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Modeling the spectrum of type 2 diabetes in mice
Lili Grieco-St-Pierre1, Myriam P Hoyeck1, Jennifer L Estall2,3
1Department of Biology and Institute of Biochemistry, Carleton University, Ottawa, ON, Canada K1S 5B6.
Abstract:
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.
Insights
Mouse models for type 2 diabetes (T2D) research are crucial but often don't fully represent human T2D heterogeneity. Standardized, sex-inclusive, and age-appropriate phenotyping is needed for better preclinical models and precision medicine in diabetes.
Area of Science:
- Endocrinology and Metabolism
- Preclinical Research Models
- Diabetes Pathophysiology
Background:
- Type 2 Diabetes (T2D) is a complex metabolic disorder with diverse patient phenotypes.
- Mouse models are vital for studying T2D mechanisms and developing treatments.
- Current models often lack clear categorization regarding specific T2D pathophysiological features.
Purpose of the Study:
- To critically review and categorize existing mouse models of T2D based on redefined subtypes.
- To assess how well current models recapitulate the spectrum of human T2D clinical presentations.
- To identify gaps and propose improvements for preclinical T2D research models.
Main Methods:
- Categorization of T2D mouse models into subtypes: insulin deficiency, insulin resistance (weight-independent), and insulin resistance (weight-associated).
- Review of onset, severity, and progression of metabolic phenotypes in these models.
- Comparison of model phenotypes with human T2D clinical manifestations.
Main Results:
- Existing T2D mouse models do not fully capture the heterogeneity observed in human T2D.
- Phenotyping data are often incomplete, biased towards young males, and lack standardization.
- Strategic model combinations and extended phenotyping could improve clinical relevance.
Conclusions:
- There is an urgent need for standardized, comprehensive phenotyping across both sexes and age groups in T2D mouse models.
- Utilizing age-appropriate models is crucial for accurately reflecting human T2D pathophysiology.
- Advancing precision medicine in diabetes research requires better-aligned preclinical models.
