Late sodium current (INaL) in pancreatic β-cells

Area of Science:

• Electrophysiology
• Cell biology
• Endocrinology

Background:

• Ranolazine (RAN) shows beneficial effects in type II diabetes, prompting investigation into the late sodium current (INaL) role in insulin secretion.
• INaL's function in glucose-stimulated insulin secretion (GSIS) is explored in rat INS-1E and human islet cells.

Purpose of the Study:

• Characterize INaL and its function in insulin-secreting cells.
• Investigate the impact of INaL on insulin secretion under normal and hyperglycemic conditions.
• Determine the relationship between INaL and Na(+)-activated K(+) current (IKNa).

Main Methods:

• Electrophysiological recordings to identify and characterize INaL using ranolazine (RAN) and tetrodotoxin (TTX).
• Pharmacological manipulation with veratridine (VERA) to enhance INaL.
• Analysis of cytosolic Ca(2+) responses and insulin secretion.
• Long-term high glucose incubation (CHG) to simulate hyperglycemic stress.

Main Results:

• INaL was identified in INS-1E and human islet cells, coupled with Na(+)-activated K(+) current (IKNa).
• Enhanced INaL by veratridine increased insulin secretion; high glucose (CHG) constitutively enhanced INaL, leading to glucose-independent secretion and impaired GSIS.
• Ranolazine or tetrodotoxin countered these effects, highlighting INaL's role in both normal and pathological insulin secretion.

Conclusions:

• INaL is present in insulin-secreting cells, coupled to IKNa, and influences Ca(2+) dynamics.
• While INaL minimally impacts basal GSIS, its enhancement under hyperglycemic stress contributes to impaired glucose responsiveness and insulin leakage.
• Targeting INaL may offer therapeutic potential for managing diabetes-associated secretory dysfunction.