Minireview: Dopaminergic regulation of insulin secretion from the pancreatic islet

Abstract

Exogenous dopamine inhibits insulin secretion from pancreatic β-cells, but the lack of dopaminergic neurons in pancreatic islets has led to controversy regarding the importance of this effect. Recent data, however, suggest a plausible physiologic role for dopamine in the regulation of insulin secretion. We review the literature underlying our current understanding of dopaminergic signaling that can down-regulate glucose-stimulated insulin secretion from pancreatic islets. In this negative feedback loop, dopamine is synthesized in the β-cells from circulating L-dopa, serves as an autocrine signal that is cosecreted with insulin, and causes a tonic inhibition on glucose-stimulated insulin secretion. On the whole animal scale, L-dopa is produced by cells in the gastrointestinal tract, and its concentration in the blood plasma increases following a mixed meal. By reviewing the outcome of certain types of bariatric surgery that result in rapid amelioration of glucose tolerance, we hypothesize that dopamine serves as an "antiincretin" signal that counterbalances the stimulatory effect of glucagon-like peptide 1.

Figure 1.

Dopaminergic Negative Feedback Regulating Insulin Secretion Schematic diagram of a β-cell expressing the molecular machinery for dopamine synthesis, storage, and secretion. The dopamine receptor D3 mediates the inhibition of glucose- stimulated insulin secretion. AADC, l-amino acid decarboxylase; DA, dopamine; GSIS, glucose-stimulated insulin secretion; INS, insulin; MAO, monoamine oxidase; LAAT, l-type amino acide transporter; DRD3, dopamine receptor D3; dopac, 3,4-dihydroxyphenylacetic acid.

Figure 2.

Dopamine Dampens GLP-1-Enhanced Glucose-Stimulated AKT Phosphorylation. INS-1E cells were grown to 80% confluence in 100-cm² flasks, washed in PBS, and then rested for 1 hour in glucose-free RPMI supplemented with 2 mM glucose and 0.5% BSA. Cells were then incubated for 30 minutes in glucose-free RPMI containing 10 mM glucose, 10 nM GLP-1 and/or 100 μM dopamine. Protein lysates were prepared from cell monolayers, and equal amounts of protein were separated by reducing SDS-PAGE and analyzed by Western blot using anti-AKT and pAKT antibodies from CST. As a loading control, the amount of β-tubulin was also measured. The amount of immunoreactive protein on each blot was quantitated by the horseradish peroxidase-enhanced chemiluminescence reaction using a Flurochem M imaging station and associated imaging software. Western blot photograph from a representative experiment in a series of 4. The data from quantitation of immunodetected proteins are mean ± SE values from the same series of 4 experiments. The single asterisk denotes a statistically significant difference (P < .05) from the mean of 10 mM glucose control, and the double asterisk denotes a statistically significant difference from the 10 mM glucose plus GLP-1 group as determined by Student's t test. DA, dopamine.