Simultaneous measurement of insulin sensitivity, insulin secretion, and the disposition index in conscious unhandled...

Of the parameters that determine glucose disposal and progression to diabetes in humans: first-phase insulin secretion, glucose effectiveness (Sg), insulin sensitivity (Si), and the disposition index (DI), only Si can be reliably measured in conscious mice. To determine the importance of the other parameters in murine glucose homeostasis in lean and obese states, we developed the frequently sampled intravenous glucose tolerance test (FSIVGTT) for use in unhandled mice. We validated the conscious FSIVGTT against the euglycemic clamp for measuring Si in lean and obese mice. Insulin-resistant mice had increased first-phase insulin secretion, decreased Sg, and a reduced DI, qualitatively similar to humans. Intriguingly, although insulin secretion explained most of the variation in glucose disposal in lean mice, Sg and the DI more strongly predicted glucose disposal in obese mice. DI curves identified individual diet-induced obese (DIO) mice as having compensated or decompensated insulin secretion. Conscious FSIVGTT opens the door to apply mouse genetics to the determinants of in vivo insulin secretion, Sg, and DI, and further validates the mouse as a model of metabolic disease.