The Third Phase of In Vitro Insulin Secretion: Evidence For Glucose Insensitivity

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Abstract
In this study, in vitro B-cell models are described, which may be applicable for studying the reported B-cell desensitization produced by hyperglycemia in IDDM and NIDDM. Using a programmable perifusion/ perfusion system, insulin secretion from perifused islets was measured at 10–30-min intervals for 24–50 h. After 3–4 h continuous glucose (11 mM), a new phase of insulin release occurs in which secretion declines to, and remains at, ∼25% maximal release. Results were similar when using: (1) perifused islets embedded in Cytodex 3, or Bio-Gel P-2,100–200 mesh; (2) batchincubated islets with hourly changes of medium; and (3) the isolated pancreas perfused for 8 h. Three different media, Hana HB104 (fortified, fully defined medium), RPMI-1640 + 10% FBS, and perfusion bufferalbumin, were used. Despite reduced secretion to continuous glucose, each system responded vigorously to an acute stimulation with glucose-forskolin. Decreased secretion was primarily caused by decreased secretagogue efficiency (reduced fractional secretion). Prolonged stimulation with glucose or glucose-IBMX produced a similar waning of secretion regardless of the amount of insulin released. It is concluded that the third phase of insulin secretion may represent a secretagogue-induced, signal desensitization of the B-cell, rather than exhaustion of a B-cell compartment of Stored insulin.

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