Translating glucose tolerance data from mice to humans: Insights from stable isotope labelled glucose tolerance tests.

The glucose tolerance test (GTT) is widely used in human and animal biomedical and pharmaceutical research. Despite its prevalent use, particularly in mouse metabolic phenotyping, to the best of our knowledge we are not aware of any studies that have attempted to qualitatively compare the metabolic events during a GTT in mice with those performed in humans. Stable isotope labelled oral glucose tolerance tests (siOGTTs; [6,6- During the siOGTT in humans, there is a long period (>3hr) of glucose absorption and, accordingly, a large, sustained insulin response and robust suppression of lipolysis and endogenous glucose production (EGP), even in the presence of glucose intolerance. In contrast, mice appear to be highly reliant on glucose effectiveness to clear exogenous glucose and experience only modest, transient insulin responses with little, if any, suppression of EGP. In addition to the impaired stimulation of glucose uptake, mice with the worst glucose tolerance appear to have a paradoxical and persistent rise in EGP during the OGTT, likely related to handling stress. The metabolic response to the OGTT in mice and humans is highly divergent. The potential reasons for these differences and their impact on the interpretation of mouse glucose tolerance data and their translation to humans are discussed.

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