Dynamics of glucose-induced insulin secretion in normal human islets.
The biphasic pattern of glucose-induced insulin secretion is altered in type 2 diabetes. Impairment of the first phase is an early sign of β-cell dysfunction, but the underlying mechanisms are still unknown. Their identification through in vitro comparisons of islets from diabetic and control subjects requires characterization and quantification of the dynamics of insulin secretion by normal islets. When perifused normal human islets were stimulated with 15 mmol/l glucose (G15), the proinsulin/insulin ratio in secretory products rapidly and reversibly decreased (∼50%) and did not reaugment with time. Switching from prestimulatory G3 to G6-G30 induced biphasic insulin secretion with flat but sustained (2 h) second phases. Stimulation index reached 6.7- and 3.6-fold for the first and second phases induced by G10. Concentration dependency was similar for both phases, with half-maximal and maximal responses at G6.5 and G15, respectively. First-phase response to G15-G30 was diminished by short (30-60 min) prestimulation in G6 (vs. G3) and abolished by prestimulation in G8, whereas the second phase was unaffected. After 1-2 days of culture in G8 (instead of G5), islets were virtually unresponsive to G15. In both settings, a brief return to G3-G5 or transient omission of CaCl2 restored biphasic insulin secretion. Strikingly, tolbutamide and arginine evoked immediate insulin secretion in islets refractory to glucose. In conclusion, we quantitatively characterized the dynamics of glucose-induced insulin secretion in normal human islets and showed that slight elevation of prestimulatory glucose reversibly impairs the first phase, which supports the view that the similar impairment in type 2 diabetic patients might partially be a secondary phenomenon.
Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium; jean-claude.henquin@uclouvain.be.
Jean-Claude
JC
Henquin
Endocrine Cell Therapy Unit, University Clinics Saint-Luc, University of Louvain, Brussels, Belgium;
Denis
D
Dufrane
Institut National de la Santé et de la Recherche Médicale U1190, Translational Research for Diabetes, and European Genomic Institute for Diabetes, University of Lille, Lille, France.
Julie
J
Kerr-Conte
Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium;
Myriam
M
Nenquin
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D011384:Proinsulin / Q000378:metabolism; D055815:Young Adult
D007328:Insulin; D011384:Proinsulin; D005947:Glucose
biphasic pattern; human islets; insulin secretion; proinsulin; type 2 diabetes