Pulsatility of insulin release – a clinically important phenomenon

Abstract

The mechanisms and clinical importance of pulsatile insulin release are presented against the background of more than half a century of companionship with the islets of Langerhans. The insulin-secreting β-cells are oscillators with intrinsic variations of cytoplasmic ATP and Ca²⁺. Within the islets the β-cells are mutually entrained into a common rhythm by gap junctions and diffusible factors (ATP). Synchronization of the different islets in the pancreas is supposed to be due to adjustment of the oscillations to the same phase by neural output of acetylcholine and ATP. Studies of hormone secretion from the perfused pancreas of rats and mice revealed that glucose induces pulses of glucagon anti-synchronous with pulses of insulin and somatostatin. The anti-synchrony may result from a paracrine action of somatostatin on the glucagon-producing α-cells. Purinoceptors have a key function for pulsatile release of islet hormones. It was possible to remove the glucagon and somatostatin pulses with maintenance of those of insulin with an inhibitor of the P2Y₁ receptors. Knock-out of the adenosine A₁ receptor prolonged the pulses of glucagon and somatostatin without affecting the duration of the insulin pulses. Studies of isolated human islets indicate similar relations between pulses of insulin, glucagon, and somatostatin as found during perfusion of the rodent pancreas. The observation of reversed cycles of insulin and glucagon adds to the understanding how the islets regulate hepatic glucose production. Current protocols for pulsatile intravenous infusion therapy (PIVIT) should be modified to mimic the anti-synchrony between insulin and glucagon normally seen in the portal blood.

Key words::

• ATP
• calcium oscillations
• diabetes
• glucagon
• insulin
• islets of Langerhans
• purinergic receptors
• somatostatin

Acknowledgements

I would like to express my gratitude to my colleagues at the Department of Medical Cell Biology, Biomedical Center, for stimulating collaboration. Progress in the understanding of hormone secretion from human islets became possible after Olle Korsgren's establishment of The Islet Transplantation Center at the Rudbeck Laboratory. Special thanks for many years of companionship in the world of the islets to: Erik Gylfe, the present Head of the Department, who has been of vital importance for the research both in Umeå and after my return in 1976 to Uppsala, Eva Grapengiesser who was the first to demonstrate the intrinsic Ca²⁺ rhythmicity of the β-cells, Anders Tengholm for keeping me updated in molecular cell biology, and Heléne Dansk, whose enthusiasm and skilfulness made it possible to reveal many secrets of the β-cells.

The author is the recipient of the Rudbeck Award 2008.