The earliest stages of type 2 diabetes are characterised by growing insulin resistance and increased insulin secretion from an expanding population of pancreatic β cells. In later stages, the β cells fail and, in the insulin-resistant environment, they cannot produce sufficient insulin to maintain blood glucose control. The ability to understand the crucial steps that precipitate diabetes and β-cell failure is hampered by limited mouse models for the early stages of the disease. Most models are examined after the failing of β cells, making it difficult to define the events leading to expansion and excessive insulin production by β cells, and their subsequent failure.

Here, the authors define a mouse model for studying the early pathological changes that result from elevated fat levels or lipotoxicity. They use the POKO mouse, a mouse model obtained by crossing the insulin-resistant ob/ob mouse (which lacks leptin) with the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout mouse that lacks the nuclear receptor PPARγ2, which is known to have a role in adipogenesis. The POKO mouse becomes lipotoxic and more insulin resistant than the ob/ob mouse. Changes are found in the lipid profiles of POKO mice as young as 4 weeks of age and are associated already with changes in β-cell proliferation and function. At this early time, pathogenic effectors that characterise the advanced stages of disease can be observed. Lipidomic analysis of the β cells in pre-diabetic mice reveal that, compared with other metabolically relevant organs such as the liver, muscle or adipose tissue, these pancreatic cells are protected from lipid-induced toxicity at the early stages of disease. This suggests a hierarchical order of ectopic lipid accumulation in which β cells are protected initially, and establishes a model for understanding the early events leading to diabetes.

Previous models are limited in their ability to address issues about the early sensing of insulin resistance and the effectors that contribute to changes in β-cell mass and function. The authors suggest that these data establish a foundation for subsequent systems biology profiling studies to identify the mechanisms by which β cells initially sense insulin resistance and eventually fail from metabolic pressure. Further work should reveal the molecular effectors that increase β-cell mass and function in the early phase of diabetes and suggest biomarkers for early stages of the disease.