Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: Diabetes meets dermatology

Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, 600 University Ave TCP5-1004, Toronto, ON M5G 1X5, Canada.
Diabetologia (Impact Factor: 6.67). 09/2011; 54(11):2741-4. DOI: 10.1007/s00125-011-2297-z
Source: PubMed


Type 2 diabetes mellitus is characterised by beta cell failure, which frequently develops in the setting of insulin resistance. Inflammation contributes to the pathophysiology of type 2 diabetes by impairing insulin action in peripheral tissues and via reduction of beta cell function. Inflammation may also play an important role in the development of complications that arise in patients with type 2 diabetes. Hence, the anti-inflammatory actions of commonly used glucose-lowering drugs may contribute, indirectly, to their mechanisms of action and therapeutic benefit. Herein we highlight the anti-inflammatory actions of glucagon-like peptide-1 (GLP-1), which exerts direct and indirect actions on immune function. The observations that GLP-1 receptor agonists exert anti-inflammatory actions in preclinical studies, taken together with case reports linking improvements in psoriasis with GLP-1 receptor agonist therapy, illustrates the emerging clinical implications of non-classical anti-inflammatory actions of incretin-based therapeutics.

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    • "Pioglitazone therapy was associated with reductions in psoriasis severity (as assessed by PASI) in a recent meta-analysis [235]; data on sulfonylureas are scarce. Sitagliptin , a dipeptidyl peptidase-IV (DPP-IV) inhibitor, was shown to improve psoriatic skin lesions [236]; similar beneficial effects have also been reported for GLP-1 agonists [237] [238]. In contrast, insulin therapy was related to psoriasis exacerbation [239] [240]. "
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    ABSTRACT: Psoriasis is a chronic systemic inflammatory disease characterized by topical skin lesions as well as an increased risk for cardiovascular disease (CVD). There is also increasing evidence that patients with psoriasis are more prone to several CVD risk factors (hypertension, obesity, dyslipidemia and smoking), non-cardiac vascular diseases (carotid, peripheral artery and chronic kidney disease) and metabolic co-morbidities (type 2 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease and obstructive sleep apnea) compared with the general population. The associations are even greater in patients with severe psoriasis and those with psoriatic arthritis. Insulin resistance, endothelial dysfunction and obesity induced by several adipokines and inflammatory cytokines are proposed as the common mechanisms linking psoriasis with CVD, vascular risk factors and metabolic diseases. The present narrative review considers the associations between psoriasis (and psoriatic arthritis) with CVD, vascular risk factors and metabolic diseases. Drugs that reduce CVD risk and improve metabolic parameters may also beneficially affect psoriasis severity and prognosis. Furthermore, anti-psoriatic drugs can exert different effects on CVD risk and metabolic co-morbidities. Therefore, physicians should be aware of these associations in order to adequately monitor and treat psoriatic patients.
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    ABSTRACT: CONTEXT AND AIM: Psoriasis is an immune-mediated skin disorder frequently associated with obesity and type 2 diabetes (T2D). This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a GLP-1 receptor agonist (exenatide). OBSERVATION: A 61-year-old male patient (BMI: 25.5 kg/m(2)) with T2D treated with metformin and sulphonylureas had also complained, since 1980, of extensive psoriasis that required multiple steroid-based treatments [Psoriasis Area and Sensitivity Index (PASI) score: 11]. In September 2008, his diabetes treatment was intensified with exenatide (Byetta(®)) to improve poor glycaemic control. The patient, as expected, lost weight and reduced HbA(1c) levels from 65 mmol/mol to 56 mmol/mol. However, after just 1 month of treatment with exenatide, the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1-year follow-up (PASI: estimated at 3-4). Withdrawal of exenatide was associated with weight gain, deterioration of glycaemic control and deterioration of psoriasis (PASI:>10). After reinstating exenatide treatment, the patient again reported a prompt improvement in psoriasis (PASI: 3.1). CONCLUSION: There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide. A possible mechanism might be through direct modulation of the immune system by GLP-1 receptor agonists.
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    ABSTRACT: In recent years, new and effective therapeutic agents for blood glucose control have been added to standard diabetes therapies: dipeptidyl peptidase-4 (DPP-4) inhibitors, which prolong the bioavailability of the endogenously secreted incretin hormone glucagon-like peptide-1 (GLP-1). Full-thickness excisional wounding was performed in wild-type (C57BL/6J) and diabetic [C57BL/6J-obese/obese (ob/ob)] mice. DPP-4 activity was inhibited by oral administration of linagliptin during healing. Wound tissue was analyzed by using histological, molecular, and biochemical techniques. In healthy mice, DPP-4 was constitutively expressed in the keratinocytes of nonwounded skin. After skin injury, DPP-4 expression declined and was lowest during the most active phase of tissue reassembly. In contrast, in ob/ob mice, we observed increasing levels of DPP-4 at late time points, when delayed tissue repair still occurs. Oral administration of the DPP-4 inhibitor linagliptin strongly reduced DPP-4 activity, stabilized active GLP-1 in chronic wounds, and improved healing in ob/ob mice. At day 10 postwounding, linagliptin-treated ob/ob mice showed largely epithelialized wounds characterized by the absence of neutrophils. In addition, DPP-4 inhibition reduced the expression of the proinflammatory markers cyclooxygenase-2 and macrophage inflammatory protein-2, but enhanced the formation of myofibroblasts in healing wounds from ob/ob mice. Our data suggest a potentially beneficial role of DPP-4 inhibition in diabetes-affected wound healing.
    Preview · Article · Apr 2012 · Journal of Pharmacology and Experimental Therapeutics
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