing this inflammatory reaction may prove to be an important step in extending the lifespan of insulin infusion devices.

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A pharmacological approach assessing the role of mast cells in insulin infusion site inflammation

Cited by 2 publications

References 30 publications

Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation

Mast Cell Deficiency in Mice Attenuates Insulin Phenolic Preservative-Induced Inflammation

Inflammation at Site of Insulin Infusion Diminishes Glycemic Control

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