Insulin has long been recognized as an important contributor to wound healing,11
and many studies have demonstrated the positive effects of insulin on wound healing.11–18
Insulin-like growth factor (IGF), which has a high sequence 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, and fibroblasts, and even promote the reformation of granulation tissue.18–20
Topical formulations of insulin was 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 insulin growth factors.
Belfield et al.21
tested the application of a cream compound with 10 U of zinc protamine insulin and 1 g of base (Ulcerin) on chronic and debilitating wounds (such as pressure sores, ulcers, and fistulae) in canine and feline subjects. The results from their study demonstrated a normalization of cell permeability, increased vascular-ization, enhanced phagocytosis (autodebridement), and stimulated proliferation. Additional benefits included reduced exudation, arrested bacteria, decreased tissue hypoxia, reduced edema, increased wound contraction, reduced inflammation, and greatly reduced healing time. Pierre and associates,14
in their study of systemic administration of insulin in nondiabetic burn patients, found that chronic administration of high doses of insulin with glucose significantly decreased donor-site healing time by two to three days and improved structural wound matrix formation and protein kinetics.
Lopez and Mena22
reported on the use of local insulin irrigation (30–60 IU of isophane insulin daily) in two cases of diabetic infectious gangrene that were resistant to all other current therapies and found that the treatment accelerated wound healing with no notable systemic side effects.
Greenway et al.17
published results from a randomized double-blind placebo-controlled trial that tested the relative roles of insulin (lletin-II) and zinc in the acceleration of wound healing of the forearm in diabetic and non-diabetic human subjects. The investigators concluded that topical application of insulin accelerated wound healing in both diabetic and nondiabetic human wounds.
Zhang and colleagues23
reported on the use of an insulin–zinc suspension delivery by local injection into skin donor sites. These investigators concluded that local injection of a small dose, 0.2 U, of long-acting insulin–zinc suspension stimulated wound DNA synthesis without any major systemic side effects and thereby provided a safe and effective approach to accelerate wound healing.
Journal of Surgical Research
published a study on the use of local insulin–zinc injection into skin donor site wounds in rabbits. In this study, Zhang and associates24
found that injections of an extended insulin–zinc suspension (Humulin, Eli Lilly and Co., Indianapolis, IN), which was added to an albumin–saline solution (75 mg albumin per ml of 0.9% sodium chloride) at a final concentration of 0.25 or 1.0 U/ml, to four sites of the wound periphery and a fifth at the wound center accelerated skin wound healing, reduced mean healing time by 25%, and did not increase plasma insulin concentration. Histological analysis of wound tissues in this study suggested that the accelerated healing was likely due to the insulin-induced stimulation of epidermal growth factor and keratinocyte proliferation, which was consistent with previous reports.25
Wilson et al.26
reported a case of topical irrigation with 20 ml normal saline and 2 U of human soluble insulin (Actrapid) being used in a chronic nonhealing wound following laparotomy of an 80-year-old woman after conventional dressing attempts and a three-week NPWT course all failed. The investigators reported that, after seven days of normal saline and insulin irrigation, there was visible improvement in wound healing without any systemic side effects such as hypoglycemia.
Rezvani and colleagues,27
in a double-blind randomized placebo-controlled trial, evaluated the effects of topical insulin on wound healing and concluded that the healing rates of the insulin treatment group was higher than in the control group, regardless of initial wound size and did not cause any major systemic side effects.