Dopamine Production in the Pancreatic β-Cells: a Possible Autocrine Regulatory Mechanism for Insulin Secretion

Abstract

Glucose homeostasis is maintained by small clusters of hormone secreting cells in the pancreas: the pancreatic islets. Insulin secreting β-cells make for 90% of each islet and secrete insulin in a tightly regulated manner.Scattered observations in the literature report that β-cells express the required machinery to synthesize and secrete dopamine. Other lines of evidence show that dopamine inhibits glucose stimulated insulin secretion (GSIS) in vitro, and the effect is mediated by the D2 isoform of the dopamine receptor. Yet, there is no evidence of dopaminergic neurons innervating pancreatic islets, and therefore, the biological relevance of such sensitivity is not clear.We test the hypothesis that pancreatic islets produce dopamine from circulating precursor L-dopa and that the resulting dopamine is released as an autocrine inhibitory signal to regulate insulin secretion. We use microfluidic devices to maintain isolated intact islets viable during imaging experiments: we monitor islet metabolic activity by imaging of NAD(P)H autofluorescence with two photon excitation and we measure intracellular [Ca2+]i oscillations by confocal microscopy. Our data from wild type and transgenic mice lacking D2 dopamine receptor support the hypothesis that dopamine is an autocrine regulator of GSIS. The results show that metabolic activity is not affected by dopamine. On the contrary, [Ca2+]i oscillation frequency is reduced by both dopamine and L-dopa, suggesting that D2 receptor activation affects GSIS downstream of glucose metabolism.This finding provides a new target for drug development in the treatment of diabetes and could help understanding the reported increased risk of developing type 2 diabetes by patients treated with antipsychotic drugs.