Glucose stabilization and the progression of diabetes

Insulin resistance, the failure of glucose homeostasis in the face of high levels of insulin, often foreshadows the onset of type 2 diabetes. To tease apart the contribution of insulin resistance in different organs to this progression, several groups have produced mice with genetic defects that affect glucose metabolism only in specific organs, such as the pancreas or liver. Here, Kim et al explore the phenotype of a recently described mouse strain lacking the glucose transporter GLUT4 specifically in skeletal muscle, the tissue type that is responsible for the bulk of blood glucose uptake following insulin stimulation. Because these mice show increasing hyperglycemia as they age, eventually becoming diabetic, the authors tested the idea that glucose toxicity drives the progression of this disease. They show here that a drug treatment favoring excretion of excess glucose blocks the development of insulin resistance in brown and white adipose tissue, as well as in the liver and muscle, suggesting that mild hyperglycemia per se promotes insulin resistance and sets the stage for type 2 diabetes. Also in this issue, Ryu et al. show that in a mouse model of type 1 diabetes, treatments blocking autoimmune responses can allow for successful beta cell engraftment to reverse the diabetic phenotype. Remarkably, in this case as well, successful control of hyperglycemia favors the long-term suppression of the disease and allows for restored function by the endogenous beta cells of the pancreas. Palmer ( p.xxx) discusses these latter findings in light of recent data from a large clinical trial testing the effects of aggressive maintenance of normal blood glucose levels on progression of type 1 diabetes.