Insulin receptor activation inhibits insulin secretion from human islets of Langerhans
H Asare-Anane, PM Jones & SJ Persaud
There is no consensus on the role of insulin secreted from pancreatic β-cells in regulating its own secretion, nether in rodent islets nor in human islets. We have now investigated whether there is an autocrine signalling role for insulin in human islets by determining insulin receptor expression and assessing the effects of insulin receptor activation using a non-peptidyl insulin-mimetic termed L-783,281. All experiments used hand-picked human islets of Langerhans. Human insulin receptor mRNA was detected by PCR amplification of human islet cDNA, and translation of the message in human islets was confirmed by Western blotting using an antibody raised against the α subunit of the insulin receptor. Perifusion experiments with human islets indicated that insulin secretion was significantly stimulated upon raising the glucose concentration from 2mM to 20mM, as expected. Addition of the insulin-mimetic, L-783,281, at 10µM resulted in a significant (P<0.05) inhibition of glucose-induced insulin secretion, such that the secretory response approached basal levels of insulin secretion after 20 minutes exposure to L-783,281. The effects of activation of human islet insulin receptors with L-783,281 at 2mM glucose were also examined. 10µM L-783,281 elicited a rapid inhibition of basal insulin secretion that was reversible, at least in part, when the perifusion medium was returned to 2mM glucose alone. These studies indicate that human islets express insulin receptors and that they are functionally coupled to an inhibition of insulin secretion.
We thank Dr. Guo Cai Huang and the Dixon's Human Islet Project at King's for the human islets and Merck for the provision of L-783,281.