Defective Amplifying Pathway of β-Cell Secretory Response to Glucose in Type 2 Diabetes: Integrated Modeling of In Vitro and In Vivo Evidence.

Grespan, Eleonora; Giorgino, Toni; Arslanian, Silva; Natali, Andrea; Ferrannini, Ele; Mari, Andrea

In vivo studies have investigated the role of β-cell dysfunction in type 2 diabetes (T2D), whereas in vitro research on islets has elucidated key mechanisms that control the insulin secretion rate. 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 by using a mathematical model. The model describes the triggering and amplifying pathways and reproduces a variety of in vitro and in vivo tests in subjects with and without T2D, identifies the mechanisms modulating first-phase insulin secretion rate in response to basal hyperglycemia or 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.

GLUCOSE metabolism; ANIMAL experimentation; BIOCHEMISTRY; BIOLOGICAL models; BIOLOGICAL transport; BLOOD sugar; CELL physiology; CELLULAR signal transduction; COMPARATIVE studies; COMPUTER simulation; CYTOPLASM; IMMUNITY; INSULIN; INSULIN resistance; ISLANDS of Langerhans; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; METABOLISM; MICE; TYPE 2 diabetes; RESEARCH; RESEARCH evaluation; TISSUE culture; EVALUATION research

Diabetes, 2018, Vol 67, Issue 3, p496

0012-1797

Academic Journal

10.2337/db17-1039