Cyclic AMP dynamics in the pancreatic β-cell

Abstract

Insulin secretion from pancreatic β-cells is tightly regulated by glucose and other nutrients, hormones, and neural factors. The exocytosis of insulin granules is triggered by an elevation of the cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) and is further amplified by cyclic AMP (cAMP). Cyclic AMP is formed primarily in response to glucoincretin hormones and other G_s-coupled receptor agonists, but generation of the nucleotide is critical also for an optimal insulin secretory response to glucose. Nutrient and receptor stimuli trigger oscillations of the cAMP concentration in β-cells. The oscillations arise from variations in adenylyl cyclase-mediated cAMP production and phosphodiesterase-mediated degradation, processes controlled by factors like cell metabolism and [Ca²⁺]_i. Protein kinase A and the guanine nucleotide exchange factor Epac2 mediate the actions of cAMP in β-cells and operate at multiple levels to promote exocytosis and pulsatile insulin secretion. The cAMP signaling system contains important targets for pharmacological improvement of insulin secretion in type 2 diabetes.

Key words::

• Epac2
• insulin secretion
• oscillations
• protein kinase A

Acknowledgements

I wish to express my gratitude to all present and past members of my laboratory as well as to colleagues within and outside the department for valuable discussions. The work in my laboratory is supported by grants from the European Foundation for the Study of Diabetes/MSD, Family Ernfors Foundation, Novo Nordisk Foundation, Swedish Diabetes Association, and the Swedish Research Council.

Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.