Considerations and guidelines for mouse metabolic phenotyping in diabetes research

Abstract

Mice are the most commonly used species in preclinical research on the pathophysiology of metabolic diseases. Although they are extremely useful for identifying pathways, mechanisms and genes regulating glucose and energy homeostasis, the specificities of the various mouse models and methodologies used to investigate a metabolic phenotype can have a profound impact on experimental results and their interpretation. This review aims to: (1) describe the most commonly used experimental tests to assess glucose and energy homeostasis in mice; (2) provide some guidelines regarding the design, analysis and interpretation of these tests, as well as for studies using genetic models; and (3) identify important caveats and confounding factors that must be taken into account in the interpretation of findings.

Keywords: Clamp; Energy balance; Genetic background; Glucose tolerance; Metabolic phenotyping; Mouse; Review.

Fig. 1

Proposed flowchart for the investigation of glucose and energy homeostasis in mice. The first simple step for metabolic phenotyping is to measure body weight, fasting blood glucose and plasma insulin levels and to perform a GTT that includes insulin measurements. If body weight is affected, we refer the reader to the guidelines proposed by Tschöp et al [43] to investigate energy balance in rodents. If glucose tolerance is found to be altered, changes in insulin sensitivity and/or secretion can be tested using ITTs and/or the gold standard, HGC, respectively. However, ITT is not very sensitive and, hence, a lack of change in insulin tolerance does not rule out insulin resistance. HIECs can be used to interrogate insulin sensitivity at the whole-body level or in a tissue-specific manner using glucose tracers. ITT, HIEC and HGC tests can be combined with ex vivo studies (e.g. analysis of insulin secretion in isolated islets, glucose transport in tissues, beta cell mass measurements) to better define the underlying mechanisms