Abstract
Thromboxane (TX)-dependent platelet activation and lipid peroxidation, as reflected in vivo by the urinary excretion of 11-dehydro-TXB2 and 8-iso-prostaglandin (PG)F2α, play a key role in atherothrombosis in obesity and type 2 diabetes mellitus (T2DM) since the earlier stages. Thirty-five metformin-treated obese subjects with prediabetes or newly-diagnosed T2DM were randomized to the glucagon-like peptide receptor agonist (GLP-RA) liraglutide (1.8 mg/day) or lifestyle counseling until achieving a comparable weight loss (−7% of initial body weight), to assess whether changes in subcutaneous (SAT) and visceral (VAT) adipose tissue distribution (MRI), insulin sensitivity (Matsuda Index) and beta-cell performance (multiple sampling OGTT beta-index), with either intervention, might affect TX-dependent platelet activation, lipid peroxidation and inflammation. At baseline, Ln-8-iso-PGF2α (Beta = 0.31, p = 0.0088), glycosylated hemoglobin (HbA1c) (Beta = 2.64, p = 0.0011) Ln-TNF-α (Beta = 0.58, p = 0.0075) and SAT (Beta = 0.14, p = 0.044) were significant independent predictors of 11-dehydro-TXB2. After achievement of the weight loss target, a comparable reduction in U-11-dehydro-TXB2 (between-group p = 0.679) and 8-iso-PGF-2α (p = 0.985) was observed in both arms in parallel with a comparable improvement in glycemic control, insulin sensitivity, SAT, high-sensitivity C-reactive protein (hs-CRP). In obese patients with initial impairment of glucose metabolism, the extent of platelet activation is related to systemic inflammation, isoprostane formation and degree of glycemic control and abdominal SAT. Successful weight loss, achieved with either lifestyle changes or an incretin-based therapy, is associated with a significant reduction in lipid peroxidation and platelet activation.
Highlights
Obesity is a risk factor for both diabetes (DM) and cardiovascular disease (CVD) [1].Platelet activation and lipid peroxidation, as reflected in vivo by enhanced isoprostane generation and thromboxane (TX) biosynthesis, play a key role in the development of atherothrombosis in obesity and type 2 diabetes mellitus (T2DM) [2,3].Our group was able to describe that in human metabolic disorders, such as obesity and DM, the underlying metabolic abnormalities may trigger inflammatory signals, with enhanced formation of reactive oxygen species (ROS), leading to increased lipid peroxidation and free radical–catalyzed conversion of arachidonic acid into bioactive isoprostanes
We previously provided biochemical evidence of persistent TX-dependent platelet activation in obese women who are otherwise healthy and relatively young [5], and in newly diagnosed type 2 diabetic patients [6], whose TX biosynthesis was at least as high as previously reported in patients with longer-standing disease [2], supporting the hypothesis that platelet activation is related to the underlying metabolic disorder and not to vascular disease per se
One-hundred and twenty-two patients consecutively referred to the outpatient Diabetes Clinic and Obesity Centre of our University Hospital were assessed for eligibility between June 2012 and September 2013
Summary
Obesity is a risk factor for both diabetes (DM) and cardiovascular disease (CVD) [1].Platelet activation and lipid peroxidation, as reflected in vivo by enhanced isoprostane generation and thromboxane (TX) biosynthesis, play a key role in the development of atherothrombosis in obesity and type 2 diabetes mellitus (T2DM) [2,3].Our group was able to describe that in human metabolic disorders, such as obesity and DM, the underlying metabolic abnormalities may trigger inflammatory signals, with enhanced formation of reactive oxygen species (ROS), leading to increased lipid peroxidation and free radical–catalyzed conversion of arachidonic acid into bioactive isoprostanes. We previously provided biochemical evidence of persistent TX-dependent platelet activation in obese women who are otherwise healthy and relatively young [5], and in newly diagnosed type 2 diabetic patients [6], whose TX biosynthesis was at least as high as previously reported in patients with longer-standing disease [2], supporting the hypothesis that platelet activation is related to the underlying metabolic disorder and not to vascular disease per se This assumption is further substantiated by the linear correlation between the urinary excretion of the major TX metabolite, 11-dehydro-TXB2 and either body mass index (BMI) or glycemic control, as reflected by fasting and postprandial plasma glucose or HbA1c. Whether TX-dependent platelet activation is sustained by different metabolic triggers in different phases along the line linking obesity to overt T2DM, is still an open and relevant question, since hyperglycemia is a weak risk factor for CVD [7,8], and interventions [9,10,11]
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