Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.This study was funded by the UK Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC_UU_12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372). Funding for the InterAct project was provided by the EU FP6 program (grant LSHM_CT_2006_037197). This work was funded, in part, through an EFSD Rising Star award to R.A.S. supported by Novo Nordisk. D.B.S. is supported by Wellcome Trust grant 107064. M.I.M. is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. M.v.d.B. is supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. I.B. is supported by Wellcome Trust grant WT098051. S.O'R. acknowledges funding from the Wellcome Trust (Wellcome Trust Senior Investigator Award 095515/Z/11/Z and Wellcome Trust Strategic Award 100574/Z/12/Z)

Efficiency of light-scattering aerosol particle counters

The counting efficiency as a function of particle size has been calculated for a particular forward scattering aerosol particle counter that uses white light illumination for spherical particles with indexes of refraction 1.33-0i, 1.40-Oi, 1.50-0i, 1.592-0i, 1.50-0.05i, 1.50-O.li, 1.50-0.5i, and 1.95-0.66i. The counting efficiency differs from 100% because of statistical effects: photoelectron statistical broadening, variation in aerosol speed through the illuminated volume, nonuniform illumination of the sampled aerosol, and nonuniformity of the photomultiplier tube photo cathode surface. These spectra broadening effects have been determined for the particle counter by measurement of monodisperse aerosols, and the efficiency calculation is based on these measurements. For the particle counter studied, the efficiencies vary from 70% to slightly over 100% in the size ranges where the counter response is single valued. The efficiency for materials for which the response is not single-valued fluctuates wildly in those size ranges from about 20% to more than 10,000%. The efficiency as a function of particle size discriminator level setting is sensitive to particle refractive index and to the aerosol size distribution locally about that particle size. The method for calculation of the efficiency can be applied to light-scattering aerosol counters available commercially