Evidence of a causal relationship between high serum adiponectin levels and increased cardiovascular mortality rate in patients with type 2 diabetes

Abstract

BackgroundDespite its beneficial role on insulin resistance and atherosclerosis, adiponectin has been repeatedly reported as an independent positive predictor of cardiovascular mortality.MethodsA Mendelian randomization approach was used, in order to evaluate whether such counterintuitive association recognizes a cause-effect relationship. To this purpose, single nucleotide polymorphism rs822354 in the ADIPOQ locus which has been previously associated with serum adiponectin at genome-wide level, was used as an instrument variable. Our investigation was carried out in the Gargano Heart Study-prospective design, comprising 356 patients with type 2 diabetes, in whom both total and high molecular weight (HMW) adiponectin were measured and cardiovascular mortality was recorded (mean follow-up = 5.4 ± 2.5 years; 58 events/1922 person-year).ResultsThe A allele of rs822354 was associated with both total and HMW adiponectin [β (SE) = 0.10 (0.042), p = 0.014 and 0.17 (0.06), p = 0.003; respectively]. In a Poisson model comprising age, sex, smoking habits, BMI, HbA1c, total cholesterol, HDL-cholesterol, triglycerides, insulin therapy and hypertension, both rs822354 (IRR = 1.94, 95 % CI 1.23–3.07; p = 0.005), as well as the genetic equivalent of total adiponectin change (IRR = 1.07, 95 % CI 1.02–1.12; p = 0.003) were significantly associated with cardiovascular mortality. The observed genetic effect was significantly greater than that exerted by the genetic equivalent change of serum adiponectin (p for IRR heterogeneity = 0.012). In the above-mentioned adjusted model, very similar results were obtained when HMW, rather than total, adiponectin was used as the exposure variable of interest.ConclusionsOur data suggest that the paradoxical association between high serum adiponectin levels and increased cardiovascular mortality rate is based on a cause-effect relationship, thus pointing to an unexpected deleterious role of adiponectin action/metabolism on atherosclerotic processes.

Is Adiponectin New Important Parameter in Adolescents with Metabolic Syndrome?

“…The Dallas heart study revealed that higher adiponectin level is associated with increased mortality and cardiovascular morbidity in a young, multiethnic population across all subgroups defined by age, gender, race, obesity, diabetes, MS, or elevated high-sensitivity C-reactive protein. The similar findings were recently detected in hemodialysis and diabetic patients [8][9][10]. These findings are paradoxical considering the fact that large studies showed that adiponectin inversely correlated with insulin and HOMA indexindex of insulin resistance [11].…”

Letter by Menzaghi et al Regarding Article, “Plasma Levels of Fatty Acid–Binding Protein 4, Retinol-Binding Protein 4, High-Molecular-Weight Adiponectin, and Cardiovascular Mortality Among Men With Type 2 Diabetes: A 22-Year Prospective Study”

“…This finding is in marked contrast with our recent report, showing a significant association between rs832354 (a single nucleotide polymorphism strongly associated with HMW adiponectin 3 ) and cardiovascular mortality in type 2 diabetes mellitus patients of both sexes. 4 Of note, our association was entirely driven by males (ie, no association observed among females), 5 thus coincidentally reinforcing the belief of a sexual dimorphic effect of serum adiponectin on cardiovascular mortality 2 and further stressing the difference with Liu et al 1 report. Here, we address some possible causes of such strident discrepancy.…”

“…In fact, HPFS patients were recruited from all over the United States, whereas ours were all recruited in a very small and homogeneous region of Central Southern Italy. In addition, whereas our participants were all Whites, 4 those of HPFS were not. 1 Because genetic background of serum adiponectin is heterogeneous across ethnicities, 6 such difference too may have contributed to discrepancy between the 2 studies.…”

“…In fact, although in HPFS only 50% patients had baseline cardiovascular disease, all our patients had established coronary artery disease. 4 That this difference may be important is suggested by the observation that when in HPFS participants with baseline cardiovascular events were excluded, the hazard ratio (95% confidence interval) of cardiovascular mortality of patients with high HMW adiponectin decreased from 2.07 (1.42-3.06) to 1.39 (0.54-3.61), 1 a 54% reduction in a log scale. It is, therefore, likely that in the absence of baseline cardiovascular disease, the deleterious effect of adiponectin on cardiovascular mortality is attenuated, thus making difficult addressing causality.…”

Association of Biomolecules of Secretory Activity of Visceral Adipocytes With Electrophysiological Signs of Metabolic Disorders of Myocardium in Coronary Atherosclerosis and Metabolic Syndrome

“…Антисклеротическое действие адипонектина включает в себя стимуляцию пролифе-рации эндотелия, ингибирование пролиферации и миграции гладкомышечных клеток сосудов, подав-ление экспрессии в эндотелии молекул адгезии. Вме-сте с тем, есть исследования с противоположными результатами [9][10][11][12].…”