Investigating the Role of IGF-1 and Insulin Receptor Mutations in the Pathogenesis of Keratosis Pilaris: A Theoretical Framework for Symptomatology and Underlying Mechanisms

Author: Devin Beaubien

Last Updated: 2/28/2025

Introduction

The skin condition Keratosis Pilaris(KP) is primarily the result of a skin barrier issue caused by skin cells not maturing/differentiating correctly.[1] These skin cells are regulated by hormones activating receptors distributed across the cell’s surface and its related cellular pathways.[10] Clinical studies that are shared in this article show that this initial disruption to the skin barrier in the follicular canal leads to many downstream symptoms such as defective skin cell shedding, atrophied sebaceous glands, trans epidermal water loss, hair shaft abnormalities, inflammation, and post inflammatory hyper-pigmentation.[1] Collectively these symptoms develop into the rough bumps and visible redness/pigmentation that we all refer to as Keratosis Pilaris (aka KP). My aim in publishing this article is to introduce new ideas and treatment theories for KP based on the underlying symptoms of this skin condition.

Summary

KP is a common skin condition that typically shows up as flat or raised bumps on the skin. These bumps are keratin plugs (created from defective shedding of corneocytes)[1] that form within the follicular canal, with or without a hair follicle being present in the follicular canal. Often times this skin condition is accompanied by redness and inflammation encircling the follicles, known as erythema, which is superficial reddening of the skin.[2] Erythema will usually appear in patches as a result of injury or irritation, causing dilation of the blood capillaries.[3] In this case it appears as a result of the compromised epithelial barrier around the follicle.

There is a clear distinction in the severity and appearance of Keratosis Pilaris categorized as "lesional' and "non-lesional", separate from its sub-types. As observed in a 2015 clinical study [1], lesional keratosis pilaris appears as keratin blockages that create a tactile protrusion or keratin lesion on the surface of the skin. Some examples of lesional KP can be seen in the following pictures:

Lesional KP is distinct from non-lesional KP due to the bumpy, raised texture and accompanied infundibular keratin plugs that form. It is possible to extract the contents of these bumps, which often appear as white and stringy plugs. Lesional KP is also differentiated from non-lesional KP in biopsies taken from lesional KP sites where it's been observed that sebaceous glands are in the process of atrophy or are already completely disintegrated.[1] Conversely, in biopsies from non-lesional KP, the sebaceous glands are not atrophied. 

Non-lesional Keratosis Pilaris does not exhibit the same tactile, raised appearance. It was noted in the same 2015 study that the sebaceous glands in non-lesional KP are still intact. Due to this, the researchers performing this study proposed that atrophied sebaceous glands and their decreased production of sebum are likely a key tipping point resulting in impaired corneocyte shedding in the follicle.[1] In simpler terms, without sebum production, skin cell shedding may become impaired and a buildup of dead skin cells (keratin) can form, creating the infundibular keratin plug seen in lesional KP. Alternatively, sebaceous gland atrophy may be a parallel symptom that appears alongside defective corneocyte shedding, with both symptoms being preceded by disrupted keratinocyte maturation and differentiation. In this scenario it is likely that the loss of sebum increases trans epidermal water loss which further dries the skin, increasing the likelihood of keratin scale to build up in the follicle.

Non-lesional KP is often called "strawberry skin" or "chicken skin" due to it's appearance as flat red or pigmented dots. Redness and inflammation surround the follicle which can sometimes result in PIH (Post Inflammatory Hyper-pigmentation)[4], which can darken the follicles. In those with naturally darker skin tones, the inflammation will often appear as dark dots instead of the redness seen in lighter skin tones. Some examples of non-lesional KP can be seen in the following figures:

Lesional and Non-lesional Keratosis Pilaris are not mutually exclusive, as both can coexist in addition to hyper-pigmentation. The severity of KP can fluctuate as well over the course of an individual's lifespan, with both lesional and non-lesional KP changing in spread and severity.[9] You can also see slightly raised bumps or keratin plugs that are not as pronounced, yet still affect the texture of the skin. Here is an example of an individual with both lesional and non-lesional KP, where lighter dotted pigmentation and erythema coexists with raised, inflamed lesions:

KP is usually exclusively distributed symmetrically on the body, affecting both sides of the face, outer arms, outer thighs, buttocks, and the torso.[9] KP can appear anywhere across the body, except for the palms of the hands and soles of the feet. It is thought that the location of the condition correlates to sebaceous gland density, where higher density areas like the groin, armpits, and inner arms/legs are less likely to exhibit KP versus the less dense areas of the outer arms and outer legs.[1]

Now that we've established a baseline regarding KP's symptoms and presentation, let's investigate lesser known elements of how KP develops.

What is Known About Keratosis Pilaris

Keratosis pilaris is a common skin disorder comprised of less common variants and rare sub-types, including keratosis pilaris rubra, erythromelanosis follicularis faciei et colli, and the spectrum of keratosis pilaris atrophicans. The most common patient population is adolescents, with 50% to 80% percent affected. The disorder is also frequently seen in adults, with upwards of 40 percent of the adult population affected. However, because keratosis pilaris is an under reported condition, the prevalence of the condition may be higher. Race and sex do not predispose patients to develop keratosis pilaris. KP is the most common follicular disorder in children, with large fluctuations in the reported prevalence rates ranging from 0.75% to 34.4%.[9] This skin condition most commonly presents in teenagers and correlates with atopic dermatitis. Those affected by keratosis pilaris will often complain of red bumpy skin without pain or pruritus. This asymptomatic eruption generally occurs on the extensor surfaces of the proximal upper and lower extremities as well as the buttocks. However, the face, trunk, and distal extremities may also be involved. While one hypothesis proposed that KP was not a primary disorder of keratinocytes, but a hair shaft or infundibular disorder, this hypothesis[16] would seem to be negated by a 2015 study that showed infundibular plugs can form with or without a hair follicle present within the follicular canal.[1] In addition to this, hair removal alone does not reduce the severity of the condition. Recent studies have postulated that abnormal keratinization and hair shaft abnormalities can be explained by the absence of sebaceous glands as a key factor in the pathophysiology of KP.[1] However, it is not clear in their work if this is a primary or secondary feature of KP.

A lack of data and critical analysis surrounding this skin condition has made it difficult the elucidate a complete pathology of the skin disorder, but by drawing connections between disparate studies we can identify the underlying mechanisms of this condition with a degree of confidence. The most widely accepted theory proposes abnormal follicular epithelial keratinization causing an infundibular plug to form, but why the abnormal keratinization occurs has not been adequately investigated.[1]

The following bullet points and sources outline some of the critical points that need to be made in order to understand my following theory for how these underlying mechanisms can manifest into Keratosis Pilaris, and why I believe that KP can be effectively treated by stimulating IGF-I production in skin tissue. 

• Ras/Raf/MAPK signaling has been highlighted as an important contributor to the pathology of Keratosis Pilaris. RAS genes play an essential role in signaling through the mitogen-activated protein kinase (MAPK) pathway, which regulates cell proliferation, differentiation, survival, and death. Specifically for Keratosis Pilaris, genes BRAF, MEK1, MEK2, and KRAS are implicated in cardio-facio-cutaneous (CFC) syndrome, where the predominant features from these gene mutations are Keratosis Pilaris and Ulerythema ophryogenes among other epidermal abnormalities.[17]
• In a clinical study on MEK1, MEK2, and BRAF mutations, the following was reported among the participants. Keratosis pilaris was reported in 80% (49/61) of participants, a significantly higher frequency than the reported population average of 34% (p=0.018) 18. When analyzed specifically by gene, 12/13 (96%) with MEK1 or MEK2 mutations reported keratosis pilaris, compared with 77% (36/47) in the participants with BRAF mutations. The differences in frequency between genotypes are not statistically significant (p=0.433, Fisher’s Exact test). The location was on the face in 51% (31/61) and dorsal arms and legs in 72% (44/61). Respondents frequently mentioned involvement of the ears, back and torso.[17]

In this figure above we can see Keratosis Pilaris and sparse hair on the arm of a 9 year old girl with a MEK1 mutation.[17]

• In the same study, Ulerythema ophryogenes, characterized by erythema of the brow with loss of follicles, occurred in a majority of participants, 55/61 (90%). The eyebrows were sparse in 59% (36/61) and absent in 31% (19/61). Normal eyebrows were reported by 8% (5/61) of the participants and one reported thick eyebrows.[17]
• The insulin-like growth factor 1 receptor (IGF-1R) is a multi-functional receptor that mediates signals for cell proliferation, differentiation, and survival. Genetic experiments showed that IGF-1R inactivation in skin results in a disrupted epidermis. IGF-1 is one of the major regulators of cellular proliferation and differentiation. IGF-1 mediates its effects through the IGF-1 receptor (IGF-1R). This receptor belongs to the tyrosine kinase family of growth factor receptors.[10]
• One of the first families of proteins that are phosphorylated by the activated IGF-1R is the insulin receptor substrate (IRS) proteins. The activated IRS proteins serve as docking proteins to which several signaling molecules bind and then become activated. This ultimately results in the activation of at least two main signaling pathways: the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide-3 kinase (PI3K)/Akt/p70S6K pathway.[10][23]
• There are several studies demonstrating the role of IGF-1R and its signaling components in skin. Skin dermal fibroblasts and epidermal keratinocytes express IGF-1R, and IGF-1 stimulation of these cells leads to proliferation and mitogenicity. Experiments using mice with disrupted IGF-1R have a thinner and disrupted epidermis.[11]
• Changes in barrier function and abnormal paracellular permeability were found in both interfollicular and follicular stratum corneum of lesional KP, which correlated ultrastructurally with impaired extracellular lamellar bilayer maturation and organization. Evidence suggested delayed processing of secreted lipids in the interfollicular epidermis and between corneocytes in the upper parts of hair follicles.[1]  
  
• Loricrin and filaggrin are terminally differentiating structural proteins that contribute to the protective barrier function of the stratum corneum. Those with FLG mutations appear to have a higher probability of developing atopic dermatitis and/or Keratosis Pilaris, but it is clear that KP is capable of manifesting without these mutations.[1]
• Normally, the proliferating cells of the basal layer of the skin express keratins 5 and 14.[18] The induction of differentiation, associated with the upward movement of the cells to the spinous compartment, is accompanied by induction of the expression of keratins 1 and 10. Terminal differentiation, occurring in the granular compartment, is characterized by flattening of cells, enucleation, and finally cell death leading to sloughing of the cells off the skin surface. This process is associated with the induced expression of loricrin, filaggrin, and other proteins. Lack of IR expression resulted in abnormal differentiation of cultured murine skin keratinocytes, as demonstrated by a decrease in the expression of early skin differentiation markers. Thus, it is suggested that IR activates and supports the initiation of the differentiation process in keratinocytes.[11]

• Insulin affects keratinocyte proliferation rates, with an increase in circulating insulin correlating with increased proliferation.[10]
• IGF-1 levels are correlated with insulin sensitivity, where lower levels of IGF-1 would appear to coincide with a decrease in in insulin sensitivity. Higher concentrations of plasma insulin have been observed in mice where mutated IGF-1 allele (genes) cause a marked decrease in circulating IGF-1 levels. It is also possible that nutritional and genetic factors influence the levels of circulating IGF-1. It is not fully understood why lower IGF-1 coincides with a decrease in insulin sensitivity, but it may be related to insulin receptors. One theory is that due to the association between increased abundance of hybrid Insulin/IGF-1 receptors on target human tissues and elevated plasma insulin observed in patients with hyperinsulinemia, that these hybrid IR receptors may cause insulin resistance in certain human tissues. These correlations would imply that the prevalence of IR receptors, IGF-1 gene mutations, circulating insulin, and circulating IGF-1 all play a part in insulin resistance in keratinocytes and their proliferation.[8]
  
• Findings show that abnormalities in permeability barrier function in KP likely reflect an impairment in lamellar bilayer (LB) architecture. Although LB density seemed normal in KP with and without FLG mutations, all KP patients displayed aberrant LB internal structures, suggesting defective loading of lipid contents into the organelles of the keratinocytes. Secretion of LB contents appeared inhomogeneous in KP compared to controls. Evidence suggested delayed processing of secreted lipids in the interfollicular epidermis and between corneocytes in the upper parts of hair follicles.[1]
• It is suggested that delayed processing of secreted lipids in the interfollicular epidermis and between the corneocytes in the upper parts of the hair follicles may be the cause of an impairment in the permeability of the epithelial barrier/Lipid Lamellae.[1]
• Observations suggest that IGF-1 produced by fibroblasts might act on the fibroblasts themselves and on keratinocytes, thereby promoting proliferation and differentiation of these cells.[11]
• IGF-1 inhibits actions on inflammatory and Th1-mediated cellular immune responses through stimulation of IL-10 production in T cells.[14][15] 
• Early KP lesions, characterized by small keratinous plugs and no hair shaft abnormalities, showed atrophic sebaceous glands. Yet, sebaceous glands appeared normal in nonlesional KP and controls. In all fully formed KP lesions it was found that there was a striking absence of sebaceous glands. The resulting paucity of sebaceous gland-derived products may lead to defective corneocyte shedding from infundibula, hyperkeratinization of the acroinfundibula, and hair shaft abnormalities.[1]
• The inflammation seen in KP could be caused by repeated mechanical irritation of the hyperkeratotic plugs, including scratching, but also by a decrease in antimicrobial peptides with accreted bacteria colonization, due to loss of sebaceous gland-derived antimicrobial peptides. In addition, an increase in skin surface pH due to reduced levels of natural moisturizing factor, as occurs in FLG-deficient epidermis, could facilitate bacterial colonization and inflammation.[1]
• It is suggested that KP develops on body sites with higher levels of skin dryness and not on sites with a high sebum production such as the seborrheic area. Sebaceous gland density may be an indicator in how patterns of KP lesions appear on the body.[1][7][9]

Pathology Theory

I theorize that KP’s pathology can be explained by an insufficient bioavailability of IGF-1 and/or mutations in insulin receptors on keratinocytes. This often can coincide with high circulating insulin and insulin sensitivity which affects the rate at which skin cells mature and differentiate throughout the strata of the epidermis.[10][11] The lack of IGF-1 causes impaired cellular differentiation and maturation to occur, which prevents lipids from being secreted in some keratinocytes that build out the lamellar bilayer of the skin at the SC-SG interface around the follicles.[1] This impairment in keratinocyte differentiation localized at the follicles results in epithelial barrier impairments as non-lamellar domains form in the lipid lamellae.[1] This abnormal keratinization and skin cell proliferation combined with down-regulating 5α-Reductase (due to insufficient IGF-1)[19] eventually atrophies the sebaceous glands by reducing sebocyte proliferation that would typically be induced by DHT, if not for the loss of 5α-Reductase regulation from IGF-1. Keratinocytes displace the sebocytes and the resulting loss of sebum affects the skin’s ability to promote beneficial bacterial colonization[7][20] and prevent scale from building up within the follicular canal. This increased redness and inflammation can also be explained by the impaired epithelial barrier allowing bacteria and allergens to pass through[1], triggering an immune response. Contributing to inflammation and redness, it is also possible that the loss of IGF-1 may increase inflammation since IGF-I inhibits actions on inflammatory and Th1-mediated cellular immune responses through stimulation of IL-10 production in T cells.[14][15] The loss of sebaceous gland derived products could also contribute to hair shaft abnormalities which can explain the curled and brittle vellus hair follicles found trapped inside the infundibular plug.[1][16] IGF-1 also regulates hair follicle growth and development, which may also be impacted and contribute to curled and brittle hair follicles. Finally, the impaired lamellar bilayer can also explain why trans epidermal water loss is a consistent issue for KP patients.[1]

From this theory, we can propose that stimulating IGF-1 in skin tissue may be a potential effective treatment for regulating skin cell differentiation, improving insulin sensitivity in the skin, reducing keratinocyte proliferation, inhibiting inflammation via stimulation of IL-10 production and up-regulating sebocyte proliferation (via IGF-1 stimulation of 5α-Reductase).

Proposed Treatment 

Current KP treatments on the market all use similar keratolytics: Urea, Alpha Hydroxy Acids (AHA), or Beta Hydroxy Acids (BHA) to help chemically exfoliate the infundibular plug, reducing the bumpy texture. The most common AHA and BHA acids used are glycolic acid, lactic acid, and salicylic acid. Retinol is also often used to increase cell turnover as a way to improve the texture of KP. Physical exfoliation is encouraged with limited frequency as physical manipulation of the keratin lesions can increase irritation of the condition. Moisturizing is generally recommended to help reduce irritation from dry skin. Curiously, the use of BHAs (salicylic acid) in many KP lotions is seemingly at odds with the symptoms of lesional KP since the severity of the condition could be exacerbated by the BHAs stripping what little sebum is produced by atrophied sebaceous glands. While some with KP may be able to tolerate limited BHA use, individuals using salicylic acid in products that are left on the skin have reported increased irritation and spread of their KP symptoms in social media groups. None of these treatments address the underlying cascade of symptoms present in KP. Barrier regulation, inflammation, and hormonal equilibrium are never addressed, and therefore only partial improvement in texture can be achieved through consistent and frequent topical exfoliation. Some laser treatments are also suggested to help with the redness and inflammation, with varying results.

To address not only the unwanted texture, but also the pigmentation, inflammation, and barrier issues found in KP, we need to identify substances that can reduce the effects seen from IGF-1 deficiency and IR mutations in skin tissue. By reducing the permeability of the epithelial barrier in the LB and up-regulating lipogensis through increased IGF-1 bioavailability, I believe we can prevent new keratin scale from forming in the follicular canal and reduce overall inflammation. Keratin plugs are shown to form after the atrophy of sebaceous glands, indicating that dry follicles are a precursor to keratin buildup. By resubstantiating sebum production and improving the cohesiveness of the epithelial barrier, we can prevent the conditions that are necessary for these keratin plugs to form. To accomplish this, I researched the following ingredients that showed promise in stimulating IGF-1 production in the skin through sensory neuron activation.

Topical application of Raspberry Ketone (a major aromatic compound contained in red raspberries) has been observed to stimulate IGF-1 secretion in skin tissue. It is suspected that the increase in dermal IGF-1 happens through sensory neuron activation within 30 minutes of application. Raspberry Ketone (RK) shares a nearly identical molecular structure to Capsaicin[12], which increases calcitonin gene-related peptide (CGRP) release from sensory neurons by stimulating vanilloid receptor-1 (VR-1). Since CGRP increases production of insulin-like growth factor-I (IGF-I) in fetal osteoblasts in vitro, it is possible that sensory neuron activation by capsaicin increases production of IGF-1[12]. The same can be said for Raspberry Ketone (RK), which affects the skin in the same way as Capsaicin.[11][12] This increase in IGF-1, brought on through consistent application of RK, could regulate keratinocyte differentiation, improve dermal insulin resistance, up-regulate 5α-Reductase which in turn would increase sebocyte proliferation, and also promote hair follicle growth[1][10][12][15][19]. In addition to these desirable effects, RK stimulating IGF-1 can also inhibit inflammation via stimulation of IL-10 production, reducing the overall visible redness seen in KP[15].

In addition to RK, Indigo Naturalis was selected to accompany RK in the topical emulsion as it acts as a dermal anti-inflammatory. Recent studies on topical Indigo Naturalis have shown it to be an effective treatment for atopic dermatitis and psoriasis as it can reduce the cytokine response in the skin while also acting on keratinocytes by reducing their proliferation.[22] This would in theory help counteract increased keratinocyte proliferation to slow the development of scale buildup in the follicular canal.

The results of this proposed treatment have been documented by the author of this article as he applied a 0.05% raspberry ketone with 0.05% Indigo Naturalis in a emulsion of jojoba oil and water to his KP Rubra. This resulted in a rapid reduction in tactile bumps, decreased redness/inflammation, and retained results for up to 3 weeks post topical application. These results plateaued after 12 weeks of twice daily topical application. After discontinuing the treatment, the results persisted but eventually the condition returns.

The figure on the left shows untreated KP on the left arm. The figure on the right is the same left arm after 12 weeks of twice daily topical RK and Indigo Naturalis.

A Theory of How Decreased IGF-1 Levels Culminate in the Skin Condition Keratosis Pilaris

Based on the findings I've laid out in previous sections, I have built a theory on how the cascading symptoms of KP develop.

IGF-1 regulates skin cell differentiation throughout the cell’s lifecycle. This is confirmed through the studies on both the effects of IGF-1 in the skin as well as the study on genetic mutations affecting Insulin Receptors on keratinocytes. Seeing as disrupted lamellar bilayers (LB) may feasibly be the result of a deficiency of IGF-1 and/or a IR mutation, I hypothesize that the results of insufficient bioavailability of IGF-1 and its effects on subsequent pathway signaling likely result in the delayed processing of LB contents as seen in the KP biopsies due to the failure to regulate differentiation as skin cells mature and differentiate at the SC-SG interface. This disrupted epidermis and the formation of an infundibular plug may also be driven by increased proliferation rates due to high circulating insulin (hyperinsulinemia) in combination with decreased IGF-1. The prevalence of keratinocytes IR receptors and associated genetic receptor mutations may also partially cause this imbalance to occur.    

This abnormal cellular differentiation and proliferation is likely the cause for permeability abnormalities in the Lipid Lamellae, resulting in abnormal keratinization of the interfollicular epidermis as some cells fail to differentiate as they travel through the strata of the epidermis. This failure to mature normally would then prevent these skin cells from secreting lipids as expected, creating malformations in the epithelial barrier around the follicle. This would seemingly be supported by the non-LB domains reported from KP biopsies.

IGF-1 is also responsible in part for the regulation of lipogenesis, which is thought to occur through IGF-1’s effects on 5α-Reductase and the enzymatic process responsible for converting testosterone into DHT, which stimulates sebocyte proliferation. In this theory, reduced amounts of IGF-1 bioavailability would impact sebocyte proliferation via the loss of regulatory functions that IGF-1 has on 5α-Reductase, while also causing impaired processing of secreted lipids in the interfollicular epidermis, which combined could result in the eventual keratinization of both the sebaceous gland and the impaired epithelial barrier of the follicular canal. Increased insulin levels could also attribute to the increase in keratinocyte proliferation, replacing sebocytes.

As the sebaceous glands become atrophied, eventually a critical level would be reached where the lack of sebum and sebaceous gland-derived products may then lead to increased defective corneocyte shedding from infundibula. At this point we would see a transition from what is viewed as “non-lesional” KP to the formation of an infundibular plug, resulting in tactile protrusions or bumps on the surface of the skin. This process would explain the delineation between lesional and non-lesional KP skin, while also explaining some of the variance seen in KP subtypes. The severity of the epithelial barrier impairment also correlates with the rate at which scale builds up in the follicle.

The loss of sebum and sebaceous gland-derived products would also lead to a decrease in antimicrobial peptides typically found in sebum. This can increase accreted bacteria colonization on the skin’s surface which could then ingress through the impaired skin barrier via the non-LB domains, provoking an immune response in the skin. In addition, an increase in skin surface pH due to reduced levels of natural moisturizing factor, as occurs in FLG-deficient epidermis, could facilitate bacterial colonization and additional inflammation. These effects could directly explain why we see variations in redness and inflammation in KP subtypes Rubra and Alba. Supporting this theory is a study done in 2018 on restoring the dermal microflora with a purified strain of AOB, Nitrosomonas eutropha (D23) and its related effects on Keratosis Pilaris[7].

In addition to the points made above, there are also life events that appear to correlate with KP development, spread, and changes in severity as described in: Wang JF, Orlow SJ. Keratosis Pilaris and its Subtypes: Associations, New Molecular and Pharmacologic Etiologies, and Therapeutic Options[9]. These same events also correlate with the user submissions frequently posted on r/Keratosis since 2015.

Conclusion

Keratosis Pilaris is a complex condition that lies at the intersection of multiple interdependent symptoms. While it is clear that more research is needed to identify all underlying mechanisms, there are too many corroborating data points showing that this condition is directly influenced by hormonal changes and genetic factors. IGF-1, Insulin Receptors, and pathway mutations all directly contribute to the barrier issues and sebaceous gland disruption seen in KP. It is my theory that increasing dermal IGF-1 levels can help to overcome receptor and pathway mutations by increasing the rate of signaling, promoting more consistent keratinocyte differentiation and maturation, while in parallel also stimulating sebocyte proliferation through  5α-Reductase and inhibiting inflammation via stimulation of IL-10 production. I believe that these effects will counteract the upstream symptoms seen in Keratosis Pilaris, resulting in a regulated skin barrier, reduced inflammation, and preventing keratin accumulation in the follicular canal. 

Sources