There has been increasing evidence over the past several years describing the association between DM and psoriasis.6,9-11 Indeed it has been proposed that psoriasis is a risk factor for the development of DM and, conversely, that DM is an intrinsic risk factor for the exacerbation of psoriasis.9–11 In 2013, Armstrong et al performed a systematic review and meta-analysis of 27 observational studies, describing a 59% overall increased prevalence of DM in psoriasis patients, with up to 97% increased prevalence in those with severe psoriasis.9 In those studies that assessed incident cases of DM, patients with psoriasis were 27% more likely to develop DM compared to those without.9 Wan et al further evaluated the association between psoriasis severity and DM, describing significantly increased incidence of DM in psoriasis patients with more disease per body surface area.12 More recently, a systematic review and meta-analysis of 38 studies by Mamizadeh et al found a similar significant association of DM in nearly 1 million psoriasis patients, reinforcing the notion that psoriasis is not limited to the skin.11 It is our own bias that these 2 diseases are not merely co-morbidities of each other but rather that they share the same pathophysiologies, and are facets of the same prism, which we aim to bring to light.

Pathophysiology of DM – 4 Basic Pathways
We believe the spectrum of DM is due to a common denominator, the defective beta cell.2 This core defect results from four basic pathophysiologic processes comprising genes and epigenetic changes, inflammation, environment, and insulin resistance.2 As a result, hyperglycemia arises through multiple pathways, the so-called Egregious Eleven.2 The beta-cell dysfunction and related mechanisms of hyperglycemia and resultant endogenous fuel excess cause oxidative stress and epigenetic changes in tissues throughout the body, including worsening beta-cell dysfunction.2 It is our view that some conditions associated with DM, such as psoriasis, are frequently concurrent due to overlapping pathophysiologies, especially shared genes and epigenetic changes (Figure 1).

Genes and Epigenetic Changes
The most important common pathophysiologic mechanism relating diabetes and psoriasis is the shared genetic mechanisms. Over the past 10 years, it has been increasingly evident that genes related to both Type 1 DM, Type 2 DM, and psoriasis share overlapping genes and susceptibility loci. In 2017, Wang et al examined 89 DM susceptibility loci in nearly 4500 psoriasis patients and 6000 controls in China, identifying the PTPN22, ST6GAL1, and JAZF1 genes as significant in both psoriasis and DM.13 The PTPN22 gene is known to encode an intracellular phosphatase that is thought to affect T-cell receptor signaling pathways in autoimmune diseases including Type 1 DM, Graves disease, rheumatoid arthritis, and systemic lupus erythematosus.14 The JAZF1 gene was found to contain an intron variant that was associated with psoriasis through an unknown mechanism, and has also been found to be a transcriptional repressor, negatively influencing glucose metabolism with associated beta-cell impairment.13 Finally, a noncoding variant was found within the first intron of the ST6GAL1 gene which is thought to encode a glycosyltransferase that participates in cell-surface carbohydrate determinants and antigen differentiation thought to be necessary in T cell activation, but the role in both DM and psoriasis is unclear.13 Furthermore, Quaranta et al noted different single nucleotide polymorphisms of the CDKAL1 gene were present in psoriasis and Type 2 DM cases.15 The function of the protein encoded by this gene is not definitively known but is thought to be associated with insulin production under glucotoxic conditions.15 Transcripts of this gene were found to be virtually absent from keratinocytes but clearly expressed in immune cells although downregulated in actively proliferating immune cells.15

With regard to epigenetics, dysregulation of miRNA expression or mutation in miRNA genes is associated with a wide variety of human diseases. Post-transcriptional changes by microRNAs (miRNAs) have also been implicated in DM and psoriasis.3,5 For example, Granata et al describes a link between DM and psoriasis through miR-21 which is up-regulated in T helper cells within psoriatic skin lesions, and activated as promoter of genes implicated in Type 1 DM.16 In addition, in pancreatic β cells, when the miR-21 gene promoter is activated, subsequent downregulation of programmed cell death protein 4 (PDCD4) occurs, thus protecting pancreatic cells from apoptosis.17 As miR-21 is also upregulated in psoriasis, the miR-21-PDCD4 axis may play a crucial role in both DM and psoriasis, representing a potential therapeutic target for treating both diseases.17

Inflammation
The known underlying pathophysiologies of psoriasis are complex in nature with a strong focus on the immune response, both innate and adaptive.6,10 Inflammation is common, associated with both DM and psoriasis, and serves as a mechanistic link between the skin lesions and comorbidities in psoriasis and metabolic derangements in DM. Inflammation is necessary for the immune system to protect against various environmental and pathogenic insults, however when it becomes chronic it can do more harm than good, increasing the risk of developing other comorbidities, including metabolic syndrome, cardiovascular disease, inflammatory bowel disease, cancer, and notably DM.18 The inflammatory cytokines implicated in psoriasis can increase the amount of insulin-like growth factor (IGF) in the skin and body.19 Binding of IGF to IGF receptors results in proliferation of keratinocytes and fibroblasts.19 Further, Davidovici et al demonstrated TNF-α secreted by macrophages in dermal and adipose tissue has been associated with altered adipokine gene transcription, increasing expression of pro-inflammatory leptin, and anti-inflammatory adiponectin.18

Environment
The pathogenesis of both DM and psoriasis is thought to be impacted by the environment, both externally and internally. Indeed an abnormal environment influences patients based on their unique genetic makeup and also triggers epigenetic modifications and impacts the immune system.20 Lifestyle factors like diet and exercise are well-established modifiable risk factors in the development of DM and are largely related to the inflammatory state associated with obesity.21 Environmental risk factors that are thought to play a critical role in psoriasis include UV exposure, medications, smoking, diet and obesity, alcohol intake, infections, and stress.20 Many of these are associated with downstream dysregulation of the immune system/immune responses, likely through epigenetic modifications.20

The gastrointestinal (GI) environment has been shown to play a major role in glucose homeostasis, mediating up to 70% of postprandial insulin release via incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).22 These hormones have also been shown to promote proliferation and prevent apoptosis of beta cells, however their levels and function are noted to be reduced in Type 2 DM.22 Interestingly, Gyldenlove et al noted significantly reduced incretin effect (39%) in 12 non-diabetic psoriasis patients after oral glucose tolerance tests compared to matched controls (57%), suggesting GI-related mechanisms of glucose control (eg, incretin response) are impacted in psoriasis patients as well.23

Insulin Resistance
Insulin resistance is an important pathophysiologic mechanism involved in DM and psoriasis. Importantly, insulin resistance and inflammation are closely intertwined. Indeed, inflammatory mediators (eg, cytokines and adipokines) involved in the development of insulin resistance are dysregulated in patients with psoriasis.18,24 It stands to reason that insulin resistance has been found in patients with psoriasis and is significantly correlated with area and severity, even in patients without concomitant metabolic syndrome.18,24 Moreover, during times of hyperinsulinemia due to insulin resistance as often seen in Type 2 DM, insulin has the potential to bind to IGF receptors, resulting in keratinocyte and fibroblast proliferation.19 Further, levels of adiponectin, an enhancer of insulin sensitivity and inducer of anti-inflammatory cytokines, are found to be reduced in both DM and psoriasis.18

Associated Comorbidities
In addition to the link between DM and psoriasis through the four described overlapping pathophysiologies, both conditions have other similar associated comorbidities. When considering DM and psoriasis through the prism of these overlapping drivers, it is understandable that other comorbidities that are driven by similar influences are also shared. Below we focus on common comorbidities and their link with psoriasis, with the understanding that DM shares these links as well.1,2,4

Psoriasis and Metabolic Syndrome and Obesity
Metabolic syndrome (MS), the co-existence of central obesity, hypertension, dyslipidemia, and hyperglycemia, are significant risk factors for DM and its associated complications.1,2 Although psoriasis patients are 2–3% of the population, over 30% of them have been found to meet criteria for MS, with up to 76% higher risk in certain populations, especially in women and those over age 40.19,25 Furthermore, when analyzing the prevalence of individual MS components, obesity, dyslipidemia, and hyperglycemia are each found more commonly in those with psoriasis compared to those without.26

The relationship between psoriasis and obesity is largely based on a chronic inflammatory state.27 White adipose tissue is metabolically active, consisting of adipocytes and immune cells like macrophages.28 It is these cells that secrete adipokines, which are pro-inflammatory cytokines such as adiponectin, leptin, chemerin, resistin, visfatin, vaspin, free fatty acids, TNF-ɑ, and several interleukins, most of which have also been implicated in the chronic diseases described above.28 For example, levels of leptin and resistin levels are higher in patients with psoriasis and correlated with disease severity and higher concentrations of TNF-α and IL-6 are considered biomarkers for psoriasis.29 Dysregulation of both pro- and anti-inflammatory adipokines that occurs with obesity leads to chronic inflammation.29 This inflammation is thought to lead to a wide array of metabolic disorders and chronic complications spanning not only psoriasis and DM, but also hypertension, lipid disorders, insulin resistance, infertility, and cancer.29 In the case of psoriasis, inflammation in the fatty tissue related to metabolic dysfunction associated with obesity can directly affect inflammatory processes in psoriatic skin lesions.29 Finally, certain epidemiological studies note that obesity might be an independent risk factor for psoriasis while others suggest that obesity is a consequence of psoriasis.27 Therefore, the association between the two appears to be a bidirectional one.27

Psoriasis and Cardiovascular Disease
With increased MS prevalence comes increased cardiovascular morbidity and mortality. Atherosclerosis associated with cardiovascular disease has been described as a process driven by inflammation.30 Moreover, the underlying pathophysiology of psoriasis is deeply rooted in inflammatory cytokines that inhibit normal functioning of insulin receptors with eventual downstream endothelial dysfunction and hyperproliferation, bridging a link between atherosclerosis and the chronic skin condition.31 Additionally, psoriasis has been found to be a risk factor for myocardial infarction, with increased psoriasis severity being associated with greater risk of an event.32 In fact, severe psoriasis has been found to be an independent risk factor for death from cardiovascular disease.33

Psoriasis and Cancer
A recent systematic review and meta-analysis of 58 observational studies by Trafford et al has found significant associations between psoriasis and both cancer incidence and mortality.34 The cohorts that were analyzed demonstrated an 18% increased risk of developing cancer in psoriasis patients compared to those without, with 22% increased risk in those with severe psoriasis. Incidence of lymphoma, keratinocyte, esophageal, liver, and pancreatic cancers was noted to be higher in the psoriatic population.34 Overall, psoriasis patients were found to have a 22% increased risk of dying from these cancers compared to the psoriasis-free populations.34 This increased risk is thought to be in part due to the chronic inflammation associated with psoriasis.34 Not surprisingly, however, the study authors deemed part of this increased risk due to lifestyle factors like obesity and smoking, as the studies that adjusted for these factors noted considerable attenuation of cancer risk.34 Nonetheless, it is becoming clear to us that the cumulative effects of inflammation and lifestyle factors are implicated in cancer, psoriasis, and DM.4

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