Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis

Abstract

Aims/hypothesisThe innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells.MethodsWe measured circulating and psoriatic plaque iNKT cell numbers in two patients with type 2 diabetes and psoriasis before and after commencing GLP-1 analogue therapy. In addition, we investigated the in vitro effects of GLP-1 on iNKT cells and looked for a functional GLP-1 receptor on these cells.ResultsThe Psoriasis Area and Severity Index improved in both patients following 6 weeks of GLP-1 analogue therapy. This was associated with an alteration in iNKT cell number, with an increased number in the circulation and a decreased number in psoriatic plaques. The GLP-1 receptor was expressed on iNKT cells, and GLP-1 induced a dose-dependent inhibition of iNKT cell cytokine secretion, but not cytolytic degranulation in vitro.Conclusions/interpretationThe clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis.

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

“…Although GLP-1 increased cytokine production in resting iNKT cells, both GLP-1 and liraglutide inhibited cytokine secretion following treatment with phorbol myristate acetate/ionomycin, or in iNKT cells activated by co-culture with glycolipidtreated CD1d-transfected C1R cells, actions blocked by the GLP-1R antagonist exendin (9-39). Hence, the authors infer that the putative immunoregulatory actions of GLP-1 on iNKT cells may have contributed to the improvement in clinical psoriasis observed in the three patients [2].…”

“…Pioglitazone has been shown to exert an anti-psoriatic effect when co-administered with the synthetic retinoid acitretin to non-obese non-diabetic participants with moderate to severe plaque-type psoriasis in a 12 week randomised clinical trial [12]. In the patients reported by Hogan et al, the improvement in psoriasis was relatively rapid following the initiation of treatment with exenatide or liraglutide, with no significant improvement in glycaemic control noted [2]. Although the reductions in PASI score were modest, they occurred rapidly, and psoriasis does not usually improve spontaneously without therapy.…”

“…In this issue of Diabetologia, Hogan and colleagues report an improvement of psoriasis in three obese patients with type 2 diabetes several weeks after the initiation of therapy with the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists exenatide and liraglutide [2]. The improvement in psoriasis was modest but clinically appreciable, with reduced itching in the index case, and a reduction in Psoriasis Area and Severity Index (PASI) scores, from 15.3 to 10.2, 13.2 to 10.8, and 4.8 and 3.8, respectively.…”

“…Although Hogan et al describe a rapid subjective improvement in psoriasis symptoms prior to the achievement of significant weight loss in their patients [2], the actions of GLP-1R agonists to reduce energy intake and produce body weight loss and the relative contribution of these effects to the overall objective improvement in skin lesions and improvements in PASI scores after 6 weeks is difficult to ascertain. A small observational study reported that a brief period of fasting alone improved the signs and symptoms of psoriasis [18], and a 4 week low-energy diet improved the clinical severity of psoriasis independent of changes in weight loss [19].…”

Factors involved in the pathogenesis of psoriasis

“…al. [2] reported that the psoriasis area and Severity Index improved in 2 psoriatic patients treated with glucagon-like peptide-1 (GLP-1) and clinical improvement was associated with an increase in circulating NKT cells and a decrease in the psoriatic lesions compared to counts prior to treatment. The use of GLP-1 for the treatment of psoriasis was suggested.…”