Modeling the spectrum of type 2 diabetes in mice

Type 2 diabetes (T2D) is a heterogenous metabolic condition characterized by varying degrees of insulin resistance and β-cell dysfunction. Preclinical mouse models are essential tools to investigate the mechanisms of T2D pathogenesis and develop therapeutic targets; yet, researchers often fail to specify which aspects of the spectrum of human T2D phenotypes are being modeled. In this mini-review, we critically examine mouse models of T2D and categorize them into recently redefined T2D subtypes according to key pathophysiological features. We focus on models that exhibit (1) insulin deficiency, (2) insulin resistance independent of weight gain, or (3) insulin resistance associated with weight gain. Onset, severity, and progression of metabolic phenotypes are described and discussed in context with clinical presentation in humans. While we find current T2D mouse models do not fully capture the heterogeneity of T2D, strategic model combinations and longer-term phenotyping could help better mimic clinical progression. Existing phenotyping data are often incomplete and largely available only for young male mice. We highlight the urgent need for thorough and standardized phenotyping of both sexes in all models. We also encourage the field to move toward using age-appropriate mice to better reflect human T2D pathophysiology and to advance precision medicine efforts in diabetes research.