Sustained Pulsatile Insulin Secretion From Adenomatous Human β-Cells: Synchronous Cycling of Insulin, C-Peptide, and Proinsulin

Abstract

The endocrine pancreas secretes insulin in a pulsatile fashion. This rhythm is generated at a site within the pancreas, although its precise location has not been determined. With an in vitro system, we tested the possibility that β-cells might generate spontaneous pulsatile insulin secretion in the absence of any external influence. Human insulinoma tissue from five patients was perifused for 7–10 h with RPMI-1640 medium and constant concentrations of glucose (5.5 mM). Insulin, C-peptide, and proinsulin were measured in the effluent collected at 3.3-min intervals. All three peptides demonstrated pulsatility of secretion in a similar, synchronous fashion that was sustained throughout each study. The Clifton cycle detection program demonstrated cycling in all five tumors, with an average period for all tumors of 28, 29, and 26 min for insulin, C-peptide, and proinsulin, respectively. Spectral analysis confirmed the regularity and consistency of the hormonal secretory patterns. Mean hormone concentrations secreted by different tumors varied, but insulin and C-peptide were secreted in a nearly 1:1 ratio. This study demonstrates 1) that β-cells are able to generate spontaneous pulsatile insulin secretory activity, which is independent of innervation or the presenceof other islet cells, and 2) proinsulin secretion from the β-cell also has an inherent pulsatility. The synchrony observed in the cycles of proinsulin andits peptide products confirms their common secretory pathway in the β-cell. We conclude that the β-cell may be the originator of insulin cycling.