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We tested the hypothesis that low plasma adiponectin is associated observationally and causally with increased risk of type 2 diabetes. Observational analyses are prone to confounding and reverse causation, while genetic Mendelian randomization (MR) analyses are much less influenced by these biases. We examined 30,045 individuals from the Copenhagen General Population Study observationally (plasma adiponectin [1,751 individuals with type 2 diabetes]), 96,903 Copenhagen individuals using one-sample MR (5 genetic variants [5,012 individuals with type 2 diabetes]), and 659,316 Europeans (ADIPOGen, GERA, DIAGRAM, UK Biobank) using two-sample MR (10 genetic variants [62,892 individuals type 2 diabetes]). Observationally, and in comparisons with individuals with median plasma adiponectin of 28.9 μg/mL (4th quartile), multivariable adjusted hazard ratios (HRs) for type 2 diabetes were 1.42 (95% CI 1.18-1.72) for 19.2 μg/mL (3rd quartile), 2.21 (1.84-2.66) for 13.9 μg/mL (2nd quartile), and 4.05 (3.38-4.86) for 9.2 μg/mL (1st quartile). Corresponding cumulative incidence for type 2 diabetes at age 70 years was 3%, 7%, 11%, and 20%, respectively. A 1 μg/mL lower plasma adiponectin conferred an HR for type 2 diabetes of 1.07 (1.06-1.09), while genetic, causal risk ratio per 1 unit log-transformed lower plasma adiponectin was 1.13 (95% CI 0.83-1.53) in one-sample MR and 1.26 (1.01-1.57) in two-sample MR. In conclusion, low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether high glucose levels in the normoglycemic range and higher have a causal genetic effect on risk of retinopathy, neuropathy, nephropathy, chronic kidney disease (CKD), peripheral arterial disease (PAD), and myocardial infarction (MI; positive control) in the general population.Research Design and Methods: This study applied observational and one-sample Mendelian randomization (MR) analyses to individual-level data from 117,193 Danish individuals, and validation by two-sample MR analyses on summary-level data from 133,010 individuals from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), 117,165 from the CKDGen Consortium, and 452,264 from the UK Biobank.Results: Observationally, glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (all P for trend <0.001). In genetic causal analyses, the risk ratio for a 1 mmol/L higher glucose level was 2.01 (95% CI 1.18-3.41) for retinopathy, 2.15 (1.38-3.35) for neuropathy, 1.58 (1.04-2.40) for diabetic nephropathy, 0.97 (0.84-1.12) for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 1.19 (0.90-1.58) for PAD, and 1.49 (1.02-2.17) for MI. Summary-level data from the MAGIC, the CKDGen Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26-9.15) for retinopathy, 1.48 (0.83-2.66) for peripheral neuropathy, 0.98 (0.94-1.01) for eGFR <60 mL/min/1.73 m2, and 1.23 (0.57-2.67) for PAD per 1 mmol/L higher glucose level.Conclusions: Glucose levels in the normoglycemic range and higher were prospectively associated with a high risk of retinopathy, neuropathy, diabetic nephropathy, eGFR <60 mL/min/1.73 m2, PAD, and MI. These associations were confirmed in genetic causal analyses for retinopathy, neuropathy, diabetic nephropathy, and MI, but they could not be confirmed for PAD and seemed to be refuted for eGFR <60 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]