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Mutations in the Skin Barrier Correlate with Increased Type 2 Diabetes Risk

Defective skin barrier function, as evidenced by common filaggrin mutations, may predispose patients to type 2 diabetes.

Adult patients in a Danish general population who reported having diabetes had a significantly higher prevalence of filaggrin null mutations than in patients without diabetes. A confirmatory subgroup analysis conducted in a separate group of Danish patients known to have diabetes showed the same results, Dr. Jacob P. Thyssen of the National Allergy Research Center at Copenhagen University Hospital reported.

This was a cross-sectional study, said Dr. Thyssen. As such, it doesn’t establish causality. They are hypothesis-generating analyses – and the hypothesis they support is that a defective skin barrier allowing ready entry of allergens, chemical irritants, and microorganisms could increase the propensity for development of low-grade inflammation beyond the skin, including perhaps inflammation of the pancreas, with resultant type 2 diabetes, he said.

Dr. Thyssen and his colleagues came up with the hypothesis as a result of a recent study by other investigators who reported the existence of a specific subtype of asthma driven by filaggrin-defect-associated skin barrier dysfunction rather than sensitization (Pediatr. Allergy Immunol. 2010; 21:954-61).

There is no filaggrin in the lung. So if deficient filaggrin expression in the outermost layer of the skin increases the likelihood of asthma, it may result in low-grade inflammation of the pancreas and type 2 diabetes, Dr. Thyssen hypothesized.

Filaggrin proteins cause keratin filaments in the epidermis to aggregate in ways that prevent epidermal water loss and impede entry of unwanted environmental chemicals, haptens, and proteins. Loss of filaggrin expression is strongly associated with atopic dermatitis.

Dr. Thyssen reported on a random sample of 3,335 adults, all of whom underwent genotyping for the two most common filaggrin mutations: R501X and 2282del4 null mutations. Among this group were 133 individuals with self-reported diabetes and 66 others with screen-detected diabetes.

The prevalence of the filaggrin mutations was 7.8% in the 3,136 subjects without diabetes, 12.8% in those with self-reported diabetes, and 9.1% in individuals who screened positive for diabetes.

Then, the investigators compared filaggrin mutation rates in the 3,136 patients without diabetes to those in 104 other patients with type 1 diabetes and 774 with type 2 diabetes. The prevalence of filaggrin mutations was 7.8% in the patients without diabetes, 6.7% in those known to have type 1 diabetes, and 9.8% in those with type 2 diabetes.

At least three studies have reported an inverse association between type 1 diabetes and atopic dermatitis, and since atopic dermatitis is associated with an increased prevalence of filaggrin mutations, it was to be expected that the patients with type 1 diabetes would have a relatively low prevalence of filaggrin mutations.

A logistic regression analysis showed the link between filaggrin mutations and type 2 diabetes was dependent upon body mass index. Patients with a BMI less than 25 kg/m2 and filaggrin mutations were 2.1-fold more likely to have diabetes than those without filaggrin mutations. Among patients with a BMI of 25-30 kg/m2, the odds of diabetes in patients with filaggrin mutations were 1.5-fold greater than in those with normal filaggrin, and in those with a BMI greater than 30 kg/m2 there was no significant association between filaggrin and diabetes. This suggests that in obese individuals, other factors dwarf any impact filaggrin genotype may have over the development of diabetes, according to Dr. Thyssen.

This study raises the possibility that the documented prevalence trends for atopic dermatitis and type 2 diabetes are related through a defective skin barrier allowing penetration of allergens and chemicals that promote low-grade inflammation, he said. Another possibility deserving further consideration is whether the repeated course of topical and oral corticosteroids commonly used in the treatment of moderate-to-severe atopic dermatitis increases the risk of type 2 diabetes.

Presented at the World Congress of Dermatology May 2011