The liver is the central glucoregulatory organ and is exposed to two- to four-fold higher levels of insulin than peripheral insulin target tissues. To determine consequences of missing insulin action in the liver, Backman, Flenkenthaler, et al. used tissue from transgenic pigs expressing mutant insulin for multi-omics analyses. These revealed increased activities in amino acid metabolism, oxidation of fatty acids, ketogenesis, and gluconeogenesis. Their study provides the first multi-omics analyses of liver in insulin-deficient diabetes mellitus and identified key drivers of known functional consequences of insulin deficiency. In addition, previously unknown consequences especially for inflammatory and immune functions of the liver were revealed.