Given the profound effects of insulin on energy metabolism and gene expression in virtually all tissues, it is not surprising that systemic deficiency in the insulin receptor (IR) leads to the early postnatal death of IR?/? mice. However, Cre/lox technology has also allowed for the creation of animals lacking the IR specifically in particular cell types, and the more subtle phenotypes in these designer mice offer deeper insights into the effects of insulin resistance in specific energy-storing or -consuming organs in the adult animal. Thus, skeletal muscle-specific IR knockout (MIRKO) mice have been available for several years, and animals lacking the receptor in pancreatic b islet cells, hepatocytes, or brown adipose cells have all been described. Belke et al. now add to this list the CIRKO mouse, which lacks the IR specifically in cardiomyocytes. In young CIRKO animals, the heart is of normal structure but is reduced in size, apparently because the cells themselves remain small. Indeed, CIRKO cardiomyocytes appear immature in several other respects, particularly their preferential use of glucose, rather than fatty acids, as a metabolic fuel and their continued high expression of the b isoform of the myosin heavy chain, which is normally suppressed after fetal development. Interestingly, one well established effect of insulin in the heart, the activation of glucose oxidation, is maintained in CIRKO animals. The authors speculate that endothelial cells or some other insulin-responsive cardiac cell type is responsible for inducing this metabolic change in the cardiac muscle, perhaps as a secondary effect of enhanced eNOS activity. Testing such a model might require the generation of yet another cell type specific IR knockout mouse, this one targeting the endothelium.

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Contact: John Ashkenas
scied@the-jci.org
416-946-7593
Journal of Clinical Investigation
27-Feb-2002

Page: 1
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