Three patterns of response of pancreatic β cells to insulin resistance. (a) In IRS–/– animals, glucose tolerance remains normal in the face of insulin resistance because their β cells (red) proliferate to compensate for reduced insulin responses. (b) In mice lacking both glucokinase and IRS-1 (GK–/–/IRS-1 double knockouts), a similar compensatory β-cell hyperplasia occurs, but the animals develop type 2 diabetes because their β cells (purple) are defective in glucose-stimulated insulin secretion. (c) IRS-2–/– mice, similarly, become overtly diabetic. These animals have functional β cells (red) that are unable to undergo hyperplasia to compensate for insulin resistance. Together, these results indicate that the compensatory response of β cells to insulin resistance plays a crucial role in preventing the development of type 2 diabetes. KO, knockout.