The β-cell glucose toxicity hypothesis: Attractive but difficult to prove

β cells in the hyperglycemic environment of diabetes have marked changes in phenotype and function that are largely reversible if glucose levels can be returned to normal. A leading hypothesis is that these changes are caused by the elevated glucose levels leading to the concept of glucose toxicity. Support for the glucose toxicity hypothesis is largely circumstantial, but little progress has been made in defining the responsible mechanisms. Then questions emerge that are difficult to answer. In the very earliest stages of diabetes development, there is a dramatic loss of glucose-induced first-phase insulin release (FPIR) with only trivial elevations of blood glucose levels. A related question is how impaired insulin action on target tissues such as liver, muscle and fat can cause increased insulin secretion. The existence of a sophisticated feedback mechanism between insulin secretion and insulin action on peripheral tissues driven by glucose has been postulated, but it has been difficult to measure increases in blood glucose levels that might have been expected. These complexities force us to challenge the simplicity of the glucose toxicity hypothesis and feedback mechanisms. It may turn out that glucose is somehow driving all of these changes, but we must develop new questions and experimental approaches to test the hypothesis. •With only slight increases in plasma glucose levels, glucose-induced first phase insulin release (FPIR) is abolished.•This loss of FPIR is associated with increased risk of progressing to diabetes.•The most attractive way to explain these changes is that they are driven by glucose.•However, while the circumstantial evidence supporting the relationship is strong, the responsible mechanisms have not been found.•The complexities of addressing this challenge are discussed and suggestions for experiments are proposed.