The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.

AIMS/HYPOTHESIS: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). METHODS: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. RESULTS: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. CONCLUSIONS/INTERPRETATION: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.S.Bra. was funded by the UK Medical Research Council [MC_UU_12015/3]

Correction to: The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study (Diabetologia, (2020), 63, 4, (744-756), 10.1007/s00125-019-05083-6).

© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Unfortunately, ‘Present address’ was omitted from one of the addresses provided for Mark I. McCarthy (#26). The corrected address details are given on the following page

Aerobic bacteria, Chlamydia trachomatis, Pneumocystis carinii and Cytomegalovirus as agents of severe peneumonia in small infants Bactérias aeróbias, Chlamydia trachomatis, Pneumocystis carinii e Cytomegalovirus: agentes causadores de pneumonia grave em pequenos lactentes

The authors studied 58 infants hospitalized for pneumonia in a semi-intensive care unit. Age ranged from 1 complete to 6 incomplete months. The infants were sent from another hospital in 20 cases and from home in a further 38. Pulmonary involvement, which was alveolar in 46 cases and interstitial in 12, was bilateral in 31 children. The investigation was carried out prospectively on the etiological agents associated with respiratory infection to look for evidence of aerobic bacteria (blood cultures), Chlamydia trachomatis and Cytomegalovirus (serology), and Pneumocystis carinii (direct microscopy of tracheal aspirated material). The following infectious agents were diagnosed in 21 children (36.2%): Aerobic bacteria (8), Chlamydia trachomatis (5), Pneumocystis carinii (3), Cytomegalovirus (3), Cytomegalovirus and Chlamydia trachomatis (1), Aerobic bacteria and Cytomegalovirus (1). Seven cases of infection by Chlamydia trachomatis and/or Cytomegalovirus were diagnosed out of the 12 cases with pulmonary interstitial involvement.<br>Os autores estudaram prospectivamente 58 lactentes internados por pneumonia em unidade semi-intensiva. A idade foi limitada entre 1 mês completo e 6 meses incompletos. A procedência das crianças foi de outro hospital em 20 casos e domiciliar em 38. O acometimento pulmonar era alveolar em 46 casos, intersticial em 12 e bilateral em 31 crianças. Foram pesquisados agentes etiológicos associados à infecção respiratória dos lactentes jovens: Bactérias aeróbias (Hemoculturas), Chlamydia trachomatis e Cytomegalovirus (sorologia), e Pneumocystis carinii (microscopia direta do aspirado traqueal). Foram diagnosticadas infecções em 21 crianças (36,2%): Bactérias aeróbias (8), Chlamydia trachomatis (5), Cytomegalovirus (3), Pneumocystis carinii (3), Cytomegalovirus e Chlamydia trachomatis (1), Bactéria aeróbia e Cytomegalovirus (1). Foram diagnosticadas 7 infecções por Chlamydia trachomatis e/ou Cytomegalovirus entre as 12 crianças com quadro intersticia

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue. Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care