The Effect Of Metabolic Syndrome On The Response Of Psoriatic Therapy And Its Mechanism

Objective: Psoriasis is a chronic immune-inflammatory-mediated disease distinguished by keratinocytes hyperproliferation and disordered differentiation.Epidemiological studies suggest that patients with psoriasis are not only burdened with its symptoms, but also have an increased prevalence of metabolic disorders, including metabolic syndrome(MS). MS has significant risk effect on severity and manifestations of psoriasis, but whether MS canaffects the response of psoriatic treatment is not clear.Our research studied the effect of MS on the response of psoriatic treatment and associated mechanism.Materials and Methods: 1.By case-control study we compared clinical features of psoriatic patients with MS with patients without MS. 2.We explored the effect of MS on the response of UVB treatment by prospective cohort study and we examined whether MS is an independent risk factor affecting the response of psoriatictreatment by multivariate logistic regression analysis. 3.Enzyme-linked immunosorbent assay(ELISA) and immunohistochemistry were applied respectively to detect the level of leptin in serum and in lesion ofpsoriatic patients with and without MS. The HaCaT cell line was cultured and western-blot assay was performed to assess the change of insulin sensibility by leptin treatment. Real-time polymerase chain reaction (PCR) and western-blot assay were applied to detect the SOCS3 expressions in leptin treatment.Knockdown of SOCS3 were generated in HaCaT cell line to detect insulin sensibility under leptin treatment. HaCaT cell line was cultured with treatment of leptin and insulin for 6 days and K10 expression was evaluated by western-blot assay.Immunohistochemistry were applied to detect the expression of SOCS3 and p-IRS-1(ser636) in skin of psoriatic patients with and without MS and healthy people.4.By randomized, but no blind study, 40 patients were randomly stratified into two groups: the metformin combined psoriatic therapygroup(n=20) and the psoriatic therapygroup (n=20). After 10 daysof psoriatic treatment, we evaluated treatment response by PASI decline index.Results: 1.The case-control study showed patients with MS need longer treatment than patients without MS. 2.Patients with MS presented lower PASI decline index than patients without MS. And the percentage of achieving PASI50 in patients with MS was less than in patients without MS. 3.Patients with MS presented higher serum level of leptin than patients without MS. And serum levels of leptin negatively correlated to PASI decline index in psoriatic patients. Immunohistochemistry showed leptin was higher in lesion of patients with MS than patients without MS. Long term treatment of leptin induced insulin resistance in HaCaT cell line, represented by higher expression of p-IRS-1(ser636) and lower p-PKB(ser473). The mRNA and protein expression levels of SOCS3 were upregulated by leptin treatment. And knockdown the expression of SOCS3 blocked the effect of insulin resistance by leptin treatment. Leptin treatment attenuated insulin-induced K10 expression. Immunohistochemistry showed the expression of p-IRS-1(ser636) and SOCS3 were both higher in lesion of patients with MS than patients without MS. 4.The group of psoriatic therapycombined with metformin presented higher PASI decline index than psoriatic therapygroup.Conclusions: 1 .MS associates with longer psoriatic treatment and shorter length of remission. 2.Existence of MS affects the response of psoriatic treatment in psoriasis patients. 3.Leptin induces insulin resistance through upregulating SOCS3 in keratinocyte, thus hindering insulin-induced differentiation of keratinocyte.4.Metformin ameliorates the resistance of MS to psoriatic therapy.