Treatment with the PPARγ agonist rosiglitazone downregulates interleukin-1 receptor antagonist in individuals with metabolic syndrome

Abstract

Objectives: Thiazolidinediones (TZDs) reduce insulin resistance, but also have pleiotropic properties including effects on inflammation. The balance between protective and proatherogenic effects may differ in various patient populations. We studied the effect of rosiglitazone on inflammatory markers in patients with metabolic syndrome (MetSyn). Methods: In a cross-over randomized controlled trial, 23 subjects with MetSyn were assigned to treatment with rosiglitazone that was uptitrated from 4 mg/day for 6 weeks followed by 8 mg/day for 6 weeks or matching placebo for 12 weeks, and then to the opposite treatment for 12 weeks. Plasma levels of inflammatory and metabolic markers were measured during follow-up. Results: Our main findings were i) compared to placebo, rosiglitazone significantly decreased the plasma levels of the naturally occurring interleukin (IL)1 inhibitor, IL1 receptor antagonist (IL1Ra; PZ0.001), potentially reflecting inflammatory effects on the IL1 system; ii) parallel to this, rosiglitazone decreased plasma levels of IL10 (PZ0.029) further suggesting inflammatory effects; iii) rosiglitazone decreased uric acid levels (PZ0.001), and monocyte chemoattractant protein-1 (PZ0.05) and C-reactive protein (PZ0.06) tended to be lower after rosiglitazone than placebo, suggesting potential pro-and anti-inflammatory effects simultaneously and iv) in vitro, rosiglitazone enhanced IL1Ra and decreased IL1b in THP-1 monocytes, illustrating the complex effects of these medications, potentially exhibiting anti-inflammatory effects on the IL1 system in certain tissues or cells at least at certain concentrations. Conclusion: Our findings suggest inflammatory effects on the IL1 system during rosiglitazone therapy in MetSyn. However, anti-inflammatory effects were also observed, and the net effect of TZDs in MetSyn should be further investigated.

Knock-Down of IL-1Ra in Obese Mice Decreases Liver Inflammation and Improves Insulin Sensitivity

“…In a recent study IL-1Ra was even identified as a novel biomarker for clinically incident diabetes, over and above the classical risk factors such as BMI and waist: hip ratio [18]. Supporting a possible role in the development of insulin resistance, thiazolidinedione (TZD) treatment significantly reduced levels of IL-1Ra in patients with metabolic syndrome [19], as well as in cell culture studies where TZDs inhibited the production of IL-1Ra from proinflammatory adipocytes [20].…”

The Association Between Adiponectin, Serum Uric Acid and Urinary Markers of Renal Damage in the General Population: Cross-Sectional Data from the Tromsø Study

“…Thus, our findings do not exclude the possibility of an interaction in subgroups, and SUA and adiponectin may act synergistically with regard to more advanced stages of CKD [58][59][60], and in subjects with less favourable values of SUA, adiponectin and the urinary biomarkers. This matter is of relevance since pharmaceutical agents such as PPAR γ agonists [21,22] and some blockers of the renin-angiotensin system [61,62] are known to simultaneously decrease SUA and increase adiponectin, and thus these biomarkers may share common pathways. Therefore, this issue should be addressed further through longitudinal studies.…”

“…The biomarkers have shown significant negative correlation [17], but not in all cohorts [18]. Pharmaceutical agents such as peroxisome proliferator-activated receptor-ɣ (PPAR ɣ) agonists and xanthine oxidase inhibitors [19,20] have been demonstrated to simultaneously decrease SUA and increase adiponectin [21,22]. Thus, it may be suggested that the two biomarkers share some common pathways.…”

A practical approach to the metabolic syndrome: review of current concepts and management

“…antidiabetic medication, including thiazolidinediones [85 ], incretin mimetics [86 ], metformin [83,84], the alpha-glucosidase inhibitors acarbose [87] and voglibose [88 ], and omega-3 fatty acids [89 ], have generated interest in the treatment of the metabolic syndrome. Although thiazolidinediones reduce insulin resistance, their effect on inflammatory pathways seems complex and has not yet been fully elucidated [85 ].…”

“…Although thiazolidinediones reduce insulin resistance, their effect on inflammatory pathways seems complex and has not yet been fully elucidated [85 ]. Bhushan et al [86 ] performed a retrospective analysis of glycemic control and cardiometabolic risk factors in 176 patients treated with exanetide, an incretin mimetic.…”