Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 7  |  Issue : 5  |  Page : 579-583  

Role of topical use of insulin in healing of chronic ulcer


Department of General Surgery, Padmashree Dr. D. Y. Patil Medical College Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India

Date of Web Publication10-Sep-2014

Correspondence Address:
Virendra S Athavale
Department of General Surgery, Padmashree Dr. D.Y. Patil Medical College, Hospital and Research Centre, Pimpri, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-2870.140400

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  Abstract 

Background : Chronic wounds, especially non-healing types, are one of the most common surgical conditions a surgeon comes across. The peculiarity of a chronic wound is that, whatever management you give, they refuse to heal, especially the pressure ulcers or bed sores. Many therapeutic methods are available to effect wound healing such as topical application of insulin, growth factors, negative pressure-assisted wound closure, oxidized regenerated cellulose/collagen, hyaluronic acid conjugated with glycidyl methacrylate or gelatin dressings. A less clinically and economically complicated approach to healing chronic wounds seems necessary.
Objectives: To study the efficacy of topical use of insulin in wound healing in following terms:-(1) rate of wound healing; (2) safety evaluation; (3) hospital stay. Materials and Methods: This was a prospective study carried out in a tertiary health centre from July 2010 to September 2012 in 50 patients after taking an informed and written consent of the patients having chronic ulcer. All the patients who were satisfying inclusion/exclusion criteria patient were randomized into two groups, Group A and Group B. Each group was again sub-divided into 1 and 2 i.e. sub-group A1, A2 and sub-group B1, B2. Patients with diabetes were grouped as A1 and B1 and non-diabetic patients were grouped as A2 and B2. Group A patients were treated with insulin dressings and Group B patient's ulcers were treated with normal saline dressings. Ulcer size and healing was recorded on weekly basis. Strict glycemic control was maintained in all diabetic patients. Results were compared at complete healing or at the end of 12 weeks which ever was earlier. Results: Our study included both diabetic and non-diabetic patients. There was no significant change in BSL(R) values after use of insulin on wounds. The number of days required for wound healing in Group A patients in both subgroups (A1 and A2) was significantly less as compared to Group B (B1 and B2). The mean rate of healing of wounds was much faster in Group A as compared to Group B. The hospital stay in Group A patients was significantly less than Group B. Conclusion: The use of topical Insulin strongly suggests accelerated wound healing in chronic ulcer. Topical insulin in chronic ulcer is safe and effective without any systemic side effect. Topical insulin significantly reduces the hospital stay of patients with chronic ulcers. Early return to work decreased economical load.

Keywords: Chronic wounds, rate of wound healing, topical application of insulin


How to cite this article:
Goenka G, Athavale VS, Nirhale DS, Deshpande N, Agrawal K, Calcuttawala M. Role of topical use of insulin in healing of chronic ulcer. Med J DY Patil Univ 2014;7:579-83

How to cite this URL:
Goenka G, Athavale VS, Nirhale DS, Deshpande N, Agrawal K, Calcuttawala M. Role of topical use of insulin in healing of chronic ulcer. Med J DY Patil Univ [serial online] 2014 [cited 2020 Apr 2];7:579-83. Available from: http://www.mjdrdypu.org/text.asp?2014/7/5/579/140400


  Introduction Top


In this millennium where mankind has succeeded in deciphering the human genetic code, wound management still remains an enigmatic challenge. The history of wound healing is as old as the history of mankind. [1] Chronic wounds, especially non-healing types, are one of the most common surgical conditions that a surgeon comes across. From time immemorial, doctors have been trying many methods to treat such wounds. [2]

Chronic wounds have been defined as wounds that have failed to proceed through the orderly process that produces satisfactory anatomic and functional integrity or that have proceeded through the repair process without producing an adequate anatomic and functional result. The majority of wounds that have not healed in 3 months are considered chronic. [1] The peculiar feature of a chronic wound is their inability to heal despite the best management which would be undertaken, especially the pressure ulcers or bed sores. The notion that wounds should be kept dry, although still held by a considerable number of clinicians, is steadily losing ground. [3]

Current estimates indicate that nearly 6 million people suffer from chronic wounds worldwide. The prevalence of chronic wounds in India has been reported as 4.5 per 1000 population, whereas that of acute wounds is nearly double, at 10.5 per 1000 population. The poor hygienic condition in some third world countries has been attributed as the main cause. [4],[5]

Wound healing is a complex biological process influenced by several agents such as insulin-like growth factor (IGF) and human acidic fibroblast growth factor (rh-aFGF). [6] In vivo studies have shown that IGF can stimulate the proliferation and differentiation of endothelial cells and fibroblasts and thus, promote granulation tissue regeneration contributing to wound healing. [7],[8]

Aim

The aim of this study was to evaluate the efficacy of topical insulin in healing of chronic ulcers.


  Materials and Methods Top


A prospective study has been conducted at Padmashree Dr. D. Y. Patil Medical College and Research Center, Pimpri, Pune, India, between April 2010 and September 2012 comprising of 50 cases.

Patients with chronic ulcer viz. pressure ulcer, post operative surgical wounds, diabetic ulcer, wound size less than 10 cm 2 were included in the study whereas patients with age more than 70 yrs, immunodeficiency, pregnancy, osteomyelitis, varicose ulcer, burns were excluded.

Institutional Ethical Committee approval was obtained. A detailed clinical examination was carried out. Patients fulfilling the inclusion criteria were randomized prospectively into two groups, Group A and Group B. Each group was again sub-divided into 1 and 2 i.e. sub-group A1, A2 and sub-group B1, B2. Patients with diabetes were grouped as A1 and B1 and non-diabetic patients were grouped as A2 and B2.

Group A received insulin dressing and Group B received normal saline dressing without insulin. All diabetic patients were brought under glycemic control with appropriate anti-diabetic therapy. Before enrolling the patients for study, culture and sensitivity swab of all the ulcers was taken and ulcers were cleaned with normal saline. Surgical debridement of dirty wounds was done under anesthesia. Then the ulcers were included in the study. Time required for preparing the ulcers from the time of admission till enrollment in the study was considered as wound preparation time. While considering the hospital stay of patients this wound preparation time was not taken into account.

In Group A, ulcers were cleaned with normal saline and then irrigated with 4 units (0.1 ml) of human soluble insulin (Actrapid) in 1 ml normal saline (0.9%) for each 10 cm 2 of wound. The solution prepared was sprayed on the ulcer surface with an insulin syringe twice daily and ulcer was left to dry and then covered with sterile cotton gauzes.

In Group B, ulcers were cleaned with normal saline without insulin and covered with sterile gauzes.

All patients were treated empirically with Cap. Ampicillin 250 mg, Cloxacillin 250 mg qid at the time of admission. Later antibiotics had been changed according to pus culture and sensitivity reports.

Wounds were measured using a sterile transparent paper placed on the wound to mark the wound borders. The two largest perpendicular diameters were measured using a ruler (in millimeters). To calculate the wound area, these two diameters were multiplied to obtain area of ulcer in mm 2 .

Even though topical Insulin is not absorbed systemically, to evaluate the safety, random blood glucose levels (BSL) (R) were measured with a glucometer 10 minutes before and 1 hour after application of topical insulin in Group A patients.

Ulcer size was measured once a week till 12 weeks or till the complete healing of ulcer, whichever was earlier.

The end point of the study has been taken as complete wound epithelisation or healing of wound at the end of 12 weeks or whichever was earlier. Rate of wound healing was calculated as the difference between the primary wound on the day 1, till complete wound healing and is reported in terms of mm 2 / week as a marker of healing.

[TAG:2]Statistical Analysis [/TAG:2]

Results from all patients who enrolled in the study were tabulated and expressed as mean and standard deviation. Statistical evaluation of the data was performed using the SPSS version 11. Comparisons between groups were performed using the "Z value test" and "chi-square test". All results were considered to be significant at the 5% critical level (P < 0.05).


  Results Top


All 50 patients achieved wound closure. The incidence of diabetic patients was 60% in Group A1 and 72% in Group B1 which was statically non-significant and comparable. Whereas of non diabetic patients was 40% in Group A2 and 28% in Group B2 which was also comparable and statically non-significant [Table 1]. All the diabetic patients were taken in the study after achieving proper glycaemia control by anti- diabetic treatment.

In our study, the BSL (R) values before dressing was 119.3+/-40.1 mg/dl whereas after dressing was 120+/-39.7 mg/dl in Group A which was comparable and statically not significant [Table 2]. No significant side effects or reactions were observed and none of the participants experienced adverse systemic effects such as hypoglycemia, headache or vertigo.
Table 1: Distribution of cases of diabetes/non-diabetes in study groups

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Table 2: Comparison of BSL (Random) before and after dressing in Group A

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In our study, the mean ulcer size on day 1 was 670 ± 215 mm 2 in Group A1 and 629 ± 257 mm 2 in Group B1 which was comparable and statistically not significant. The sizes of ulcers were 648 ± 299 mm 2 in Group A2 and 555 ± 298 mm 2 in Group B2 [Table 3].
Table 3: Comparison of ulcer size in mm2 on Day 1 in study groups

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No. of days required for healing was 38 ± 17.03 days in Group A1 and 44.3 ± 17.5 days in Group B1. Whereas number of days required for healing was 30.5 ± 13 days in Group A2 and 40 ± 18.8 days in Group B2 which were comparable and statistically significant [Table 4].
Table 4: Comparison of no. of days required for healing in study groups

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The mean rate of healing was 130 ± 25.3 mm 2 /wk in Group A1 and 95.1 ± 34.9 mm 2 / wk in Group B1. Whereas the mean rate of wound healing for Group A2 was 142.1 ± 42.2 mm 2 / wk and 98.5 ± 43.4 mm 2 / wk in Group B2 which were comparable and statically significant [Table 5].
Table 5: Comparison of rate of healing in study groups

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The mean hospital stay was 40.1 ± 16.6 days in Group A1 and 46.2 ± 17.9 days in Group B1. The mean hospital stay in Group A2 was 35.8 ± 10.4 days and 45.4 ± 19.9 in Group B2 which were comparable and statically significant [Table 6].
Table 6: Comparison of hospital stay in study groups

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  Discussion Top


Since Banting's discovery of Insulin in 1921, many benefits beyond blood glucose regulation have been documented. The use of insulin for non-diabetic purposes was popular in the early part of the 20 th century, was "forgotten" during the 1940s and 1950s, and it became again reinvigorated during the latter half of the century. [9] For example, daily injections of insulin were used to improve bone healing in rats, incision wounds of the skin, healing in the distal limb of horses, and in cutaneous ulcerations in diabetic and non-diabetic mice. [10],[11] Insulin was also used in the 1960s to treat diabetic wounds in humans, and more recently, insulin spray has been successfully used to treat patients with diabetic ulcers. Furthermore, this hormone has been used to treat burns in humans, rats, and rabbits with good success. With the strong evidence that insulin stimulates healing, thereby decreasing the time of wound closure, the underlying mechanisms of insulin-induced improved healing are far from being understood. [12] Our study had demonstrated positive effects of insulin on wound healing.

Insulin has long been recognized as an important contributor to wound healing, [13] and many studies have demonstrated the positive effects of insulin on wound healing. IGF, which has a high sequence of similarity to the hormone insulin, has been shown through in vivo studies to stimulate the proliferation, migration and extracellular matrix excretion by keratinocytes, endothelial cells, fibroblasts and even promote the reformation of granulation tissue. [14] Topical formulations of insulin were utilized in the 20th century in an attempt to control local hyperglycemia of peripheral tissue. However, later investigations have focused on topical insulin applications as it relates to IGF.

The amino acid chain in the IGF is similar to proInsulin, which is manufactured in the pancreatic Langerhans cells, with 86 amino acids (Insulin is produced when a 35-amino acid chain - C-peptide - detaches from proInsulin25). IGF-1 binds to at least two cell surface receptors: The IGF-1 receptor (IGFR) and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor, binding to IGF-1 at significantly higher affinity than it binds the Insulin receptor. Like the insulin receptor, the IGF-1 is a tyrosine kinase receptor - i.e. it causes the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1 times the potency of insulin. Part of this signaling may be via the IGF-1R-Insulin receptor heterodimers. Binding studies show that IGF-1 binds the insulin receptor 100-fold well than insulin, which does not correlate with the actual potency of IGF-1 in vivo at inducing phosphorylation of the insulin receptor and hypoglycemia. [8],[15],[16]

In this and other studies, an initial wound area correlated with wound healing rate - i.e. larger wounds healed at a faster pace than smaller wounds. However, in the current study, the healing rate in the treatment group was higher than in the control group, regardless of initial wound size.

In our study, number of days required for healing was 38 ± 17.03 days in Group A1 and 44.3 ± 17.5 days in Group B1. Both these Groups A1 and B1 had diabetic patients. But the ulcers in Group A1 required less number of days than Group B1. Whereas number of days required for healing was 30.5 ± 13 days in Group A2 and 40 ± 18.8 days in Group B2 which were comparable and statistically significant [Figure 1],[Figure 2],[Figure 3] and [Figure 4]. Both these Groups A2 and B2 had non-diabetic patients. But the ulcers in Group A2 got healed much faster than in Group B2. In studies done by Pierre et al., [15] in 1998, healing time was reduced from 6.5 ± 1.0 days with placebo to 4.7 ± 1.2 days during insulin infusion (P < 0.05) and study by Rezvani et al. in 2009 [8] found a healing time of 41.85 ± 20.56 days in the insulin group and 43.50 ± 22.85 days in the normal saline dressing group. In other studies done by Greenway et al., [17] Kanth et al., [18] Rezvani et al., [8] wound healing rates were significantly accelerated in insulin groups and were comparable to our study. Omid et al. found the rate of healing to be 40.09 mm 2 /day in the insulin group and 32.24 mm 2 /day in the normal saline dressing group. Thus, insulin dressing decreases time required for healing. Our study has the limitation of having a very small sample size, but our study has indeed highlighted the effectiveness of insulin role in wound healing and further encouraged the research on this topic.
Figure 1: Day 1

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Figure 2: Day 11

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Figure 3: Day 18

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Figure 4: Day 28

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  Conclusion Top


The use of topical insulin strongly suggests accelerated wound healing in chronic ulcer, found to be safe and effective without any systemic side effect. In our study it shows reduced hospital stay of the patients.

 
  References Top

1.Barbul Adrian. Brunicardi FC, Wound Healing. In: Schwartz′s Principles of Surgery. 9 th ed, Ch.9, New York, McGRAW-HILL; 2005: 209-33.  Back to cited text no. 1
    
2.Cooper L, Johnson C, Burslem F, Martin P. Wound healing and inflammation genes revealed by array analysis of ′macrophage less′ PU.1 null mice. Genome Biology 2004;6:R5.  Back to cited text no. 2
    
3.Bjarnsholt T, Kirketerp-Møller K, Madsen KG, Phipps R, Krogfelt K, Høiby N, et al. Why chronic wounds will not heal: A novel hypothesis. Wound Repair Regen 2008;16:2-10.  Back to cited text no. 3
    
4.Sasidharan S, Nilawatyi R, Xavier R, Latha LY, Amala R. Wound healing potential of elaeisguineensisjacq leaves in an infected albino rat model. Molecules 2010;15:3186-99.  Back to cited text no. 4
    
5.Gupta N, Gupta SK, Shukla VK, Singh SP. An Indian community-based epidemiological study of wounds. J Wound Care 2004;13:323-5.  Back to cited text no. 5
    
6.Liu Y, Petreaca M, Yao M, Martins-Green M. Cell andmolecular mechanisms of keratinocyte function stimulated by insulin during wound healing. BMC Cell Biol 2009;10:1186/1471/2121.   Back to cited text no. 6
    
7.Zhang XJ, Chinkes DL, Sadagopa Ramanujam VM, Wolfe RR. Local injection of insulin-zinc stimulates DNA synthesis in skin donor site wound. J Wound Repair Regan 2007;15:258-26.  Back to cited text no. 7
    
8.Rezvani O, Shabbak E, Aslani A, Bidar R, Jafari M, Safarnezhad S. A Randomized double- blind, placebo- controlled trial to determine effects of topical insulin on wound healing. Ostomy Wound Manage 2009;55:22-8.  Back to cited text no. 8
    
9.Lawrence RT, Salter JM, Best CH. The effect of insulin on nitrogen retention in the hypophysectomized rat. Br Med J 1954;2:437-9.  Back to cited text no. 9
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10.Hardman JG, Limbird LE, Gilman AG, editors. The pharmacological basis of therapeutics. 10 th ed. New York, NY; McGraw-Hill; 2001. p.1679-81.   Back to cited text no. 10
    
11.Panuncialman J, Hammerman S, Carson P, Falanga V. Wound edge biopsy sites in chronic wounds heal rapidly and do not result in delayed overall healing of the wound. J Wound Repair Regan 2010;18:21-5.  Back to cited text no. 11
    
12.Liu Y, Petreaca M, Yao M, Martins-Green M. Cell and molecular mechanisms of keratinocyte function stimulated by insulin during wound healing. BMC Cell Biol 2009;10:1.  Back to cited text no. 12
    
13.Rosenthal SP. Acceleration of primary wound healing by insulin. Arch Surg 1968;96:53-5.  Back to cited text no. 13
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14.Sureshbabu A, Okajima H, Yamanaka D, Shastri S, Tonner E, Rae C, et al. IGFBP-5 induces epithelial and fibroblast responses consistent with the fibrotic response. BiochemSoc Trans 2009;37:882-5.  Back to cited text no. 14
    
15.Pierre EJ, Barrow RE, Hawkins HK, Nguyen TT, Sakurai Y, Desai M, et al. Effect of insulin on wound healing. JTrauma 1998;44:342-5.  Back to cited text no. 15
    
16.Lima MH, Caricilli AM, de Abreu LL, Arau´jo EP, Pelegrinelli FF. Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: A double-blind placebo-controlled clinical trial PLoS One2012;7:e36974.  Back to cited text no. 16
    
17.Greenway SE, Filler LE, Greenway FL. Topical insulin in wound healing: A randomised, double-blind, placebo-controlled trial. J Wound Care 1999;8:526-8.  Back to cited text no. 17
    
18.Kanth S, Bhat PR. Wound Dressing - Topical Insulin. J SWCR 2011;4:11-4.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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