Genetic studies of insulin resistance

Epidemiologic studies in humans indicate that resistance to insulin action in muscle represents the first abnormality in the onset of diabetes, but is not sufficient for the development of the full-blown disease. Thus, it remains unclear whether and how other tissues contribute to the development of diabetes. To examine this question, we have used genetic reconstitution experiments in mice. The insulin receptor mediates actions of insulin on its target tissues. Genetic ablation of insulin receptors causes early postnatal death from diabetic ketoacidosis. In our studies, we have asked whether reconstituting insulin receptor function in selected tissues would rescue insulin receptor knockout mice from diabetes. We show that combined restoration of insulin receptor function in brain, liver and pancreatic beta cells rescues insulin receptor knockout mice from neonatal death, prevents diabetes in a majority of animals and normalizes adipose tissue content, life span and reproductive function (referred to as L1 mice). In contrast, mice with insulin receptor expression limited to brain or liver and beta cells are rescued from neonatal death, but develop lipoatrophic diabetes and die prematurely. These data indicate that insulin receptor signaling in non-canonical insulin target tissues is sufficient to maintain fuel homeostasis and prevent diabetes. In spite of lifetime absence of diabetes in majority of animals, L1 mice exhibit severe hyperinsulinemia. To delineate underlying mechanisms, we performed hyperinsulinemic euglycemic clamp studies in L1 mice. These studies revealed that L1 mice are insulin-resistant in liver. Analyses of protein expression indicated that L1 mice have normal insulin signaling in liver but a near complete ablation of the signaling in the arcuate and paraventricular nuclei of hypothalamus. Based on these results, we propose that inability of insulin to suppress glucose production despite normal insulin signaling in liver of L1 mice is due to deficiency in hypothalamic insulin signaling. In summary, mice with tissue-restricted insulin receptor expression provide insight into relative contributions of individual organs to the pathophysiology of insulin resistance, and suggest that therapeutic alternatives based on preserving insulin sensitivity in the brain should be pursued.