No Association between Glycemia and Wound Healing in an Experimental <i>db/db</i> Mouse Model

Berdal, Margrete; Jenssen, Trond

doi:10.1155/2013/307925

Cited by 8 publications

(9 citation statements)

References 22 publications

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“… 9 , 10 By contrast, the role of hyperglycemia per se is not well elucidated and remains controversial. 3 , 11 , 12 Clinical studies reported that hyperglycemia may interfere with ischemia and adversely affect the outcome of ischemic insults, 13 – 17 but this interaction has not been investigated in wound repair yet.…”

mentioning

confidence: 99%

Hyperglycemia Interacts with Ischemia in a Synergistic Way on Wound Repair and Myofibroblast Differentiation

Tobalem¹,

Lévigne²,

M³

et al. 2015

Plastic and Reconstructive Surgery - Global Open

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Background:Hyperglycemia is known to adversely affect the outcome of ischemic insults, but its interaction with ischemia has not been investigated in wound repair yet. In this study, we develop a new animal model allowing to investigate the interaction between hyperglycemia and ischemia during the wound repair process. We focus on myofibroblast differentiation, a key element of wound repair.Methods:Ischemia was inflicted in Wistar rats by resection of the femoral to popliteal arteries on the left side, whereas arteries were dissected without resection on the right side. Full-thickness skin wounds (1 cm2) were created on both feet. Hyperglycemia was induced by injection of streptozotocin. Normoglycemic animals served as control (n = 23/group). Blood flow, wound closure, and myofibroblast expression were measured.Results:Wound closure was significantly delayed in ischemic compared with nonischemic wounds in all rats. This delay was almost 5-fold exacerbated in hyperglycemic rats compared with normoglycemic rats, while hyperglycemia alone showed only a slight effect on wound repair. Delayed wound repair was associated with impaired wound contraction and myofibroblast differentiation.Conclusions:Our model allows to specifically quantify the effect of hyperglycemia and ischemia alone or in combination on wound repair. We show that hyperglycemia amplifies the inhibitory effect of ischemia on wound repair and myofibroblast expression. Our data reveal for the first time the synergic aspect of this interaction and therefore stress the importance of a strict glycemic control in the management of ischemic wounds.

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confidence: 99%

Hyperglycemia Interacts with Ischemia in a Synergistic Way on Wound Repair and Myofibroblast Differentiation

Tobalem¹,

Lévigne²,

M³

et al. 2015

Plastic and Reconstructive Surgery - Global Open

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“… 27 – 29 Investigators have documented that the impairment in excisional wound closure in db/db and ob/ob mice does not correlate with the magnitude of hyperglycemia. 30 , 31 …”

Section: Discussionmentioning

confidence: 99%

Myocutaneous revascularization following graded ischemia in lean and obese mice

Clark¹,

Coffman²,

McGuire

et al. 2016

DMSO

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Background Murine models of diabetes and obesity have provided insight into the pathogenesis of impaired epithelialization of excisional skin wounds. However, knowledge of postischemic myocutaneous revascularization in these models is limited. Materials and methods A myocutaneous flap was created on the dorsum of wild type (C57BL/6), genetically obese and diabetic (ob/ob, db/db), complementary heterozygous (ob + /ob − , db + /db − ), and diet-induced obese (DIO) mice (n=48 total; five operative mice per strain and three unoperated mice per strain as controls). Flap perfusion was documented by laser speckle contrast imaging. Local gene expression in control and postoperative flap tissue specimens was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). Image analysis of immunochemically stained histologic sections confirmed microvascular density and macrophage presence. Results Day 10 planimetric analysis revealed mean flap surface area necrosis values of 10.8%, 12.9%, 9.9%, 0.4%, 1.4%, and 23.0% for wild type, db + /db − , ob + /ob − , db/db, ob/ob, and DIO flaps, respectively. Over 10 days, laser speckle imaging documented increased perfusion at all time points with revascularization to supranormal perfusion in db/db and ob/ob flaps. In contrast, wild type, heterozygous, and DIO flaps displayed expected graded ischemia with failure of perfusion to return to baseline values. RT-PCR demonstrated statistically significant differences in angiogenic gene expression between lean and obese mice at baseline (unoperated) and at day 10. Conclusion Unexpected increased baseline skin perfusion and augmented myocutaneous revascularization accompanied by a control proangiogenic transcriptional signature in genetically obese mice compared to DIO and lean mice are reported. In future research, laser speckle imaging has been planned to be utilized in order to correlate spatiotemporal wound reperfusion with changes in cell recruitment and gene expression to better understand the differences in wound microvascular biology in lean and obese states.

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“…Strengths of the present study include first, examination of different AGu doses (1 g/L, 5 g/L) and their effects. Second, the experiments were conducted in a well-recognized animal model of type 2-diabetes and wound healing [7] [21] [24]. Third, metabolic effects (body weight, A1C) associated with the relatively long lasting intervention were detected and accounted for.…”

Section: Discussionmentioning

confidence: 99%

“…All experiments were performed within a time frame of 24 months, and results from group 4 have previously been presented [24].…”

Section: Woundingmentioning

confidence: 99%

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Effects of AGE Inhibition with Aminoguanidine in a Diabetic <i>db/db</i> Mouse Wound Model

Berdal¹,

Jenssen²

2014

JDM

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Advanced glycation end products (AGEs) react non-enzymatically with tissue proteins to form irreversible structures involved in atherosclerosis, nephropathy, retinopathy, neuropathy, and wound healing. Studies on AGE-inhibitors have demonstrated possible prevention of diabetes complications. The present open label study was conducted on aminoguanidine (AGu), an inhibitor of AGE-formation, to examine potential effects on wound healing in diabetes type 2-like db/db mice during 5-6 weeks. The animals were divided into 4 groups: AGu from the day of wounding (day 0) topically and/or systemically in drinking water (1 g/L; group 1, n = 13); AGu 1 g/L in drinking water from 7 weeks prior to day 0 (group 2, n = 21); AGu 5 g/L in drinking water from 9-11 weeks prior to day 0 (group 3, n = 6); placebo controls (group 4, n = 8). Results: Glycated hemoglobin (A1C) was significantly lower in group 3 compared to the other groups (P < 0.05). Percentage change in A1C and body weight from baseline to the end of the experiment were both related to the AGu doses (1 or 5 g/L; A1C-change, P = 0.01; weight-change, P = 0.04, both for linear trend across groups 4, 2, and 3, respectively). Even so, percentage wound closure was not improved in the AGu-treated groups compared to controls (P ≥ 0.8).

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No Association between Glycemia and Wound Healing in an Experimental db/db Mouse Model

Cited by 8 publications

References 22 publications

Hyperglycemia Interacts with Ischemia in a Synergistic Way on Wound Repair and Myofibroblast Differentiation

Hyperglycemia Interacts with Ischemia in a Synergistic Way on Wound Repair and Myofibroblast Differentiation

Myocutaneous revascularization following graded ischemia in lean and obese mice

Effects of AGE Inhibition with Aminoguanidine in a Diabetic <i>db/db</i> Mouse Wound Model

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No Association between Glycemia and Wound Healing in an Experimental db/db Mouse Model

Cited by 8 publications

References 22 publications

Hyperglycemia Interacts with Ischemia in a Synergistic Way on Wound Repair and Myofibroblast Differentiation

Hyperglycemia Interacts with Ischemia in a Synergistic Way on Wound Repair and Myofibroblast Differentiation

Myocutaneous revascularization following graded ischemia in lean and obese mice

Effects of AGE Inhibition with Aminoguanidine in a Diabetic &lt;i&gt;db/db&lt;/i&gt; Mouse Wound Model

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Effects of AGE Inhibition with Aminoguanidine in a Diabetic <i>db/db</i> Mouse Wound Model