Anti-incretin, Anti-proliferative Action of Dopamine on β-Cells.
Human islet β-cells exploit an autocrine dopamine (DA)-mediated inhibitory circuit to regulate insulin secretion. β-Cells also express the DA active transporter and the large neutral amino acid transporter heterodimer enabling them to import circulating DA or its biosynthetic precursor, L-3,4-dihydroxyphenylalanine (L-DOPA). The capacity to import DA or L-DOPA from the extracellular space possibly indicates that DA may be an endocrine signal as well. In humans, a mixed meal stimulus is accompanied by contemporary serum excursions of incretins, DA and L-DOPA, suggesting that DA may act as an anti-incretin as postulated by the foregut hypothesis proposed to explain the early effects of bariatric surgery on type 2 diabetes. In this report, we take a translational step backwards and characterize the kinetics of plasma DA and incretin production after a mixed meal challenge in a rat model and study the integration of incretin and DA signaling at the biochemical level in a rodent β-cell line and islets. We found that there are similar excursions of incretins and DA in rats, as those reported in humans, after a mixed meal challenge and that DA counters incretin enhanced glucose-stimulated insulin secretion and intracellular signaling at multiple points from dampening calcium fluxes to inhibiting proliferation as well as apoptosis. Our data suggest that DA is an important regulator of insulin secretion and may represent 1 axis of a gut level circuit of glucose and β-cell mass homeostasis.
Division of Endocrinology (A.M., P.H.), Department of Medicine, and Department of Surgery (A.M.S.), Columbia University Medical College, New York, New York 10032; Institute of Genetics and Biophysics (A.M.), Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche, 80131 Naples, Italy; and Division of Endocrinology, Diabetes and Bone Diseases (J.C.A.-P., A.G.-O.), Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai and The Mindich Child Health and Development Institute, New York, New York 10029.
Antonella
A
Maffei
Ann Marie
AM
Segal
Juan Carlos
JC
Alvarez-Perez
Adolfo
A
Garcia-Ocaña
Paul E
PE
Harris
D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004298:Dopamine / Q000494:pharmacology*; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D013004:Somatostatin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D004298:Dopamine