ROCK1 regulates insulin secretion from β-cells

Area of Science:

• Endocrinology
• Cell Biology
• Metabolism

Background:

• Pancreatic beta cells are vital for glucose homeostasis, but intracellular regulators of their function are not fully understood.
• Dysregulation of beta cell function is a hallmark of all diabetes types.
• ROCK1's role in beta cell function and glucose metabolism requires further elucidation.

Purpose of the Study:

• To investigate the physiological role of ROCK1 in regulating insulin secretion.
• To determine the impact of ROCK1 deficiency in beta cells on glucose homeostasis.
• To elucidate the molecular mechanisms by which ROCK1 modulates beta cell function.

Main Methods:

• Generated mice with ROCK1 specifically deleted in pancreatic beta cells (β-ROCK1-/-).
• Assessed glucose tolerance, insulin tolerance, and glucose-stimulated insulin secretion (GSIS) in these mice.
• Evaluated insulin secretion, intracellular calcium, ATP levels, and oxygen consumption in isolated islets and beta cell lines with ROCK1 deficiency or knockdown. Investigated ROCK1-pyruvate kinase (PK) interaction using proximity ligation assay.

Main Results:

• β-ROCK1-/- mice exhibited hyperglycemia, reduced serum insulin, impaired glucose tolerance, and diminished GSIS.
• ROCK1 deficiency in islets and beta cell lines led to decreased insulin secretion, intracellular calcium, ATP levels, and oxygen consumption.
• Pyruvate or PK activator treatment rescued GSIS in ROCK1-deficient beta cells, and ROCK1 was found to bind PK upon glucose stimulation.

Conclusions:

• Beta-cell ROCK1 is essential for effective glucose-stimulated insulin secretion and maintaining glucose homeostasis.
• ROCK1 functions as a key upstream regulator of glycolytic pyruvate kinase signaling in beta cells.
• Targeting ROCK1 may offer a novel therapeutic strategy for diabetes treatment.