Insulin's effect on glucose production: direct or indirect?

Insulin’s effects on glucose homeostasis have been studied as extensively as any area of metabolic regulation. It is therefore particularly exciting when new technologies allow a fresh look at older, well-studied but unresolved issues. This excitement is heightened when information from new approaches challenges accepted paradigms. Recent studies have proved that tissue-specific knockout mice provide such an approach. For example, tissue-specific deletion of the insulin receptor in skeletal muscle yields a mouse (the muscle-specific insulin receptor knockout or MIRKO) with a smaller musculature but with normal fasting and postchallenge glucose and insulin concentrations (1). This was quite unexpected inasmuch as physiologic studies in humans had indicated that greater than 80% of insulin-mediated glucose disposal occurred in skeletal muscle. Why then, despite severe skeletal muscle insulin-resistance, was overall body glucose homeostasis not impaired? Recognizing that developmental compensation for the absence of insulin receptors in muscles might have occurred, investigators examined downstream signaling molecules of the insulin receptor pathway as well as the amount of IGF-1 receptor in muscle. No compensatory processes were identified. By default they concluded that tissues other than muscle, at least in the mouse, were more important in the maintenance of normal glucose metabolism. Interestingly, selective disruption of the Glut-4 transporter in muscle produced insulin resistance as well as glucose intolerance in some mice. Again however, this did not have as profound metabolic consequences as might be expected (2). Notably, deletion of Glut-4 in adipose also produced insulin resistance in muscle (and liver), however the mechanism for these secondary effects has not been defined (3).