Tissue-specific knockout of the IR gene in the pancreatic β cell has also been achieved by breeding the same mice used to generate the MIRKO with transgenic mice expressing the Cre recombinase under the control of the rat insulin promoter (11). The resultant mice exhibit a selective loss of insulin secretion in response to glucose and a progressive impairment of glucose tolerance. These data indicate an important functional role for IR in glucose-sensing by the pancreatic β cell and suggest that defective insulin signaling at the level of the β cell contributes to the insulin secretion deficit in type

2 diabetes. Another tissue-specific knockout of the IR gene in the liver, in which the Cre recombinase was under the control of the rat albumin promoter (12), generated mice with severe insulin resistance associated with glucose intolerance at the age of 2 months. However, by 4 months of age, the fasting hyperglycemia had returned to normal levels. Therefore, isolated liver insulin resistance is sufficient to cause severe defects in glucose homeostasis, but not uncontrolled fasting hyperglycemia or diabetes. Changes in insulin action in various tissues and the phenotypes resulting from systemic or tissue-specific deficiency in the insulin receptor or its known substrates (IRSs) are summarized in Table 1.