Modulation of β-cell function: a translational journey from the bench to the bedside

Area of Science:

• Endocrinology
• Metabolic Diseases
• Cell Biology

Background:

• Type 2 Diabetes (T2D) pathogenesis involves decreased insulin secretion and action.
• Insulin receptors and signaling proteins in pancreatic beta cells regulate growth and function.
• Beta cell insulin signaling is crucial for adapting to insulin resistance.

Purpose of the Study:

• To investigate the role of insulin signaling within pancreatic beta cells in T2D.
• To determine if beta cell insulin resistance contributes to T2D pathophysiology.

Main Methods:

• Utilized rodent models with tissue-specific knockout of the insulin receptor in beta cells (βIRKO).
• Examined insulin signaling protein expression in human islets from T2D patients.
• Assessed glucose-stimulated insulin secretion (GSIS) in isolated human beta cells and in vivo human studies.

Main Results:

• βIRKO rodents exhibited reduced first-phase GSIS, glucose intolerance, and diabetes with aging.
• Reduced expression of insulin signaling proteins was observed in islets of T2D patients.
• Insulin potentiated GSIS in human beta cells, an effect diminished in insulin-resistant individuals.

Conclusions:

• Defects in beta cell insulin signaling can cause pancreatic beta cell dysfunction.
• Beta cell insulin resistance may lead to loss of beta cell function and/or mass, contributing to T2D.
• Beta cell function is closely correlated with whole-body insulin sensitivity.