Plasma adiponectin and risk of asthma: observational analysis, genetic Mendelian randomisation and meta-analysis

BackgroundAdiponectin, an adipocyte-secreted protein-hormone with inflammatory properties, has a potentially important role in the development and progression of asthma. Unravelling whether adiponectin is a causal risk factor for asthma is an important issue to clarify as adiponectin could be a potential novel drug target for the treatment of asthma.ObjectiveWe tested the hypothesis that plasma adiponectin is associated observationally and causally (using genetic variants as instrumental variables) with risk of asthma.MethodsIn the Copenhagen General Population Study, we did an observational analysis in 28 845 individuals (2278 asthma cases) with plasma adiponectin measurements, and a genetic one-sample Mendelian randomisation analysis in 94 868 individuals (7128 asthma cases) with 4 genetic variants. Furthermore, in the UK Biobank, we did a genetic two-sample Mendelian randomisation analysis in 462 933 individuals (53 598 asthma cases) with 12 genetic variants. Lastly, we meta-analysed the genetic findings.ResultsWhile a 1 unit log-transformed higher plasma adiponectin in the Copenhagen General Population Study was associated with an observational OR of 1.65 (95% CI 1.29 to 2.08) for asthma, the corresponding genetic causal OR was 1.03 (95% CI 0.75 to 1.42). The genetic causal OR for asthma in the UK Biobank was 1.00 (95% CI 0.99 to 1.00). Lastly, genetic meta-analysis confirmed lack of association between genetically high plasma adiponectin and causal OR for asthma.ConclusionObservationally, high plasma adiponectin is associated with increased risk of asthma; however, genetic evidence could not support a causal association between plasma adiponectin and asthma.

Vascular Endothelial Adiponectin Signaling Across the Lifespan

Cardiovascular disease risk increases with age regardless of sex. Some of this risk is attributable to changes in natural hormones throughout the lifespan. The quintessential example of this being the dramatic increase in cardiovascular disease following the transition to menopause. Plasma levels of adiponectin, a "cardioprotective" adipokine released primarily by adipose tissue and regulated by hormones, also fluctuates throughout one's life. Plasma adiponectin levels increase with age in both men and women, with higher levels in both pre- and post- menopausal women compared to men. Younger cohorts seem to confer cardioprotective benefits from increased adiponectin levels yet elevated levels in the elderly and those with existing heart disease are associated with poor cardiovascular outcomes. Here, we review the most recent data regarding adiponectin signaling in the vasculature, highlight the differences observed between the sexes, and shed light on the apparent paradox regarding increased cardiovascular disease risk despite rising plasma adiponectin levels over time.

Exploring the determinants of ethnic differences in insulin clearance between men of Black African and White European ethnicity

Aim People of Black African ancestry, who are known to be at disproportionately high risk of type 2 diabetes (T2D), typically exhibit lower hepatic insulin clearance compared with White Europeans. However, the mechanisms underlying this metabolic characteristic are poorly understood. We explored whether low insulin clearance in Black African (BA) men could be explained by insulin resistance, subclinical inflammation or adiponectin concentrations. Methods BA and White European (WE) men, categorised as either normal glucose tolerant (NGT) or with T2D, were recruited to undergo the following: a mixed meal tolerance test with C-peptide modelling to determine endogenous insulin clearance; fasting serum adiponectin and cytokine profiles; a hyperinsulinaemic–euglycaemic clamp to measure whole-body insulin sensitivity; and magnetic resonance imaging to quantify visceral adipose tissue. Results Forty BA (20 NGT and 20 T2D) and 41 WE (23 NGT and 18 T2D) men were studied. BA men had significantly lower insulin clearance (P = 0.011) and lower plasma adiponectin (P = 0.031) compared with WE men. In multiple regression analysis, ethnicity, insulin sensitivity and plasma adiponectin were independent predictors of insulin clearance, while age, visceral adiposity and tumour necrosis factor alpha (TNF-α) did not significantly contribute to the variation. Conclusion These data suggest that adiponectin may play a direct role in the upregulation of insulin clearance beyond its insulin-sensitising properties.

Antioxidant Potential of Adiponectin and Full PPAR-γ Agonist in Correcting Streptozotocin-Induced Vascular Abnormality in Spontaneously Hypertensive Rats

Oxidative stress, which is associated with metabolic and anthropometric perturbations, leads to reactive oxygen species production and decrease in plasma adiponectin concentration. We investigated pharmacodynamically the pathophysiological role and potential implication of exogenously administered adiponectin with full and partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists on modulation of oxidative stress, metabolic dysregulation, and antioxidant potential in streptozotocin-induced spontaneously hypertensive rats (SHR). Group I (WKY) serves as the normotensive control, whereas 42 male SHRs were randomized equally into 7 groups ( n = 6 ); group II serves as the SHR control, group III serves as the SHR diabetic control, and groups IV, V, and VI are treated with irbesartan (30 mg/kg), pioglitazone (10 mg/kg), and adiponectin (2.5 μg/kg), whereas groups VII and VIII received cotreatments as irbesartan+adiponectin and pioglitazone+adiponectin, respectively. Diabetes was induced using an intraperitoneal injection of streptozotocin (40 mg/kg). Plasma adiponectin, lipid contents, and arterial stiffness with oxidative stress biomarkers were measured using an in vitro and in vivo analysis. Diabetic SHRs exhibited hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and increased arterial stiffness with reduced plasma adiponectin and antioxidant enzymatic levels ( P < 0.05 ). Diabetic SHRs pretreated with pioglitazone and adiponectin separately exerted improvements in antioxidant enzyme activities, abrogated arterial stiffness, and offset the increased production of reactive oxygen species and dyslipidemic effects of STZ, whereas the blood pressure values were significantly reduced in the irbesartan-treated groups (all P < 0.05 ). The combined treatment of exogenously administered adiponectin with full PPAR-γ agonist augmented the improvement in lipid contents and adiponectin concentration and restored arterial stiffness with antioxidant potential effects, indicating the degree of synergism between adiponectin and full PPAR-γ agonists (pioglitazone).

Low plasma adiponectin in risk of type 2 diabetes: observational analysis and one- and two-sample Mendelian randomization analyses in 756,219 individuals

<p>We tested the hypothesis that low plasma adiponectin is observationally and genetic, causally associated with increased risk of type 2 diabetes. Observational analyses are prone to confounding and reverse causation, while genetic Mendelian randomization analyses are much less influenced by these biases. We examined 30,045 Copenhagen individuals observationally (1,751 type 2 diabetes; plasma adiponectin), 96,903 Copenhagen individuals using <a>one-sample Mendelian randomization </a>(5,012 type 2 diabetes; five genetic variants), and 659,316 Europeans (ADIPOGen, GERA, DIAGRAM, UK Biobank) using two-sample Mendelian randomization (62,892 type 2 diabetes; ten genetic variants). Observationally, and compared to individuals with median plasma adiponectin of 28.9µg/mL(4th quartile), multivariable adjusted hazard ratios for type 2 diabetes were 1.42(95% CI:1.18-1.72) for 19.2µg/mL(3rd quartile), 2.21(1.84-2.66) for 13.9µg/mL(2nd quartile), and 4.05(3.38-4.86) for 9.2µg/mL(1st quartile). Corresponding cumulative incidences for type 2 diabetes at age 70 were 3%, 7%, 11%, and 20%, respectively.<b> </b>A 1µg/mL lower plasma adiponectin conferred a hazard ratio for type 2 diabetes of 1.07(1.06-1.09), while genetic, causal risk ratios per 1 unit log-transformed lower plasma adiponectin were 1.13(0.83-1.53) in one-sample Mendelian randomization and 1.26(1.01-1.57) in two-sample Mendelian randomization. <a>In conclusion, </a>low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship.</p>