Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes

Abstract

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

Soluble CD163, adiponectin, C-reactive protein and progression of dysglycaemia in individuals at high risk of type 2 diabetes mellitus: the ADDITION-PRO cohort

“…Mendelian randomisation studies are needed to elucidate the causality between biomarkers of low-grade inflammation and the metabolic changes leading to type 2 diabetes mellitus. The causality of the association between adiponectin and insulin resistance and type 2 diabetes mellitus has previously been investigated in Mendelian randomisation studies, with diverging results [32,33], while a similar study for CRP found that its relation to insulin resistance, glycaemia and type 2 diabetes mellitus was probably non-causal [34]. No Mendelian randomisation studies to date have examined the causality of the association between sCD163 and type 2 diabetes mellitus.…”

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

“…This approach has been adopted by several groups with mixed results. Two studies found that genetically determined lowering of plasma adiponectin did indeed associate with reduced insulin sensitivity (69,70), while the largest study, with the greatest statistical power, found no such association (71). One family has been reported in which a rare missense ADIPOQ variant suppressing plasma adiponectin was found to associate with IR (72).…”

Adiponectin as a Link Between Type 2 Diabetes and Vascular NADPH Oxidase Activity in the Human Arterial Wall: The Regulatory Role of Perivascular Adipose Tissue

“…Adiponectin is an important adipokine with anti-inflammatory and insulin-sensitizing effects (8), the circulating levels of which are reduced in individuals with type 2 diabetes and obesity (7). While some studies support a causal link between low adiponectin levels and impaired glucose tolerance (9), others have failed to find such evidence (10). Low circulating levels of adiponectin are associated with increased cardiovascular risk in healthy individuals (11), although recent studies (12) suggest that in advanced cardiovascular disease states the level of circulating adiponectin is increased as a "stress hormone," and its levels become predictive of adverse clinical outcome.…”