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Simultaneous presence of Ins2C96Y mutation uncovers the insulin resistance phenotype in the adipose tissue of PPARγP465L female mice

Mutations in Peroxisome Proliferator Activated Receptor‐γ (PPARγ) affect adipose tissue and insulin sensitivity. The heterozygous PPARγP467L (L/+) mutation was originally identified in insulin resistant patients. Yet, L/+ mice have normal plasma glucose and insulin sensitivity. They have mild hyperinsulinemia and increased pancreatic islet mass, especially on high‐fat diet. We hypothesized that L/+ mutation leads to insulin resistance; however the hyperinsulinemia in mice compensates for it to retain normal plasma glucose. Thus, we introduced Ins2C96Y (akita, A/+) mutation, which reduces plasma insulin, in L/+ mice. Unlike +/+;A/+ littermates, male L/+;A/+ mice have dramatically reduced life span. When compared with +/+;A/+ mice, female L/+;A/+ mice have significant hyperglycemia, smaller pancreatic islets, reduced plasma insulin levels and upregulated gluconeogenesis. In an Insulin Tolerance Test, female L/+;A/+ mice have a smaller reduction in plasma glucose indicating impaired sensitivity to insulin. Adipose tissue explants from L/+;A/+ mice have impaired glucose uptake in response to exogenous insulin. Thus, insulin resistance phenotype can indeed be attributable to L/+ mutation. Our data also provides an excellent mouse model to study diabetes in the context of gender specific physiology.