Skin Disease and Metabolic Syndrome: Early Warning Signs of a Greater Problem

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Skin disorders, particularly those with known inflammatory mechanisms, may be considered potential early markers for the development of insulin resistance which contributes to other diseases.
Skin disorders, particularly those with known inflammatory mechanisms, may be considered potential early markers for the development of insulin resistance which contributes to other diseases.

The convergence of metabolic syndrome (MetS) and skin disorders covers a broad spectrum of patients. An estimated 25% of the world's population fits the criteria for MetS, defined as abdominal obesity, dyslipidemia, insulin resistance, and hypertension. These conditions, either alone or in combination, are associated with a higher-than-usual risk for skin diseases such as hidradenitis suppurativa and psoriasis, with associations with a multitude of other cutaneous diseases including acne, rosacea, vitiligo, scleroderma, keratosis pilaris, seborrheic dermatitis, lichen planus, recurrent aphthous stomatitis, Behcet disease, necrobiosis lipoidica, granuloma annulare, skin tags, knuckle pads, eruptive xanthomas, and urticaria.1-3

Numerous studies have shown these associations to be more than superficial, and are instead strongly suggestive of a series of shared inflammatory mechanisms. In their 2018 review of MetS and skin disease, Stefanadi and colleagues1 pointed out that, "In fact any pathophysiologic dysfunction that results in a loss of metabolic control in the body can result in cutaneous disease."

Cause and Effect

The accepted pathophysiological mechanism underlying MetS is insulin resistance, which is believed to set in motion a cascade of interactions leading to multiple organ systems.1 With increased adipose fat occurring as a result of obesity, the quantity of circulating free fatty acids increases, which interferes with insulin-mediated glucose uptake by cells in the muscles. This in turn drives higher insulin production and increases triglycerides and very low density lipoproteins, amplifying free fatty acid production. Changes in the cholesteryl ester core cause high-density lipoproteins to decrease and low density lipoproteins to increase, completing the pattern of hyperlipidemia.

Chronic hyperinsulinemia overworks the pancreas until it can no longer meet the demand for insulin, triggering hyperglycemia while also suppressing insulin production, ultimately resulting in diabetes mellitus (DM).

Insulin resistance also has effects on vasodilation and sympathetic nervous system excitation, whereas high circulating free fatty acids cause vasoconstriction, all contributing to the development of hypertension. Microvascular effects are early signs of both DM and coronary artery disease.

Diabetes and the Skin

Skin disorders secondary to DM and insulin resistance develop through a number of mechanisms. Hyperglycemia leads to the formation of advanced glycation products from proteins, lipids, and nucleic acids that affect collagen flexibility and solubility in the skin, specifically those associated with disorders of collagen degeneration such as necrobiosis lipoidica and AG. Other skin disorders related to DM include acanthosis nigricans, eruptive xanthomas, acquired perforating dermatosis, skin tags, and psoriasis. When diagnosed with comorbidity in patients with DM, these disorders are predictive of a worsened course and greater end-organ damage and suggest the need for aggressive diabetes management.

Psoriasis: The Most Common Link

The association between the severity of psoriasis and the risk for MetS is particularly well documented. A diagnosis of severe psoriasis is associated with a 3 times greater risk for MetS and 2 times greater risk for DM compared with people without psoriasis.1,3 The efficacy of insulin-stimulating glucagon-like peptides against psoriasis provides greater evidence of the link between inflammatory psoriasis and MetS.1

In addition, psoriasis has been linked to underlying mechanisms of cardiovascular disease (CVD), including chronic systemic inflammation and insulin resistance. Increased vasoconstriction promoting arterial stiffness is believed to be related to higher reported rates of myocardial infarction and stroke. A 2016 study by Praveenkumar et al4 found significantly more patients with psoriasis had lower high-density lipoprotein compared with individuals who did not have psoriasis. The prevalence of obesity, high blood pressure, and insulin resistance were also found to increase in the presence of psoriasis, but to nonsignificant degrees.4

Recommendations

The appearance of various skin manifestations may provide early markers of risks for metabolic disorders and CVD.

The greater propensity for MetS and increased risk for CVD suggests a high level of suspicion in patients presenting to dermatologists with psoriasis, particularly where it is severe and involves nail pitting. Stefanadi and colleagues recommend referral for CVD evaluation if more than 3 defining characteristics of MetS are also present.1 Monitoring for the development of type 2 diabetes and tight management of glycemic control is also suggested. Although less well studied, atopic dermatitis has similar risks to psoriasis, and lichen planus demonstrates an increased risk for dyslipidemia and CVD.1

Similar types of associations suggest screening for insulin resistance in patients who present with androgenic alopecia (based on severity in females and early onset in males) and the need for glycemic management with other cutaneous manifestations, such as skin tags and age-related collagen glycation. Cutaneous manifestations of systemic lupus erythematosus are also suspicious for insulin resistance, as is chronic urticaria.1

In totality, skin disorders of all types, particularly those with known inflammatory mechanisms, may be considered potential early markers for the development of insulin resistance leading to MetS, type 2 diabetes, and CVD. The severity of such consequences suggests elevating the importance of these presentations in clinical dermatology practice. At the same time, therapeutic interventions for all parameters of MetS, including dyslipidemia, insulin resistance, and hypertension, are recommended to reduce the incidence and severity of inflammatory skin disorders, most prominently rosacea, hidradenitis suppurativa, early onset alopecia, and psoriasis.

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References

1. Stefanadi EC, Dimitrakakis G, Antoniou CK, et al. Metabolic syndrome and the skin: a more than superficial association. Reviewing the association between skin diseases and metabolic syndrome and a clinical decision algorithm for high risk patients. Diabetol Metab Syndr. 2018;10:9.

2. Seremet S, Gurel MS. Miscellaneous skin disease and the metabolic syndrome. Clin Dermatol. 2018;36:94-100.

3. Karadag AS, Ozlu E, Lavery MJ. Cutaneous manifestations of diabetes mellitus and the metabolic syndrome. Clin Dermatol. 2018;36:89-93.

4. Praveenkumar U, Ganguly S, Ray L, Nanda SK, Kuruvila S. Prevalence of metabolic syndrome in psoriasis patients and its relation to disease duration: a hospital based case-control study. J Clin Diagn Res. 2016;10:WC01-5.

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