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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.

BackgroundAdiponectin is a protein hormone produced by adipocytes that may play an important role in obesity. However, the causal interrelation between plasma adiponectin and body mass index (BMI) is still uncertain. We tested the hypotheses that (a) plasma adiponectin and BMI are inversely associated observationally, (b) genetically high BMI is associated with lower plasma adiponectin, and (c) genetically high plasma adiponectin is associated with lower BMI.MethodsInformation on 108 896 individuals from the Copenhagen General Population Study was used in observational and bidirectional one-sample Mendelian randomization analyses, using 5 genetic variants for BMI and 3 for adiponectin. For independent confirmation, information on 322 154 individuals from the GIANT consortium, and 29 347 individuals from the ADIPOGen consortium was used in bidirectional two-sample Mendelian randomization analysis, using 68 genetic variants for BMI and 14 for adiponectin.ResultsIn observational analyses, a 1 kg/m2 increase in BMI was associated with −0.44 µg/mL (95% confidence interval: −0.46, −0.42) in plasma adiponectin, whereas a 1 µg/mL increase in plasma adiponectin was associated with −0.11 kg/m2 (−0.12, −0.11) in BMI. In causal genetic analyses, no associations were observed between BMI and plasma adiponectin and vice versa. In one-sample Mendelian randomization analyses, a 1 kg/m2 genetically determined increase in BMI was associated with −0.13 µg/mL (−0.53, 0.28) in plasma adiponectin, whereas a 1 µg/mL genetically determined increase in plasma adiponectin was associated with 0.01 kg/m2 (−0.05, 0.07) in BMI. Corresponding estimates in the two-sample Mendelian randomization analyses were 0.03 µg/mL (−0.02, 0.07) and 0.03 kg/m2(−0.02, 0.07), respectively.ConclusionsObservationally, plasma adiponectin and BMI are inversely associated. In contrast, genetically high plasma adiponectin is unlikely to influence BMI, and genetically high BMI is unlikely to influence plasma adiponectin.

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 one-sample Mendelian randomization (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. 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. In conclusion, low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship.

Aim To examine the effect of high-intensity interval training (HIIT) on glucose clearance rates in skeletal muscle and explore the mechanism within the muscle. Methods Ten males with type 2 diabetes mellitus (T2DM) and ten matched healthy subjects performed 2 weeks of one-legged HIIT (total of eight sessions, each comprised of 10 × 1 minute ergometer bicycle exercise at >80% of maximal heart rate, interspersed with one min of rest). Insulin sensitivity was assessed by an isoglycaemic, hyperinsulinaemic clamp combined with arteriovenous leg balance technique of the trained (T) and the untrained (UT) leg and muscle biopsies of both legs. Results Insulin-stimulated glucose clearance in T legs was ~30% higher compared with UT legs in both groups due to increased blood flow in T vs UT legs and maintained glucose extraction. With each training session, muscle glycogen content decreased only in the training leg, and after the training, glycogen synthase and citrate synthase activities were higher in T vs UT legs. No major changes occurred in the expression of proteins in the insulin signalling cascade. Mitochondrial respiratory capacity was similar in T2DM and healthy subjects, and unchanged by HIIT. Conclusion HIIT improves skeletal muscle insulin sensitivity. With HIIT, the skeletal muscle of patients with T2DM becomes just as insulin sensitive as untrained muscle in healthy subjects. The mechanism includes oscillations in muscle glycogen stores and a maintained ability to extract glucose from the blood in the face of increased blood flow in the trained leg.