Early on, he found that the primary cause of insulin resistance in Type 2 diabetes, and most other common human insulin resistant states, occurs distal to the insulin binding step, and he has gone on to identify basic post-receptor cellular defects which can cause insulin resistance. With respect to clinical research, his work has established the principles of insulin versus non-insulin mediated glucose uptake and its relevance to human physiology, the dominance of skeletal muscle as the major organ of decreased glucose disposal, and that increased hepatic glucose production triggers the advent of fasting hyperglycemia in Type 2 diabetes.

In the basic research arena, he has showed the multi- functional nature of insulin and IGF- I receptors, demonstrating by site directed mutagenesis that different regions of the insulin receptor are mapped for mitogenic, metabolic and endocytotic activities. He also discovered that these two receptors couple into unique G protein signaling components, which can explain their differential mitogenic versus metabolic signaling properties. This work also established the principle of heterologous desensitization between the insulin/ IGF- I signaling pathway and 7TMR signaling systems. Recent research from the lab has elucidated key principles of PPARγ biology, particularly as they relate to glucose and insulin metabolism. He found that genetic deletion of PPARγ from muscle or from fat leads to insulin resistance, and this is likely due to activation of the proinflammatory pathway in the receptor deleted tissues. An important extension of this concept is the lab’s recent discovery that macrophage specific knockout of IKKß leads to a global state of heightened insulin sensitivity while macrophage PPARγ knockout causes insulin resistance, showing that activation of the inflammatory pathway, specifically within macrophages, can be the initiating etiology for decreased insulin sensitivity in traditional insulin target tissues of fat, liver and muscle.