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Glucose Stimulates Pulsatile Insulin Secretion from Human Pancreatic Islets by Increasing Secretory Burst Mass: Dose-Response Relationships

Division of Endocrinology and Diabetes (R.A.R., P.C.B.), Keck School of Medicine, University of Southern California, Los Angeles, California 90033; and Endocrine Division (J.D.V.), Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Peter C. Butler, M.D., Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, 1333 San Pablo Street, BMT-B11. E-mail: pbutler{at}usc.edu.

Insulin is secreted almost exclusively in discrete bursts, and physiological regulation is accomplished by modulation of the pulse mass. How the integrity of contiguous anatomic structures in the human pancreas (islets, splanchnic innervation, exocrine tissue, local hormones) directs the coordinated insulin secretion is not known. We posed the hypothesis that glucose stimulates insulin secretion from isolated human islets by an amplification of insulin pulse mass with no change in pulse frequency and that the glucose dose-response curve for the regulation of insulin pulse mass mirrors that recognized in vivo. Islets from five nondiabetic cadaveric donors were perifused in a recently validated perifusion system at 4 mM and subsequently at 8, 12, 16, or 24 mM glucose. The effluent was collected in 1-min intervals and used for the measurement of insulin (ELISA). Pulsatile insulin secretion was analyzed by deconvolution analysis. Total insulin secretion increased progressively (P < 0.0001). This augmentation was due to amplified pulse mass (3-fold, 24 mM vs. 4 mM glucose; P < 0.0001) with no change in pulse interval (4 min). Pulsatile insulin secretion was stimulated most effectively in a physiologic concentration range of 4–8 mM. The islet insulin content was significantly correlated to the magnitude of first and second phase insulin secretion (P < 0.0001). The quantifiable orderliness of pulsatile insulin secretion rose with escalating glucose concentration (P = 0.02). In conclusion, glucose stimulates pulsatile insulin secretion from isolated human islets by amplification of insulin pulse mass without altering pulse interval. The in vitro concentration-response relationship is comparable with that observed in vivo. These data imply that transplanted human islets should be able to reproduce glucose-regulated insulin secretion as observed in the intact human pancreas.

This work was supported by NIH Grant DK-61539 and the Juvenile Diabetes Research Foundation. R.A.R. is a recipient of a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (Ri 1055).

Abbreviation: ApEn, Approximate entropy.

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