ABSTRACT
The metabolic staging of Type 2 diabetes includes a progression from insulin resistance and impaired glucose tolerance to β-cell failure. Animal models, such as the Zucker diabetic fatty (ZDF) rat, can be used to analyze the sequence of these metabolic events and evaluate the consequences of pharmacological intervention at various steps in the process. Agents that activate PPARγ and increase insulin sensitivity prevent diabetes in the spontaneously diabetic ZDF male, but can not treat established hyperglycemia indicating a rapid progression from prediabetes to β-cell failure. Diabetes in the ZDF female fed a high fat diet can be successfully treated with thiazolidinediones several weeks after the onset of hyperglycemia. This establishes the fundamental role of insulin resistance in diabetes in this animal model and allows a window of opportunity for studying the sequence of events that occur between defective β-cell function and β-cell failure.
