The phenotype “insulin resistance” is often a manifestation of genetic, epigenetic, and environmental adversity. How much is “the genetics” of a person? An how much is the “signal being received” from the environment?
Insulin resistance is a key mediator of obesity-related cardiometabolic disease –– yet the mechanisms underlying this link remain obscure. In the attached report, authors used an integrative genomic approach to identify 53 genomic regions associated with insulin-resistance phenotypes [higher fasting insulin levels adjusted for body mass index (BMI), lower HDL cholesterol levels, and higher triglyceride levels). Their studies provide evidence that the link of these three phenotypes concerning higher cardiometabolic risk –– is underpinned by an association with lower adipose mass in peripheral compartments.
Using these 53 loci, authors show a polygenic contribution to familial partial lipodystrophy type-1 (a severe form of insulin resistance) and highlight shared molecular mechanisms in common-to-mild and rare-to-severe insulin resistance. Population-level genetic analyses –– combined with experiments in cellular models –– implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules that influence adipocyte differentiation. These data support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease.
Nat Genet Jan 2o17; 49: 17-26