SEARCH

SEARCH BY CITATION

Keywords:

  • acne;
  • hyperglycaemic food;
  • IGF-1;
  • insulin;
  • metformin;
  • milk;
  • smoking

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

Abstract:  It is the purpose of this viewpoint article to delineate the regulatory network of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signalling during puberty, associated hormonal changes in adrenal and gonadal androgen metabolism, and the impact of dietary factors and smoking involved in the pathogenesis of acne. The key regulator IGF-1 rises during puberty by the action of increased GH secretion and correlates well with the clinical course of acne. In acne patients, associations between serum levels of IGF-1, dehydroepiandrosterone sulphate, dihydrotestosterone, acne lesion counts and facial sebum secretion rate have been reported. IGF-1 stimulates 5α-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation and lipogenesis. Milk consumption results in a significant increase in insulin and IGF-1 serum levels comparable with high glycaemic food. Insulin induces hepatic IGF-1 secretion, and both hormones amplify the stimulatory effect of GH on sebocytes and augment mitogenic downstream signalling pathways of insulin receptors, IGF-1 receptor and fibroblast growth factor receptor-2b. Acne is proposed to be an IGF-1-mediated disease, modified by diets and smoking increasing insulin/IGF1-signalling. Metformin treatment, and diets low in milk protein content and glycaemic index reduce increased IGF-1 signalling. Persistent acne in adulthood with high IGF-1 levels may be considered as an indicator for increased risk of cancer, which may require appropriate dietary intervention as well as treatment with insulin-sensitizing agents.


Abbreviations:
ACTH

adrenocorticotropic hormone

AGA

appropriate for gestational age

AMP

adenosine monophosphate

AMPK

AMP-activated kinase

AR

androgen receptor

DHEAS

dehydroepiandrosterone sulphate

DHT

dihydrotestosterone

EGCG

(-)-epigallocatechin-3-gallate

FGF

fibroblast growth factor

FGFR

FGF receptor

GH

growth hormone

GHR

growth hormone receptor

GLUT4

glucose transporter protein 4

HCG

human chorionic gonadotrophin

IGF

insulin-like growth factor

IGFBP

IGF-binding protein

IGF1R

IGF-1 receptor

IGF2R

IGF-2 receptor

IR

insulin receptor

LH

luteinizing hormone

LGA

large for gestational age

MAPK

mitogen-activated protein kinase

PCOS

polycystic ovary syndrome

PI3K

phosphoinositide-3-kinase

PKB

protein kinase B (=Akt)

SGA

small for gestational age

SREBP

sterol response element binding protein

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

The purpose of this review is to delineate the regulatory network of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signalling during puberty, the associated hormonal changes in adrenal and gonadal androgen metabolism, and the impact of dietary factors and smoking involved in the pathogenesis of acne.

Growth hormone and IGF-1 play an important role for epidermal homeostasis. GH is secreted by the anterior pituitary and binds to GH-receptor (GHR), expressed on most peripheral cells of the body (1). GH induces hepatic synthesis and secretion of IGF-1, the mediator of the growth. GH, insulin and IGF-1 have distinct effects on sebocyte growth and differentiation (2,3). IGF-1 exerts its major effect on proliferation, while having an effect similar to insulin on differentiation (2).

Insulin-like growth factor-1 has been localized to the peripheral cells of sebaceous glands in the rat (4). In human skin appendages, the strongest expression of IGF-1 protein was found in maturing sebocytes and suprabasal cells of sebaceous ducts (5).The expression of IGF1R mRNA was the strongest in basal cells of sebaceous glands and immature sebocytes, whereas IGF1R-protein expression was uniform and intense in all regions of the gland (5). This pattern of expression suggests a role for IGF-1 as a sebaceous mitogen and morphogen (5).

More than 90% of circulating IGFs are bound to IGF-binding protein-3 (IGFBP-3), the rest to IGFBP-1, -2, -4, -5 and -6, and less than 1% of IGFs circulate as free IGFs. IGF signal transduction is mediated by the IGF-1 receptor (IGF1R) and IGF2R. The IGF1R is a tyrosine kinase receptor, which is able to form heterodimers with insulin receptor (IR). The IGF2R is a scavenger receptor involved in the degradation of IGF-2. Insulin primarily binds to IR, but it can also bind to IGF1R. IGF-1 and IGF-2 primarily bind to their specific receptors but are also able to bind to IR (1,6,7), explaining the significant overlap in signal transduction (Fig. 1). IGF1R-mediated signals activate the Ras-Raf-MAP kinase and the phosphoinositide 3-kinase (PI3K)/Akt pathway (6,7). The IR-B isoform mediates the classic metabolic responses induced upon insulin binding and has very low affinity for IGFs (7). Activation of the IR-A isoform by either insulin or IGF-2 leads to mitogenic responses similar to those observed for IGF1R.

image

Figure 1.  IGF-1, IGF-2 and insulin signal transduction and receptor cross-reactivity inducing mitogenic responses.

Download figure to PowerPoint

Correlations between serum IGF-1 and acne

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

Acne is regarded as an androgen-dependent disease (2). The course of acne corresponds less closely to plasma androgen levels than it does to GH and IGF-1 levels (8). Increased serum levels of IGF-1 have been observed in adult women and men with acne (9,10). The number of total acne lesions, inflammatory lesions, serum levels of dihydrotestosterone (DHT) and dehydroepiandrosterone sulphate (DHEAS), each correlated with serum IGF-1 levels in women with acne. A correlation between the mean facial sebum excretion rate and serum IGF-1 levels has been demonstrated in postadolescent acne patients (11).

IGF-1, insulin and sebaceous lipogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

Insulin-like growth factor-1 and insulin stimulate lipogenesis of sebaceous glands (2). In sebaceous gland organ cultures, IGF-1 induced sebaceous lipogenesis (12). In SEB-1 sebocytes, IGF-1 increased lipogenesis by the induction of sterol response element-binding protein-1 (SREBP-1) (13). SREBP-1 preferentially regulates genes of fatty acid synthesis. In the hamster ear sebaceous model, androgens rapidly induced the expression of SREBP-1 (14). Insulin regulates SREBP-1c on the transcriptional level (15). The importance of IGF-1 for lipid synthesis in SZ sebocytes and for keratinocyte proliferation has been demonstrated (16,17).

Melanocortins regulate lipogenesis in sebocytes expressing both melanocortin-1 receptor (MC-1R) and MC-5R (18,19). Sebocytes and keratinocytes of the ductus seboglandularis of acne-involved and non-involved skin showed very intense MC-1R expression in contrast to less intense immunoreactivity in normal skin (20). Sonic hedgehog-Gli-signalling induces terminal differentiation of sebocytes, up-regulates MC-5R expression and MC-5R-dependent lipogenesis (21). MC-5R is regarded as a marker of human sebocyte differentiation (22). Sonic hedgehog is a downstream target of activated fibroblast growth factor receptor-2b (FGFR2b) (23), which shares common downstream signaling cascades with IGF1R (24).

In human SEB-1 sebocytes, IGF-1 activated PI3K/Akt and MAPK/ERK-signal transduction pathways and induced the expression SREBP-1 resulting in increased sebaceous lipogenesis (25). Addition of a specific PI3K-inhibitor down-regulated IGF-1-induced expression of SREBP-1 and sebaceous lipogenesis (25). SREBP-1c increases also in response to insulin signalling (26). SREBP-1 has been implicated in the development of insulin resistance and regulates components of the insulin signalling pathway such as IRS-2 and PI3KR3 (27). All the recently identified promoters of the human genome, which bind SREBP-1 and its two associated transcription factors Sp1 and NFY, form an interconnected regulatory circuit and bind to distinct sets of target genes (28). Members of the Sp-family may be key mediators of gene expression induced by insulin (29). Insulin regulates the subcellular localization, stability and trans-activation potential of Sp1 (29).

The GH-IGF-1 axis and androgen synthesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

Adrenal gland

The fetal adrenal cortex derives from a common adrenogonadal precursor lineage that also gives rise to the steroid-secreting cells of the gonads. The GH-IGF-1 axis plays an important role for the ACTH-dependent production of DHEAS of the human adrenal gland (30,31). IGF-1 enhances the sensitivity of the adrenal for ACTH, and induces the expression and activity of key enzymes of adrenal androgen biosynthesis (31). In healthy prepubertal girls as well as prepubertal girls with premature adrenarche, a positive correlation between IGF-1 and DHEAS serum levels has been reported (32). Serum IGF-1 levels rise and fall in a pattern similar to serum DHEAS, and normal puberty is characterized by a state of transient insulin resistance associated with an increase in gonadal sex steroid production and adrenal androgens (30).

Ovary

The IGF-system plays an important role in ovarian androgen synthesis. After the rise of luteinizing hormone (LH), a significant increase in IGF-1 and progesterone could be detected in the dominant follicle (33). IGF-1 exerts stimulatory effects on oestrogen synthesis of granulosa cells and ovarian steroidogenesis (33). IGF-1 and IGF-2 increased the efficacy of LH on interstitial theca-cells increasing ovarian androgen production (34). The IGF-system has been implicated in the pathogenesis of ovarian hyperandrogenism and polycystic ovary syndrome (PCOS) (34).

Testes

Proliferation and differentiation of adult Leydig cells is a prerequisite for increasing levels of circulating androgens of puberty (35). IGF-1 mRNA, -protein and IGF1R have been identified in Leydig cells, peritubulular cells and spermatocytes (36,37). Testicular levels of IGF-1 increase during puberty and coincide with increased production of testosterone. IGF-1, in addition to LH, stimulates the proliferation of Leydig-cell precursors and is an essential local mediator of testicular DNA synthesis and steroidogenesis (35). Specific inhibition of IGF1R resulted in increased Leydig-cell apoptosis (38). Thus, the IGF-system is of importance for Leydig-cell differentiation, mitogenesis, anti-apoptosis and androgen biosynthesis (37–39).

IGF-1 potentiates peripheral androgen-mediated signal transduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

5α-Reductase

Addition of IGF-1 to cultures of rat and human skin scrotal fibroblasts significantly increased 5α-reductase activity in a dose-dependent manner (40). Conversion of testosterone to DHT increases androgen signalling. The IGF-1-induced activation of 5α-reductase points to an important role of IGF-1 as a peripheral amplifier of androgen metabolism in the skin (40) (Fig. 2).

image

Figure 2.  Regulatory network of ACTH, LH, GH and IGF-1 in adrenal and gonadal androgen synthesis and cutaneous intracrine androgen metabolism.

Download figure to PowerPoint

Androgen receptor

Insulin like growth factor-1 induces androgen receptor (AR) trans-activation. In the nucleus, AR binds to the AR repressive protein Foxo1. IGF-1, as well as insulin activates PI3K, which leads to Akt-mediated Foxo1 phosphorylation. Phosphorylated Foxo1 leaves the AR and translocates from the nucleus into the cytoplasm (41). By this mechanism, IGF-1 signalling alleviates AR repression resulting in AR gain-of-function. Thus, IGF-1 has direct influence on the intracrine androgen regulation of the skin and potentiates androgen signalling by the induction of 5α-reductase activity and activation of AR.

Pharmacological down-regulation of insulin- and IGF-1 signalling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

Metformin

In patients with PCOS, metformin treatment decreased elevated serum IGF-1 and androgen levels (42). Girls with precocious pubarche and low birth weight demonstrate increased IGF-1 serum levels and insulin resistance, which leads to rapid progression of puberty and a predisposition to develop PCOS. Metformin treatment of these girls prevented the onset of early puberty by 0.4 years and significantly decreased serum levels of IGF-1, fasting insulin, DHEAS and testosterone (43). Improvement of insulin sensitivity by metformin treatment is associated with a decrease in IGF-1 levels in girls with precocious pubarche as well as adult patients with PCOS. In normal girls, IGF-1 and insulin resistance have been implicated in the mechanism of adrenarche during prepuberty (44). Metformin shifts IGF-1 to lower levels, thereby preventing an early onset of puberty. Thus, metformin treatment has ‘counter-regulatory’ action to the puberty-induced shift of the insulin/IGF-1 axis to higher levels.

Insulin resistance and action of metformin

Insulin resistance is characterized by decreased cellular uptake of glucose and normal or increased serum levels of insulin. In states of insulin resistance, the intracellular pool of the insulin-responsive glucose transporter 4 (GLUT4) is markedly reduced. GLUT4 proteins are stored in recycling endosomes until insulin stimulates the cell to deliver large numbers of recycling endosomes with GLUT4 to the plasma membrane to facilitate increased glucose uptake. However, in insulin-resistant states, higher than normal insulin levels are required to increase the membrane pool of GLUT4 for adequate glucose uptake.

Metformin has two mechanisms of action to improve the activity of GLUT4. In women with PCOS, metformin as well as rosiglitazone significantly increased GLUT4 mRNA expression (45). Hyperinsulinaemia and hyperglycaemic conditions result in increased cellular GLUT4 endocytosis leading to decreased uptake of glucose. GLUT4 endocytosis is reversed by metformin treatment (46). The metformin-induced reduction in GLUT4 endocytosis is dependent on AMP-activated protein kinase (AMPK) (47). The second mechanism of metformin action enhances GLUT4 gene expression. The GLUT4 promoter is repressed by histone deacylase 5 (HDAC5). Stimulation of AMPK activity by metformin results in increased phosphorylation of HDAC5 leading to a release of HDAC5 from the GLUT4 promoter thereby enhancing GLUT4 gene expression (48). Thus, metformin delays GLUT4 endocytosis and increases GLUT4 gene expression, and both mechanisms accelerate glucose uptake. The improvement in insulin sensitivity normalizes increased insulin levels. As insulin is a stimulator of hepatic IGF-1 secretion (49), the insulin-lowering effect of metformin will reduce elevated serum IGF-1 levels.

Thiazolidinediones

Rosiglitazone and pioglitazone are two synthetic hypoglycaemic agents of the thiazolidinedione family and are potent ligands of peroxisome proliferator-activated receptor-γ (PPARγ). PPARγ normally represses the GLUT4 promoter. The thiazolidinediones alleviate PPARγ repression of the GLUT4 promoter, thereby enhancing insulin responsiveness with improved glucose uptake (50). In the basal state, the transcription factor Foxo1 is mostly localized in the nucleus where it represses PPAR-γ. Increased insulin and IGF-1 signalling leads to phosphorylation of Foxo1, which leaves the nucleus and de-represses PPARγ. Increased activity of PPARγ represses the GLUT4 promoter leading to insulin resistance. Thus, chronic insulin- or IGF-1-stimulation with increased phosphorylation of Foxo1 results in insulin resistance and increased AR signalling, biochemical characteristics observed in puberty and PCOS. In this regard, insulin-sensitizing drugs may represent suitable options for the treatment of PCOS and acne.

Retinoids

Retinoids not only suppress FGFR2-signalling but also have opposing effects on IGF1R and AR signal transduction (51). In human dermal papilla cells, all-trans-retinoic acid induced a fivefold increase of IGFBP-3, which inhibits the activity of free IGF-1. IGFBP-3 forms a complex with IGF-1, thereby reducing its free concentration important for maintaining the hair anagen growth phase (52). IGF-1 is an inducer of 5α-reductase activity (40), whereas isotretinoin significantly reduces the activity of 5α-reductase in the skin of acne patients (53). IGF1R signalling stimulates cell proliferation and exerts strong anti-apoptotic activity (6,7). On the contrary, isotretinoin induces apoptosis and cell cycle arrest in human SEB-1 sebocytes (54). IGF-1 and insulin activate Foxo1 phosphorylation, thereby augmenting AR signalling (41), whereas oral isotretinoin treatment decreased the AR binding capacity constant in the skin of acne patients by a factor of 2.6 (55). Metformin-mediated suppression of IGF-1 serum levels and retinoid-induced up-regulation of IGFBP-3 expression both down-regulate IGF1R signal transduction thereby exerting inhibitory effects on the synthesis and conversion of androgens and AR ligand binding.

Interactions between IGF1R- and FGFR2b-signalling pathways

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

The role of androgen-dependent FGFR2b signalling in keratinocyte and sebocyte differentiation in acne has been recently elaborated (23,56). IGF1R primarily regulates cellular proliferation and to a lesser extent differentiation (2), whereas FGFR2b is predominantly involved in cellular differentiation (23,56). Comedogenesis is considered to be a process of increased keratinocyte proliferation as well as exaggerated keratinocyte differentiation (hyperkeratinization) (57). From studies on human keratinocyte cell culture models, it has been concluded that the normalizing activity of retinoids on diseases with hyperkeratinization is mediated by modulation of differentiation rather than cell growth (58). IGF1R expressed on basal cells, and FGFR2b expressed on suprabasal cells, regulate canonical cellular pathways involved in proliferation and differentiation of sebocytes and keratinocytes and activate MAPK- and PI3K/Akt signalling pathways. Substantial qualitative overlap in their recruitment profiles has been demonstrated (24) (Fig. 3). The androgen-dependent expression of FGF7 and FGF10, the ligands of FGFR2b, is increased by IGF-1-mediated AR signalling. In this regard, IGFR1-signalling has cooperative effects for FGFR2b signal transduction (Fig. 3).

image

Figure 3.  IGF-1 signalling in the pilosebaceous follicle and related interactions with androgen metabolism, androgen-dependent FGF-FGFR2b-signalling, endocrine and nutritional impact on IGF-1 homeostasis.

Download figure to PowerPoint

Endocrine disorders with increased insulin- and IGF-1 serum levels and acne

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

Premature adrenarche and precocious pubarche

Insulin resistance and hyperinsulinaemia have been observed in prepubertal girls with premature adrenarche. In many of these girls, high IGF-1, low IGFBP-1 and higher DHEAS serum levels have been reported (30). Treatment of these girls with metformin decreased elevated IGF-1 and DHEAS serum levels (43,59). Premature pubarche shares many clinical characteristics with PCOS (30). The IGF-1 axis may be programmed by diet early in infancy (60). An inverse relation between IGF-1 levels during the first months of life and IGF-1 levels in adulthood could be observed (60). Low levels of IGF-1 in the postnatal period are associated with high IGF-1 levels in adolescence. Low levels of IGF-1 are reported in small-for-gestational age (SGA) newborn infants (61). Girls with low birth weight and precocious pubarche are at risk for early onset of puberty and menses and further progress to anovulation, hyperinsulinaemic hyperandrogenism, PCOS and acne (62). It appears that the IGF-1 axis in SGA/low birth weight newborns later drifts to higher IGF-1 levels, which can promote the development of precocious pubarche and PCOS.

Polycystic ovary syndrome

Polycystic ovary syndrome is associated with increased serum levels of IGF-1, DHEAS, hyperinsulinaemia, insulin resistance, acne and hirsutism (56,63). Twofold elevated serum levels of free IGF-1 have been detected in women with PCOS in comparison with healthy controls (64). Metformin is the therapy of choice for PCOS and has been demonstrated to reduce serum androgen levels and gonadotrophins with an improvement of acne and hirsutism, menstrual cycle, ovulation and fertility (65,66).

Acromegaly

Acromegaly, the clinical state of GH hypersecretion and increased serum IGF-1 levels, is usually the result of somatotropic adenomas of the pituitary. Patients with acromegaly often have greasy skin and an increased sebum excretion rate (67). Although acne is not always observed in acromegaly, several studies report an association between acromegaly and acne. As in PCOS, patients with acromegaly often exhibit insulin resistance and hirsutism.

Induction of acne by IGF-1 treatment

Recombinant human IGF-1, approved for the treatment of the short child, elicits androgenesis and acne (68). Laron syndrome is characterized by GH resistance, molecular defects of the GHR or postreceptor pathways leading to inability to synthesize IGF-1. During IGF-1 treatment of six female patients with Laron syndrome, four developed oligo/amenorrhoea and acne associated with significant elevations in serum testosterone and androstenedione (69). Reduction of the IGF-1 dose or interruption of IGF-1 treatment normalized androgen levels and resulted in a resolution of acne and oligomenorrhoea (69).

Aggravation of acne by dietary modification of insulin/IGF-1signalling

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

Epidemiological observations point to a role of Western diet in the development or aggravation of acne. Cordain et al. (70) studied 1200 Kitavan islanders of Papua New Guinea and 115 Aché hunter-gatherers of Paraguay who do not consume dairy products and have low glycaemic diets. No case of acne has been detected in these two non-westernized populations.

High glycaemic diets

Diets rich in carbohydrates with a high glycaemic index are associated with hyperglycaemia, reactive hyperinsulinaemia and increased formation of IGF-1. Diets with a low glycaemic load decreased serum IGF-1 levels and significantly improved acne following a 12-week diet (71). The endocrine effects of low glycaemic load versus a high glycaemic load diet on 12 male acne patients showed a significant increase in IGFBP-1 and IGFBP-3 in the low glycaemic load group, suggesting that low glycaemic diet reduces free IGF-1 activity and bioavailablity (72).

Association between milk consumption and acne

Prospective cohort studies in the United States in 4273 teenage boys and 6094 teenage girls demonstrated a correlation between milk consumption and acne (73,74). In boys, the strongest association has been found between intake of skim milk and acne (74). Thus, it is conceivable that not the lipophilic androgenic steroids enriched in milk fat (75), but more likely the hydrophilic protein fraction in cow’s milk, which increases insulin/IGF-1 signalling, might have a stronger influence on the milk-induced aggravation of acne.

Cow’s milk contains active IGF-1 and IGF-2 (76). High levels of IGF-1 are still detectable after pasteurization and homogenization of milk. Intriguingly, bovine and human IGF-1 shares the same amino acid sequence and thus binds to the human IGF1R. Several lines of evidence indicate that IGFs in milk may survive digestion and remain bioactive in the plasma of milk-consumers.

Milk consumption increases IGF-1 serum levels

High milk consumption is associated with a 10–20% increase in circulating IGF-1 levels among adults and a 20–30% increase among children (77–80). In 2109 European women, serum IGF-1 levels were positively related with the intake of milk (81). Milk and dairy products increase IGF-1 levels more than other dietary sources of protein such as meat (78). Moreover, milk consumption raises the ratio of IGF-1/IGFBP-3 indicating an increased bioavailability of IGF-1. Prolonged consumption of ultraheat-treated (UHT) milk shifts the GH/IGF-1 axis in children to higher levels (82). After a month of drinking 710 ml of UHT milk daily, Mongolian children, who had not previously consumed milk, had a higher mean plasma level of IGF-1, higher IGF-1/IGFBP-3 and GH levels (82). Their mean serum IGF-1 levels were significantly raised after 4 weeks of milk consumption by 23.4% (82).

The insulinotropic effect of milk

Fermented and ‘non-fermented’ milk products give rise to insulinaemic responses far exceeding than what could be expected from their low glycaemic indexes (GI). Despite low GI of 15–30, milk products produce three- to sixfold higher insulinaemic indexes (II) of 90–98 (83). A large and similar dissociation of the GI and II exists for both whole milk and skim milk (84). It has already been suggested that some factor within the protein fraction of milk is responsible for milk`s insulinotropic effect (84). Skim milk has been identified as a potent insulin secretagogue in type 2 diabetic patients (85). Except for cheese, milk and all dairy products have potent insulinotropic properties (86). In a 1-week intervention study of 24 prepubertal 8-year-old boys, the effect of daily intake of 53 g of either lean meat or skim milk (1.5 l per day) was studied with regard to insulin and IGF-1 responses. In the skim milk group, insulin significantly increased by 105% and IGF-1 by 19% respectively (78, 78a). There was no significant increase in either insulin or IGF-1 in the meat group. The addition of an ordinary amount of 200 ml milk to a meal with a low GI increased the insulin response by 300% to a level typically seen from a meal with a very high GI (87). The comparison of 43 breast-fed and 43 cow’s milk formula-fed 1-week-old term infants showed higher postprandial insulin levels in cow’s milk formula-fed group (88).

Differential induction of insulin and IGF-1 by milk protein fractions

The major protein fraction of cow’s milk is casein (80%), and the remaining 20% are whey proteins. The effect of whey and casein fractions of milk on fasting concentrations of IGF-1 and insulin has been examined in fifty-seven 8-year-old boys who received over 7 days either casein or whey proteins in amounts similar to that found in 1.5 l of skim milk. In the casein group, serum IGF-1 increased by 15%, whereas there was no change in fasting insulin. In the whey group, fasting insulin increased by 21%, with no change in IGF-1 (89). The insulin response to a whey meal has been reported to be higher than that of a milk meal. This differential response suggests that the insulinotropic component of milk resides predominantly within the whey fraction, whereas casein has a stronger IGF-1 stimulating effect than does whey (89). Typical Western diet, comprised of milk and hyperglycaemic foods, may have potentiating effects on serum insulin and IGF-1 levels, thereby promoting the development of acne. Young men of the fitness-centre environment reveal increasing androgen abuse in combination with recombinant GH, insulin and consumption of insulinotropic whey protein concentrates (90,91).

Smoking and insulin resistance

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

There is evidence that smokers are insulin resistant and hyperinsulinaemic compared with non-smokers (92). Hyperinsulinaemia, dyslipidaemia and exaggerated adrenal androgen response to ACTH have been observed in male smokers (93). The response of 17-hydroxyprogesterone, DHEAS and androstenedione to ACTH was higher in smokers than in non-smokers. The DHEAS response to ACTH was a significant determinant of insulin. Thus, smoking may inhibit the adrenal 21-hydroxylase resulting in an increase in the production of adrenal androgens, which contribute to the insulin resistance in smokers (93). Although the role of smoking as an aggravating factor in acne is still controversial (94,95), its role in hidradenitis suppurativa (acne inversa) is well appreciated (96,97). The contribution of smoking to insulin resistance and hyperinsulinaemia might shed a new light on its role as a promoter of hidradenitis suppurativa and acne.

Persistent acne in adulthood – an indicator of increased risk of cancer?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

Severe, persistent acne in males has been associated with an increased frequency of prostate carcinoma (98). There are further acne-associated diseases exhibiting increased IGF-1 serum levels and increased incidence of cancer. Patients with acromegaly and PCOS have an increased prevalence of cancer (99). Increased serum insulin and IGF-1 levels are associated with an increased incidence of a variety of cancers (6,100,101). In this regard, persistent acne in adulthood with insulin resistance and high IGF-1 serum levels should be regarded as a clinical indicator of increased risk for tumor promotion. Treatment of these patients with insulin-sensitizing agents will not only improve acne, but may also reduce the risk of cancer development.

Conclusions and outlook

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References

A growing body of evidence underlines the role of insulin resistance with increased insulin/IGF-1 signalling in the pathogenesis of acne. IGF-1 is the key hormonal mediator regulating adreno-gonadal androgen synthesis, amplifying cutaneous androgen activity and stimulating proliferation of sebaceous follicle. Endocrine diseases or nutritional influences leading to increased insulin and IGF-1 serum levels are frequently associated with acne (Table 1). IGF-1 mediates the action of pituitary GH during puberty, the induction of androgen production and stimulation of peripheral androgen metabolism. Milk consumption and hyperglycaemic diets can induce insulin and IGF-1-mediated PI3K/Akt-activation inducing sebaceous lipogenesis, sebocyte and keratinocyte proliferation, which can aggravate acne. Persistent IGF-1-mediated activation of the PI3K/Akt-pathway might not only contribute to the development of acne, but also to the induction of the lipogenic phenotype recently emphasized in cancer pathogenesis. Individuals with persistent acne, patients with endocrine disorders, especially those with genetic variations of the IGF1 gene expressing increased IGF-1 serum levels, may benefit from dietary modifications including a reduction of dairy and hyperglycaemic foods. Persistent acne in adulthood should be considered as a clinical indicator of increased susceptibility for cancer. Suppression of IGF-1 activity has been recently suggested for the treatment of endocrine disorders, atherosclerosis and cancer. IGF-1 lowering diets, limiting milk intake and high glycaemic loads may represent promising approaches to improving acne. Pharmacological down-regulation of IGF-1 by metformin or other insulin-sensitizing agents as well as selective inhibitors of IGF1R and its PI3K downstream signalling components might be promising new options for the treatment of acne vulgaris and conditions with insulin resistance and increased IGF-1 serum levels (102,103).

Table 1.   Overview of conditions with increased IGF-1 serum levels
  1. *Conditions frequently associated with acne.

Large for gestational age newborns of mothers with milk consumption during pregnancy
Large for gestational newborns of mothers with diabetes during pregnancy
Cow milk formula-fed newborn infants
Recombinant IGF-1 therapy of dwarfism*
Precocious pubarche*
Puberty*
Adolescents or adults who were SGA or had low birth weight
PCOS*
Milk and milk protein consumption*
High glycaemic food*
Acromegaly*
Obesity
States of hyperinsulinaemia and insulin resistance*
IGF1 gene variations like absence of IGF1 CA 19/19 allele

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Correlations between serum IGF-1 and acne
  5. IGF-1, insulin and sebaceous lipogenesis
  6. The GH-IGF-1 axis and androgen synthesis
  7. IGF-1 potentiates peripheral androgen-mediated signal transduction
  8. Pharmacological down-regulation of insulin- and IGF-1 signalling
  9. Interactions between IGF1R- and FGFR2b-signalling pathways
  10. Endocrine disorders with increased insulin- and IGF-1 serum levels and acne
  11. Aggravation of acne by dietary modification of insulin/IGF-1signalling
  12. Smoking and insulin resistance
  13. Persistent acne in adulthood – an indicator of increased risk of cancer?
  14. Conclusions and outlook
  15. Dedication
  16. Conflict of interest
  17. Funding
  18. References