Glucose Metabolism In Vivo in Four Commonly Used Inbred Mouse Strains

Abstract

OBJECTIVE-To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains.RESEARCH DESIGN AND METHODS-Hyperinsulinemic-euglycemic (ϳ8.5 mmol/l) and -hypoglycemic (ϳ3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (ϳ15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets.RESULTS-Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets.CONCLUSIONS-Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments. Diabetes 57:1790-1799, 2008 T he development of new mouse models has allowed investigators to address questions related to glucose metabolism in ways that were not previously possible. Use of inbred mouse strains and proliferation of techniques to produce genetic modifications have been invaluable in defining the role of select genes under physiological conditions. To rigorously examine complex physiological processes in vivo has required the development of new experimental approaches for the mouse and the adaptation of techniques previously used in larger animals. Important technical advancements, including surgical catheterization (1) and miniaturization of clamp techniques (2) for the mouse, have furthered our ability to dissect the physiology underlying insulin action, insulin secretion, and counter-regulation to insulin-induced hypoglycemia under well-controlled physiological conditions.Mouse models produced through genetic modification have been generated in a variety of mouse strains. It is widely recognized that the background mouse strain can influence phenotypes. Several examples have been described where identical genetic mutations in different inbred mouse strains result in different phenotypes (3-5). These findings indicate that the contribution of the inbred strain genetic background to the phenotype is an important factor to consider when designing and interpreting experiments.The goal of the current s...

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