Tissue-specific Ablation of the GLUT4 Glucose Transporter or the Insulin Receptor Challenges Assumptions about Insulin Action and Glucose Homeostasis*

The prevalence of type 2 diabetes mellitus is growing worldwide. Most forms of type 2 diabetes are polygenic with complex inheritance patterns strongly influenced by environmental factors. The specific gene defects are unknown, but they affect both insulin action and insulin secretion. Glucose homeostasis is maintained by the fine orchestration of insulin secretion and insulin action to promote glucose transport into muscle and adipocytes and to inhibit hepatic glucose output. Resistance to these effects of insulin is a classic pathogenic feature of obesity and type 2 diabetes. Insulin action on lipid metabolism also has important effects on glucose homeostasis. Recent studies using tissue-specific gene targeting of the GLUT4 glucose transporter or the insulin receptor in mice reveal intercommunication among insulin target tissues which can modify the impact of genetic defects in individual tissues. These studies provide new concepts regarding the importance of adipose tissue versus muscle in whole-body insulin sensitivity and the role of proximal versus distal components of the insulin action cascade in the pathogenesis of obesity and type 2 diabetes. The insulin receptor (IR) is present in virtually all mammalian cells, and insulin binding results in activation of several phosphorylation-dephosphorylation cascades (1). The phosphoinositide 3-kinase cascade is necessary, albeit insufficient, for stimulation of glucose transport, and the mitogen-activated protein kinase cascade underlies the mitogenic effects of insulin. These insulin signaling cascades have pleiotrophic metabolic and growth-promoting effects (see Fig. 1 in Supplemental Material). Insulin stimulation of glucose transport in muscle and adipose cells is essential for maintenance of glucose homeostasis. This is mediated by sodium-independent, facilitated-diffusion glucose transporters (GLUTs). In tissues with insulin-sensitive glucose transport (i.e. skeletal and cardiac muscle and adipose cells), GLUT4 is the predominant glucose transporter and GLUT1 plays a minor role. The large stimulatory effect of insulin in these tissues results from the translocation of GLUT4-containing vesicles from intracellular storage sites to the plasma membrane where they dock and fuse with the membrane (2, 3), markedly augmenting glucose transport into the cell. GLUT4 is present primarily in white and brown adipocytes, skeletal muscle, and cardiac muscle, with expression in discrete areas of other tissues (e.g. brain and kidney) that are not traditionally thought to play a major role in glucose homeostasis (4). In insulin-resistant states including obesity and type 2 diabetes, GLUT4 expression is reduced in adipocytes but not in skeletal muscle (4, 5). This down-regulation in adipocytes was not thought to be important because skeletal muscle accounts for up to 85% of glucose disposal following a glucose infusion (6) and at least 50% following glucose ingestion (7), whereas adipose tissue accounts for much less. Glucose transport is the rate-controlling step in skeletalmuscle glucose metabolism in normal and type 2 diabetic subjects (8). Impaired glucose uptake in skeletal muscle is present even in nondiabetic relatives of type 2 diabetic subjects and is a risk factor for developing diabetes (9, 10). Defects in GLUT4 trafficking or function in skeletal muscle are thought to be most important in the development of insulin resistance. To understand the role of IR and GLUT4 in glucose homeostasis, mice were engineered to destroy the function of these genes. Genetic ablation of IR in all tissues results in lethality at 4–5 days after birth due to severe diabetic ketoacidosis (11). When GLUT4 is “knocked out” of all tissues (GLUT4-null), mice are growth-retarded, with markedly reduced fat mass, cardiomegaly, and shortened lifespan but no diabetes (12). In contrast, at least 50% of heterozygous GLUT4-null mice developed diabetes by 6 months of age (13). Hence, to distinguish the role of the insulin receptor and GLUT4 in adipose tissue and muscle in glucose homeostasis, diabetes, and adiposity, tissue-specific knock-out mice were made using Cre/loxP gene targeting (14). These mice challenge long held concepts about the control of glucose homeostasis (Fig. 1).