Section 4: Oscillations in -Cells Control Mechanisms of the Oscillations of Insulin Secretion In Vitro and In Vivo

The mechanisms driving the pulsatility of insulin secretion in vivo and in vitro are still unclear. Because glucose metabolism and changes in cytosolic free Ca ([Ca ]c) in -cells play a key role in the control of insulin secretion, and because oscillations of these two factors have been observed in single isolated islets and -cells, pulsatile insulin secretion could theoretically result from [Ca ]c or metabolism oscillations. We could not detect metabolic oscillations independent from [Ca ]c changes in -cells, and imposed metabolic oscillations were poorly effective in inducing oscillations of secretion when [Ca ]c was kept stable, which suggests that metabolic oscillations are not the direct regulator of the oscillations of secretion. By contrast, tight temporal and quantitative correlations between the changes in [Ca ]c and insulin release strongly suggest that [Ca ]c oscillations are the direct drivers of insulin secretion oscillations. Metabolism may play a dual role, inducing [Ca ]c oscillations (via changes in ATP-sensitive K channel activity and membrane potential) and amplifying the secretory response by increasing the efficiency of Ca on exocytosis. The mechanisms underlying the oscillations of insulin secretion by the isolated pancreas and those observed in vivo remain elusive. It is not known how the functioning of distinct islets is synchronized, and the possible role of intrapancreatic ganglia in this synchronization requires confirmation. That pulsatile insulin secretion is beneficial in vivo, by preventing insulin resistance, is suggested by the greater hypoglycemic effect of exogenous insulin when it is infused in a pulsatile rather than continuous manner. The observation that type 2 diabetic patients have impaired pulsatile insulin secretion has prompted the suggestion that such dysregulation contributes to the disease and justifies the efforts toward understanding of the mechanism underlying the pulsatility of insulin secretion both in vitro and in vivo. Diabetes 51 (Suppl. 1):S144–S151, 2002 Oscillations occurring at highly variable rhythms characterize many biological events such as contraction, neurotransmission, and secretion. At the cellular level, they may involve oscillations of signals as diverse as membrane potential, Ca concentration, metabolism and activity of protein kinases, protein phosphatases, or pumps. Insulin secretion is also a pulsatile phenomenon. The mechanisms underlying this pulsatility have been widely studied but are still a matter of debate. They will be briefly reviewed in this article, which complements recent articles on the same subject (1,2) but presents different interpretations. In vivo oscillations of insulin secretion. The plasma insulin concentration oscillates even during postabsorptive periods (3–6). Two major frequencies characterize these oscillations. Ultradian oscillations (period of 120 min) probably result from a feedback loop between glucose production and insulin secretion and will not be further discussed here (7,8). There also exist faster oscillations that were initially reported to have a period of 15 min in peripheral blood (3–5,9), and turned out later to have a period between 5 and 10 min in portal blood (10,11) or in peripheral blood using deconvolution algorithms (6,12). The finding that the C-peptide concentration oscillates nearly in phase with insulin indicates that cyclic secretion rather than cyclic clearance produces the oscillations of insulinemia (13–15). Pulsatile insulin secretion has been reported to account for 70% of total insulin secretion in normal human subjects (6,10), and the major effect of glucose is to increase the amplitude of the oscillations (11,12,16,17). In vitro oscillations of insulin secretion. The first convincing evidence for pulsatile insulin secretion in vitro was obtained with the isolated dog pancreas perfused with a constant concentration of glucose (18,19). The oscillations had a period of 5–10 min. Similar findings were made with the isolated pancreases of other species including monkeys (20) and humans (21). Oscillations of insulin secretion from groups of 12–200 islets have also been reported; their period was 5–10 min (22–24) or 15–30 min (25–28). Monitoring insulin secretion from single islets requires a sensitive radioimmunoassay (29) or enzymelinked immunosorbent assay (30), or uses an indirect approach, based on the amperometric detection of 5-hydroxytryptamine (5-HT) that has accumulated in insulin granules during preincubation of the islet with the amine From the Unité d’Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, Brussels, Belgium. Address correspondence and reprint requests to [email protected]. Accepted for publication 13 June 2001. 5-HT, 5-hydroxytryptamine; [Ca ]c, cytosolic free Ca 2 concentration; IP3, inositol 1,4,5-trisphosphate; KATP channel, ATP-sensitive K channel. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier, Paris.