Insulin resistance is a precursor to and primary cause of Type 2 diabetes mellitus. In addition, insulin resistance is associated with other chronic diseases, including gestational diabetes, cardiovascular disease, and cancer. Resistance to insulin's effects on carbohydrate metabolism include diminished actions of insulin to enhance glucose uptake and suppress endogenous glucose production. This chapter introduces new concepts related to the mechanism by which insulin stimulates glucose utilization in vivo and demonstrates that these processes are mechanistically linked to glucose production. Insulin acts rapidly in vitro to stimulate glucose uptake; in contrast, its effects in vivo are relatively slow in the conscious animal or human subject. The explanation for this difference between in vitro and in vivo dynamics is the delay associated with insulin transport across capillary endothelium of insulin-sensitive tissues (primarily muscle). Also, interstitial insulin is attenuated in concentration compared to plasma insulin at basal as well as under hyperinsulinemic conditions (plasma: interstitial ratio, 3: 2). The sluggishness of insulin action and the attenuation in insulin concentration can be explained by a model in which transendothelial insulin transport is restricted and interstitial insulin binds to insulin-sensitive cells, where the hormone is internalized and degraded. Whether insulin transport occurs by a hormone-specific mechanism (ie, via receptors on endothelial cells) was tested by comparing transport at physiological with pharmacological insulin concentrations-evidence supports a nonspecific mechanism of transport across endothelium (ie, diffusion or transcytosis). Transendothelial transport alters the in vivo patterns of insulin signaling-biphasic plasma insulin after glucose injection is reflected in a simple, rapid increase in interstitial insulin to an elevated concentration. The time course of insulin's effect to suppress endogenous glucose output is a mirror image of its effect to enhance glucose uptake; however, there is no transendothelial barrier to insulin action at the liver. The similarity in action dynamics at periphery and liver was explained by a mechanism in which insulin crosses into peripheral tissue and alters a" second (blood-borne) signal" that, in turn, suppresses liver glucose production. Of various possible alternative candidates for the second signal, declining plasma free fatty acids appear to signal suppression of glucose production. We have proposed the" single gateway hypothesis" to explain insulin's action on carbohydrate metabolism in vivo: insulin crosses the endothelial boundary in skeletal muscle (to stimulate glucose disposal) and traverses the endothelial barrier in adipose tissue to suppress lipolysis. The declining free fatty acids are proposed to be a major factor in the insulin-mediated decline in glucose output. This mechanism can be contrasted with the classical concept that portal insulin controls the liver directly. Recent evidence supports the concept that, under normal levels of glucagonemia, less than 25% of the suppression of hepatic glucose output by insulin is due to a direct effect of insulin via the portal vein and that most of the effect (approximately 75%) is explained by the indirect single gateway mechanism. These results raise the question of whether hepatic insulin resistance in Type 2 diabetes can be explained by insulin resistance at the adipocyte, which causes a failure of reduction of FFA by insulin, leading to overproduction of glucose by the liver. The possible role of the single gateway mechanism in diabetes is under investigation.