Defective Amplifying Pathway of β-cell Secretory Response to Glucose in Type 2 Diabetes: Integrated Modeling of in vitro and in vivo Evidence

In vivo studies have investigated the role of β-cell dysfunction in type 2 diabetes (T2D), while in vitro research on islets has elucidated key mechanisms controlling insulin secretion rate (ISR). However, the relevance of the cellular mechanisms identified in vitro, i.e., the triggering and amplifying pathways, has not been established in vivo Furthermore, the mechanisms underpinning β-cell dysfunction in T2D remain undetermined. We propose a unifying explanation of several characteristic features of insulin secretion, both in vitro and in vivo, using a mathematical model. The model describes the triggering and amplifying pathways and reproduces a variety of in vitro and in vivo tests in healthy and T2D subjects, identifies the mechanisms modulating first-phase ISR in response to basal hyperglycemia or to insulin resistance, and shows that β-cell dysfunction in T2D can be explained by an impaired amplifying pathway, with no need to postulate defects in intracellular calcium handling.