Topical insulin & wound healing

26 Mar

Written By Joey .

Insulin is one of the most studied molecules in human physiology — yet its role in wound healing and skin repair remains largely unknown outside of specialist research circles. Most clinicians think of insulin purely as a glucose-regulating hormone. The evidence, however, tells a more compelling story: insulin is an active growth factor at the skin level, with direct and measurable effects on keratinocyte migration, angiogenesis, collagen synthesis, barrier repair, and inflammation resolution. The research on topical insulin and wound healing spans nearly a century of clinical observation, multiple randomised controlled trials, and increasingly well-characterised molecular mechanisms — and the clinical implications extend beyond diabetic wound care into a range of skin conditions and barrier recovery contexts.

◆ Quick Answer

Does topical insulin help wound healing? Yes — multiple RCTs and systematic reviews have confirmed that topical insulin accelerates wound healing in both diabetic and non-diabetic patients. The mechanisms include: stimulation of keratinocyte migration and re-epithelialisation via the PI3K-Akt-Rac1 pathway, promotion of angiogenesis through VEGF and eNOS upregulation, enhancement of collagen synthesis and granulation tissue formation, and resolution of pro-inflammatory cytokines. In one RCT of diabetic and non-diabetic volunteers, insulin-treated wounds healed 2.4 days faster than saline-treated wounds on the same patient (p < 0.001). A 2023 systematic review confirmed faster healing rates and improved wound appearance across both clinical and experimental settings.^1,2,3

A Brief History: Insulin and Wound Healing

Early 20th Century

Surgeons first observe that diabetic patients have markedly worse postoperative wound healing than non-diabetic patients — wounds failing to re-epithelialise, increasing infection susceptibility, and higher mortality from wound complications.⁴

1920s–1940s

Early clinical experiments: Thalhofer treats post-operative acidosis with insulin; Joseph administers 10 units of insulin daily to five patients with non-diabetic bedsores, documenting 50–100% wound healing after 14 days of therapy.⁴

1999 — First RCT

Greenway et al. publish the first randomised, double-blind, placebo-controlled trial of topical insulin in diabetic and non-diabetic volunteers. Insulin-treated wounds healed 2.4 ± 0.8 days faster than saline-treated wounds on the same patients (p < 0.001).¹

2009 — Iranian RCT

Rezvani et al. conduct a randomised, double-blind, placebo-controlled trial confirming the benefit of topical insulin in wound healing, with statistically significant improvements in healing rate.⁵

2012 — Molecular Mechanisms Established

Lima et al. publish the landmark double-blind placebo-controlled clinical trial (NCT 01295177) combined with animal mechanistic data, demonstrating that topical insulin cream normalises wound healing time in diabetic animals by restoring the IR/IRS/PI3K/AKT and IRK/SHC/ERK signalling pathways.⁶

2017 — Non-Diabetic Confirmation

Yu et al. confirm topical insulin accelerates wound healing in insulin-resistant diabetic rats — specifically through stimulation of keratinocyte migration, increased angiogenesis, and more mature skin formation — while also showing efficacy in non-diabetic wound models.⁷

2023 — Systematic Reviews

Two independent systematic reviews (Ramirez-GarciaLuna et al. in Plastic and Reconstructive Surgery, and Bhuiyan et al. in Wound Repair and Regeneration) confirm that local insulin administration accelerates wound healing in both diabetic and non-diabetic adults, with low risk of bias in the included RCTs.^2,3

How Topical Insulin Works: The Molecular Mechanisms

Understanding why topical insulin accelerates wound healing requires understanding the role of insulin signalling in normal skin repair. Insulin receptors (IR) are expressed on keratinocytes, fibroblasts, and endothelial cells throughout the skin — meaning that the wound healing cascade is, in part, insulin-dependent at a cellular level.^4,8

The Three Core Pathways of Topical Insulin in Wound Healing

PI3K-Akt-Rac1 pathway → Keratinocyte migration: Topical insulin activates the insulin receptor on keratinocytes, triggering phosphorylation of IRS-1/IRS-2 and downstream activation of PI3-kinase and AKT (protein kinase B). AKT activation drives Rac1-mediated cytoskeletal reorganisation enabling keratinocyte migration — the critical first step of re-epithelialisation. This is insulin receptor-dependent and EGF receptor-independent.^4,6,8
AKT-VEGF-eNOS pathway → Angiogenesis: AKT phosphorylates eNOS (endothelial nitric oxide synthase), increasing nitric oxide production and enhancing blood flow. AKT also drives VEGF biosynthesis from keratinocytes, macrophages, and fibroblasts — stimulating angiogenesis, new microvessel formation, and granulation tissue maturation. Topical insulin increases microvessel density (MVD) in healing tissue.^6,7,8
ERK pathway → Proliferation and collagen synthesis: The IR/SHC/ERK signalling arm of the insulin pathway drives fibroblast and keratinocyte proliferation. Topical insulin treatment increases collagen deposition and maturation (evidenced by elevated hydroxyproline levels), reduces advanced glycation end-products (AGEs), and upregulates the structural matrix supporting wound closure.^4,6,8

The Lima et al. (2012) study was particularly important in establishing that these pathways are attenuated in diabetic wound tissue — confirming that the impaired wound healing in insulin resistance and diabetes is mechanistically driven by deficient insulin signalling at the wound site, not merely by hyperglycaemia alone. Topical insulin bypasses the systemic insulin resistance by delivering insulin directly to insulin-receptor-deficient skin cells, restoring the signalling deficit locally.⁶

The Four Phases of Wound Healing and Where Insulin Acts

Phase 1: Haemostasis

Insulin has limited direct role. However, by reducing pro-inflammatory signals, it prevents excessive clot persistence that would impair subsequent healing phases.⁴

Phase 2: Inflammation

Topical insulin reduces pro-inflammatory cytokines including IL-6 and oxidative stress markers (8-OHdG). Acts as a chemotactic factor for macrophages, regulating macrophage function and transitioning the wound from inflammatory to proliferative phase.^5,8

Phase 3: Proliferation

The most insulin-sensitive phase. Drives keratinocyte migration (PI3K-Akt-Rac1), angiogenesis (VEGF/eNOS), fibroblast proliferation, collagen synthesis (ERK), granulation tissue formation, and re-epithelialisation. Topical insulin's most measurable effects occur here.^4,6,7,8

Phase 4: Remodelling

Insulin promotes collagen maturation and cross-linking, reduces AGE accumulation (which impairs remodelling in diabetic skin), and supports formation of a more organised extracellular matrix — resulting in improved scar quality.^4,8

Clinical Evidence: RCTs and Systematic Reviews

In Diabetic and Non-Diabetic Volunteers (Greenway et al., 1999)

📄 Greenway et al., J Wound Care (1999) — First RCT

Six diabetic and five non-diabetic volunteers each had two uniform cuts on their forearms. One wound received topical regular insulin (Iletin-II) four times daily; the other received normal saline as placebo — in a double-blind, randomised design. Insulin-treated wounds healed 2.4 ± 0.8 days faster than saline-treated wounds (p < 0.001). This was the first RCT evidence establishing efficacy in both diabetic and non-diabetic human subjects simultaneously.¹

2.4 days faster wound healing with topical insulin vs saline in the first RCT (p < 0.001). This result was consistent across both diabetic and non-diabetic subjects in the same study.¹

Double-Blind Placebo-Controlled Trial: AKT and ERK Pathways (Lima et al., 2012)

📄 Lima et al., PLOS ONE (2012) — Mechanistic RCT

In parallel animal and clinical research, this landmark study demonstrated that the insulin signalling pathway (IR → IRS-1/2 → AKT and IR → SHC → ERK) is upregulated in healing skin compared to intact skin — confirming that insulin signalling is a fundamental part of normal wound repair, not a pharmacological augmentation. In diabetic rats, these pathways were attenuated and healing time prolonged. Topical insulin cream normalised healing time and reversed the signalling deficit. In the randomised clinical trial of diabetic patients with ulcers, those receiving insulin cream showed significantly greater wound closure over the study period compared to placebo, with increased VEGF, eNOS, and SDF-1α expression in the wound tissue.⁶

In Non-Diabetic Adults: 2023 Systematic Review and Meta-Analysis

📄 Bhuiyan et al., Wound Repair and Regeneration (2023)

This systematic review specifically focused on non-diabetic adults — addressing a notable gap in the evidence base, since most topical insulin research had been conducted in diabetic populations. Seven RCTs published between 2009 and 2021 (from China, Egypt, India, and Iran) were included. The primary outcome demonstrated that insulin administration is associated with faster wound healing rates compared to placebo. Local insulin administration also stimulated formation of new microvessels, increasing blood flow to the wound site. Risk of bias assessment rated all included studies as low overall risk. The review concluded that local insulin is an affordable, accessible, and effective option for wound healing in non-diabetic adults — representing a genuinely underutilised clinical intervention.²

Systematic Review of Diabetic Foot Ulcers (Ramirez-GarciaLuna et al., Plast Reconstr Surg, 2023)

📄 Ramirez-GarciaLuna et al., Plastic and Reconstructive Surgery (2023)

This systematic review confirmed the efficacy of local insulin application for faster healing rates and improved wound appearance in diabetic wounds. Key findings included: significant improvement in granulation tissue neogenesis, increased VEGF levels, elevated microvessel density counts, reduced inflammatory factor levels, and decreased wound area. The authors found topical insulin therapy to be safe, feasible, and cost-effective — particularly important given the considerable financial and health burden of diabetic foot ulcers, which affect 15–20% of all diabetic patients.³

Topical Insulin in Non-Diabetic Wound Healing: Why This Matters

A critical point that is often missed in discussion of topical insulin is that its benefits are not confined to diabetic wounds. The mechanism — restoration or augmentation of insulin receptor signalling in keratinocytes and fibroblasts — is relevant in any situation where wound healing is impaired or suboptimal. This includes:

Post-surgical wounds in patients who are insulin-resistant but not yet diabetic (a very common clinical scenario given the prevalence of prediabetes)
Chronic wounds in patients with subclinical metabolic dysfunction
Burn wounds — where topical insulin on donor sites has shown improved healing⁷
Skin barrier repair in conditions like atopic dermatitis, where insulin signalling influences AQP3 expression, glycerol transport, and barrier protein synthesis⁹
Post-procedural healing following aesthetic treatments — chemical peels, laser resurfacing, microneedling — particularly in patients with metabolic risk factors

As I discussed in my post on insulin resistance and the skin, obesity-associated insulin resistance directly impairs skin barrier function by downregulating aquaporin-3, filaggrin, and barrier lipid synthesis. Topical insulin may offer a mechanism to partially restore these deficits at the skin level — independently of systemic metabolic status.

Safety: Does Topical Insulin Cause Hypoglycaemia?

This is invariably the first clinical concern raised, and the evidence is consistently reassuring. Topical insulin applied to skin wounds does not cause clinically significant hypoglycaemia in the doses studied.

📄 Safety Evidence — Multiple Studies

Across the systematic reviews and RCTs included in the literature, no clinically significant hypoglycaemia was reported with topical insulin application at the doses typically used (0.1–0.5 U/cm² of wound surface, or creams containing approximately 0.5–1 U/mL). The Bhuiyan 2023 systematic review specifically assessed safety as a primary outcome and found no adverse effects attributable to topical insulin across the included studies. The AbdelKader et al. (2016) review similarly found no side effects reported in any topical insulin study reviewed — noting that this is a key advantage of topical over systemic delivery.^2,4 Systemic absorption through intact skin is minimal; through wound surfaces, absorption is higher but insufficient to cause meaningful glycaemic effects at therapeutic wound-healing doses.

Clinical note: Topical insulin should still be used with monitoring in insulin-dependent diabetic patients and those on intensive insulin therapy, where even small additional insulin absorption could theoretically contribute to hypoglycaemia risk in certain clinical contexts. The safety data is most robust for wound surface application; dermal use on large surface areas or compromised barriers warrants appropriate precaution and professional guidance.

Formulation and Delivery: How Topical Insulin Is Applied

The research has used various formulations, concentrations, and delivery systems for topical insulin. The key findings from the formulation literature include:

Simple insulin cream or gel: Direct application of diluted regular insulin (typically 0.5–1 U/mL in an appropriate base) to the wound surface, applied 1–4 times daily, is the most studied approach and the basis for most clinical evidence.^1,5,6
Insulin-loaded hydrogels: Research has demonstrated that insulin incorporated into hydrogel dressings maintains bioactivity, provides sustained delivery, and enhances neovascularisation and collagen deposition compared to PBS controls.⁸
Cyclodextrin complexes: Besson et al. showed that insulin complexed with cyclodextrins provides more sustained release and more prolonged keratinocyte proliferation and neovascularisation effects compared to simple insulin gel.⁸
Concentration matters: The McCarron et al. (2016) review established that keratinocyte migration stimulation by insulin is dose- and time-dependent — suggesting that therapeutic concentration must be adequately maintained at the wound surface for optimal effect.⁴

The Broader Context: Insulin Signalling as a Skin Health Factor

The topical insulin wound healing evidence fits into a broader clinical picture of insulin's role in skin biology. As I covered in my posts on insulin resistance and the skin and menopause and skin changes, skin cells depend on growth factor signalling — including insulin receptor signalling — for their structural integrity, barrier function, and repair capacity. When this signalling is impaired (through insulin resistance, metabolic dysfunction, or the ageing-related decline in insulin sensitivity), the consequences are visible in the skin: impaired barrier function, slower healing, accelerated structural deterioration.

Topical insulin addresses this deficit from the outside in — restoring the local signalling environment at the tissue level regardless of the systemic metabolic state. This is conceptually important: it reframes wound healing not as a passive biological process waiting to happen, but as an active insulin-dependent process that can be augmented pharmacologically with a safe, affordable, and widely available agent.

Is Topical Insulin the Same as Applying Systemic Insulin to Skin?

No — topical insulin works through local receptor activation at the wound site, not through systemic metabolic effects. When applied topically to a wound, insulin does not significantly raise systemic insulin levels or lower blood glucose in the therapeutic doses studied. Its effects are entirely mediated by local binding to insulin receptors on keratinocytes, fibroblasts, and endothelial cells at the wound surface — activating the PI3K-Akt and ERK signalling pathways that drive re-epithelialisation, angiogenesis, and collagen synthesis. This local receptor-dependent mechanism means topical insulin bypasses systemic insulin resistance — making it effective even in patients whose cells are systemically resistant to insulin.^4,6,7

Who Is Most Likely to Benefit from Topical Insulin for Wound Healing?

The patients most likely to benefit are those with any degree of insulin resistance or metabolic dysfunction — including prediabetes, type 2 diabetes, obesity-associated insulin resistance, and postmenopausal women — as well as patients with chronic or non-healing wounds regardless of metabolic status. In insulin-resistant skin, the deficient local insulin signalling impairs every phase of the wound healing cascade. Topical insulin restores this signalling directly at the wound site. However, the 2023 non-diabetic systematic review confirms benefit even in metabolically healthy patients — suggesting a role as a general wound healing augmentation strategy rather than exclusively a diabetic wound intervention.^2,3

Frequently Asked Questions: Topical Insulin and Wound Healing

Can topical insulin be used on any type of wound?

The evidence covers a range of wound types including surgical wounds, excision wounds, diabetic foot ulcers, burn donor sites, and chronic ulcers. The most robust evidence is for chronic and surgical wounds in diabetic patients and for acute wounds in non-diabetic patients from the 2023 systematic review.^2,3 Application to infected wounds or wounds with significant debris requires standard wound bed preparation first — insulin's growth-promoting effects are most beneficial in a clean, well-prepared wound environment.

Will topical insulin lower my blood sugar?

At the doses used in wound healing research, topical insulin does not cause clinically significant hypoglycaemia. No adverse effects or significant systemic absorption-related glycaemic changes were reported across the systematic reviews.^2,4 That said, patients on intensive insulin therapy or with high wound surface areas should apply topical insulin under professional guidance and appropriate monitoring.

How quickly does topical insulin speed up wound healing?

The first RCT (Greenway et al., 1999) demonstrated wounds healing 2.4 days faster on average over the total healing period.¹ The molecular studies show that insulin's effects begin rapidly — IRS-1 phosphorylation is observed from day 3 post-wounding, and keratinocyte migration differences are visible histologically within the first week. Clinically meaningful effects on wound size reduction are apparent within the first 1–2 weeks of application.

Is topical insulin available as a commercial product?

Topical insulin is not yet widely available as a licensed commercial wound care product, though compounding pharmacies can prepare insulin creams and gels at specified concentrations. The research has primarily used regular insulin (the same formulation used in injectable therapy) diluted in appropriate vehicles. The lack of a commercial product does not reflect lack of evidence — it reflects the commercial challenges of developing wound care products around a cheap, off-patent molecule. Clinical use typically requires preparation by a compounding pharmacist or specialist clinic.

Can topical insulin help with skin conditions beyond wound healing?

The research primarily establishes topical insulin's role in acute and chronic wound healing. However, given that insulin signalling in keratinocytes regulates barrier protein expression (filaggrin, loricrin), aquaporin-3-mediated glycerol transport, and barrier lipid synthesis — all of which are impaired by systemic insulin resistance — there is a plausible biological rationale for broader skin barrier applications. As I discuss in my post on insulin resistance and the skin, the skin barrier of insulin-resistant patients is functionally compromised, and topical insulin could in principle partially restore this. This area requires further clinical investigation.⁹

Conclusion: An Underutilised Intervention with a Century of Evidence

The story of topical insulin and wound healing is, in many ways, a story of an evidence base that has existed for over a century but has never found its commercial pathway into mainstream wound care. The mechanisms are well-characterised, the safety profile is excellent, the cost is minimal, and the evidence from RCTs and systematic reviews is consistent across diabetic and non-diabetic populations.

From a clinical perspective, this makes topical insulin an intelligent addition to wound care protocols — particularly for patients with insulin resistance, metabolic syndrome, or diabetes, where the deficiency in local insulin signalling is a direct driver of impaired healing. It also opens broader questions about the role of insulin receptor signalling in skin barrier health, post-procedural healing, and inflammatory skin disease — questions that the emerging research is beginning to address.

Interested in evidence-based approaches to wound healing and skin barrier repair?

Book a functional skin consultation to discuss whether metabolic factors are contributing to your skin condition and explore targeted interventions including topical therapeutic options.

References

Greenway SE, Filler LE, Greenway FL. Topical insulin in wound healing: a randomised, double-blind, placebo-controlled trial. J Wound Care. 1999;8(10):526–528. doi:10.12968/jowc.1999.8.10.26217.
Bhuiyan ZA, Ahmed Z. Localised insulin administration for wound healing in non-diabetic adults: a systematic review and meta-analysis of randomised controlled trials. Wound Repair Regen. 2023. doi:10.1111/wrr.13098.
Ramirez-GarciaLuna JL, et al. Local insulin improves wound healing: a systematic review. Plast Reconstr Surg. 2023;152(6). doi:10.1097/PRS.0000000000010709.
AbdelKader DH, Osman MA, Elgizawy SA, Faheem AM, McCarron PA. The role of insulin in wound healing process: mechanism of action and pharmaceutical applications. J Anal Pharm Res. 2016;2(1):00007. doi:10.15406/japlr.2016.02.00007.
Rezvani O, Shabbak E, Aslani A, Bidar R, Jafari M, Safarnezhad S. A randomized, double-blind, placebo-controlled trial to determine the effects of topical insulin on wound healing. Ostomy Wound Manage. 2009;55(8):22–28.
Lima MHM, Caricilli AM, de Abreu LL, et al. Topical insulin accelerates wound healing in diabetes by enhancing the AKT and ERK pathways: a double-blind placebo-controlled clinical trial. PLOS ONE. 2012;7(5):e36974. doi:10.1371/journal.pone.0036974. PMC3360697.
Yu T, Gao M, Yang P, et al. Topical insulin accelerates cutaneous wound healing in insulin-resistant diabetic rats. Am J Transl Res. 2017;9(10):4682–4693. PMC5666074.
Emanuelli T, Burgeiro A, Carvalho E. Effects of insulin on the skin: possible healing benefits for diabetic foot ulcers. Arch Dermatol Res. 2016;308:677–694. doi:10.1007/s00403-016-1686-z.
Aoki M, Murase T. Obesity-associated insulin resistance adversely affects skin function. PLOS ONE. 2019;14(10):e0223528. doi:10.1371/journal.pone.0223528.
Bhattacharyya S, et al. Insulin modulates wound healing through receptor signalling — review of animal and clinical evidence. Life Sci. 2017. doi:10.1016/j.lfs.2017.01.018.

Joey .