Insulin Therapy for Wound Healing: A Meta-Analysis
Overview
Insulin, known for its affordability and widespread availability, has emerged as a promising agent in the realm of wound healing. This study delved into the potential of local insulin administration to facilitate the recovery of damaged skin among non-diabetic adults. To achieve this, a systematic search was conducted across electronic databases, including Embase, Ovid MEDLINE, and PubMed. The gathered studies were meticulously screened and extracted by two independent reviewers. In total, seven randomized controlled trials aligning with the inclusion criteria were subjected to analysis. The Revised Cochrane Risk-of-Bias Tool for Randomized Trials was employed to assess the risk of bias, followed by a meta-analysis.
The primary outcome of this investigation revolved around the rate of wound healing, measured in square millimeters per day. The findings in this domain revealed a noteworthy enhancement in the insulin-treated group, showcasing an overall significant mean improvement (IV=11.84; 95% CI: 0.64–23.04; p=0.04; I2=97%) when compared to the control group.
Examining secondary outcomes, it was determined that there existed no statistically significant difference in the healing time, measured in days (IV=5.40; 95% CI:11.28 to 0.48; p=0.07; I2=89%). However, a compelling discovery emerged: a substantial reduction in wound area was observed in the insulin-treated group. Furthermore, the administration of localized insulin did not yield any adverse events, underscoring its safety. As wounds healed, irrespective of insulin administration, there was a marked improvement in the quality of life.
While this study unveiled an improved rate of wound healing associated with insulin, other parameters did not exhibit statistically significant differences. Hence, the call for larger prospective studies becomes imperative to comprehensively explore the impact of insulin on various types of wounds. Such endeavors aim to formulate an appropriate insulin regimen tailored for clinical practice, offering renewed hope for accelerated wound healing in non-diabetic individuals.
Introduction
Wounds, which disrupt the skin’s tissue structure, have a substantial impact on both individuals and healthcare systems. In the United Kingdom alone, they affect approximately 2.2 million people annually, with an expenditure exceeding £5.3 billion for treatment and associated complications. The wound healing process is intricate, encompassing clot formation, inflammation, granulation tissue development, and remodeling. Factors like insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) can influence this process.
Various therapeutic methods, including skin grafts, hydrocolloid dressings, hyperbaric oxygen therapy, skin substitutes, and negative pressure wound healing, are available to expedite wound healing. However, these methods may have complications and may not be suitable for all patients due to wound type, preference, or cost. In the initial stages of healing, re-epithelialization plays a critical role, involving the proliferation, migration, and differentiation of keratinocytes from the wound margins.
Research suggests that insulin holds potential in enhancing these processes, increasing blood flow, and promoting granulation tissue regeneration, all of which contribute to effective wound healing. Insulin, a well-known peptide hormone and growth factor, possesses the ability to reduce inflammation by altering the expression of pro- and anti-inflammatory cytokines. It activates anti-inflammatory cytokines such as interleukin (IL)-10, IL-4, and VEGF, inhibiting cell apoptosis while promoting cell proliferation. Additionally, it suppresses the pro-inflammatory protein transcription factor nuclear factor kappa beta (NFkβ) P50/P65, leading to decreased expression of inflammatory markers like IL-6, IL-12, and tumor necrosis factor alpha (TNF-α), thereby expediting regeneration and healing.
Insulin also influences glucose metabolism, protein biosynthesis, and lipid biosynthesis, further supporting wound healing. Its affordability and widespread availability make it an attractive candidate for pioneering new wound healing remedies. While systemic insulin treatment has shown efficacy, it carries the risk of inducing hypoglycemia and hypokalemia. However, limited research on localized insulin treatment suggests that it could overcome these issues and represent a promising therapeutic approach for wound treatment.
The objective of this systematic review and meta-analysis was to assess the efficacy and safety of localized insulin application for acute and chronic wounds, particularly in non-diabetic adults. Unlike previous studies that often included diabetic patients, this research specifically focused on non-diabetic adults, addressing a notable gap in the existing evidence despite the prevalence of various wound types in this population.
Methods
Inclusion Criteria:
The systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for search strategies and inclusion criteria. The search was conducted from the inception of the databases up to July 10, 2022, by two independent reviewers, Zunira Areeba Bhui-yan and Zubair Ahmed. The electronic databases Embase, Ovid MEDLINE, and PubMed were systematically searched. A filter was applied to the PubMed database to narrow the search results to include only clinical trials and randomized controlled trials (RCTs). The key terms used in the search included ‘insulin,’ ‘adult,’ ‘human,’ and ‘wound healing OR ulcer healing,’ with Boolean operators. Additional relevant studies were sought by screening the reference lists of reviewed articles.
Exclusion Criteria
The review applied the following exclusion criteria:
- Non-English studies were excluded.
- Studies were limited to RCTs only, as they are considered the highest level of primary research in the hierarchy of evidence.
- No limitations were set regarding the publication date, making all studies published before July 10, 2022, eligible for inclusion.
Any disagreements or conflicts related to the eligibility criteria were resolved through discussion with the senior author, Zubair Ahmed.
Data Extraction
The systematic review involved the following steps:
- Initial screening of studies based on title and abstract by two independent reviewers, Zunira Areeba Bhui-yan and Oluwasemilore Adebayo.
- Full-text analysis of relevant studies to determine eligibility, with any discrepancies resolved through discussion with the senior author, Zubair Ahmed.
- Data extraction, including study characteristics (e.g., author, year, title, country of study, inclusion/exclusion criteria, intervention/control protocols, outcome measures, and results), population characteristics (e.g., sample size, age, gender, wound location), and outcome measures (primary and secondary).
- In cases where information was unavailable, the corresponding sections in the tables were left blank, and no assumptions were made.
The primary outcome extracted from the studies was the rate of wound healing (measured in mm²/day), and secondary outcomes included healing time (days), reduction in wound area (cm²), safety evaluation, adverse effects of insulin, and quality of life (QoL). Trials with multiple treatment arms were included, and data from the best treatment effects in these trials were used for comparison in the meta-analysis.
Risk of Bias Assessment
The risk of bias in the included studies was assessed using the Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2). This assessment was performed by two independent reviewers, Zunira Areeba Bhui-yan and Oluwasemilore Adebayo. Five bias domains were considered, including bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, and bias in measurement.
Statistical Analysis
The assessment of heterogeneity in this study involved a meticulous examination of differences among the included studies, with a focus on methodological variations. To quantify and understand the extent of heterogeneity, the researchers utilized ReviewManager (RevMan 5.3), a software tool developed by Cochrane Informatics & Technology in London, UK.
To quantify heterogeneity, two statistical measures were employed: the Q statistic and the I2 statistic, expressed as percentages. These statistics were essential for determining the degree of variation among the studies attributed to heterogeneity. The Q statistic helps identify whether observed differences in study results are beyond what would be expected due to random chance. On the other hand, the I2 statistic quantifies the proportion of total variation across studies that can be attributed to heterogeneity rather than chance.
Subsequently, a meta-analysis was carried out using RevMan 5.3, which facilitated the integration of data from multiple studies. In this meta-analysis, a random effects model was employed. This statistical model is appropriate when there is an expectation of variability in the true effect size among the included studies, which is a common consideration in systematic reviews and meta-analyses. It takes into account both within-study and between-study variability, providing a more conservative estimate of the overall treatment effect.
This study employed robust statistical methods, including the Q and I2 statistics, to assess and quantify heterogeneity among the included studies. The meta-analysis, conducted using a random effects model in RevMan 5.3, allowed for the synthesis of data from diverse sources to derive meaningful conclusions.
Results
In the process of conducting this systematic review, the researchers initially identified a total of 518 studies through a comprehensive literature search, with an additional two studies discovered via other sources, such as reference lists. After the removal of duplicate studies, 347 records remained for further evaluation. Upon the initial screening of titles and abstracts, 329 studies were excluded, as they did not meet the predefined inclusion and exclusion criteria. Subsequently, a full-text analysis was conducted on the remaining 18 studies, leading to the exclusion of 11 additional studies. Reasons for exclusion are elaborated in the PRISMA flow chart in Figure 1. Ultimately, seven studies were deemed eligible for inclusion in both the qualitative and quantitative synthesis of data within this review.
One noteworthy exclusion involved a randomized controlled trial (RCT) by Martínez-Jiménez et al., which explored insulin’s impact on wound healing in non-diabetic patients. This particular study was excluded from the systematic review due to a unique experimental design where the control and insulin intervention were applied in different areas of the same wound on individual patients. Consequently, the effects of the control and insulin intervention might have been compromised, introducing bias into the interpretation of the data.
The seven RCTs included in this review were published between August 2009 and November 2021 and conducted in countries such as China, Egypt, India, or Iran. Among these studies, four employed a two-armed RCT design, with one group receiving insulin treatment for wound healing and the other receiving a standard saline placebo. Two studies adopted a three-armed RCT design, where different insulin dosages or solutions were compared. Lastly, one study utilized a five-armed RCT design to explore various insulin dosages and controls.
Patient characteristics were well-documented in the included studies, encompassing information on age, gender, wound location (upper or lower limb), and the number of participants. Five of the studies focused on the primary outcome of the rate of wound healing, measured in square millimeters per day (mm²/day), although one study used a different parameter, percentage of healing at Days 7 and 14, instead of mm²/day. Nevertheless, this omitted study still demonstrated a statistically significant difference favoring the insulin groups.
A meta-analysis of the four studies reporting wound healing rate in mm²/day revealed an overall significant weighted mean improvement of 11.84 mm²/day (95% CI: 0.64–23.04; p=0.04; I²=97%) in favor of the insulin treatment group.
Additionally, five studies examined the time taken for wounds to heal, measured in days. While three studies found a significant difference in the insulin group compared to the control group, two studies did not detect any discernible disparities. A meta-analysis for healing time across these five studies did not exhibit a major clinical difference between the groups (p=0.07).
Furthermore, insulin’s effect on reducing wound area (cm²) was explored, with some studies showing a significant reduction in wound area in the insulin group. Safety evaluations and adverse effects of insulin on wounds were also considered. Most studies did not report significant adverse events, though some variations in wound infection rates were noted. Quality of life (QoL) assessments did not reveal notable improvements due to insulin.
In summary, this systematic review encompassed a thorough selection process of studies and provided valuable insights into the effects of insulin on wound healing in non-diabetic adults. The quantitative analysis highlighted a significant improvement in the rate of wound healing in the insulin treatment group, while other outcomes, such as healing time and QoL, did not demonstrate major clinical differences between groups. These findings contribute to the understanding of insulin as a potential therapeutic agent for wound healing and underscore the need for further research in this area.
Conclusion
This systematic review focused on assessing the efficacy and safety of local insulin administration for wound healing in non-diabetic adults. The primary outcome of the review indicated that insulin administration is associated with a faster rate of wound healing compared to patients who did not receive insulin. This effect can be attributed to the role of insulin in facilitating the migration of keratinocytes through its receptors, promoting re-epithelialization, and expediting the healing process. Animal studies, such as the one conducted by Apikoglu-Rabus et al., have supported this theory by demonstrating that topical insulin enhances wound healing in non-diabetic rats by shortening the duration of epithelialization.
Furthermore, local insulin administration was found to stimulate the formation of new microvessels, increasing blood flow to the wound site, which can encourage primary healing. However, it’s important to note that while the primary outcome showed a significant improvement in the rate of healing, the average wound healing time was not significantly different in the insulin group compared to the control group. This discrepancy might be due to underpowered results, suggesting the need for larger sample sizes in future studies to thoroughly explore this aspect. Another potential explanation is that initial wound areas in participants from the insulin group may have been larger, leading to longer healing times. Nonetheless, this selection bias is theoretically less likely to occur due to the randomized nature of the included studies.
It’s worth mentioning that four out of the five studies examining healing time had an unclear risk of bias in the randomization process, which could contribute to the non-significant results in wound healing time. Additional research is required to investigate the correlation between initial wound area and healing rate more comprehensively.
Regarding secondary findings, this review concluded that insulin administration appears to be a potentially safe procedure, with no reported adverse events or side effects. However, the absence of reported risks does not definitively establish the safety of insulin administration, emphasizing the need for further high-quality studies to draw conclusive safety conclusions. Notably, low levels of insulin administration were associated with minimized risk of wound infections and improved healing. This aligns with other studies indicating that topical insulin can enhance bacterial clearance rates in wounds, reducing the likelihood of wound infection. Given that sustained skin wounds are susceptible to bacterial contamination, methods to mitigate infection risks, such as insulin administration, warrant exploration due to their potential to directly combat infections and reduce complications.
In summary, this systematic review underscores the promising role of local insulin administration in expediting wound healing in non-diabetic adults. While the primary outcome demonstrated significant improvements in healing rates, further research is needed to clarify the impact on healing time and establish the safety profile of insulin administration conclusively. Nevertheless, insulin’s potential to minimize infection risks and enhance wound healing makes it a valuable intervention worth further investigation.
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