Characterization of somatostatin receptor subtype-specific regulation of insulin and glucagon secretion: an in vitro study on isolated human pancreatic islets.
BACKGROUND
Pancreatic A- and B-cells express somatostatin receptors (SSTRs). Five pharmacologically distinct SSTR subtypes are known (SSTR1-SSTR5). In rodents, SSTR2 inhibits glucagon secretion, whereas SSTR5 suppresses the release of insulin. Human pancreatic A- and B-cells express SSTR1-3 and SSTR5; however, their contribution to the regulation of glucagon and insulin secretion is not well known.


OBJECTIVE
The goal of this study was to characterize the role of individual SSTR subtypes in regulating human glucagon and insulin secretion in vitro.


METHODS
Human pancreatic islets were isolated from healthy donors and incubated with somatostatin, SSTR1-3-selective and SSTR5-selective agonists, or an SSTR2-selective antagonist (DC-41-33). Stimulation of insulin secretion was induced by glucose (10, 20 mm) alone or in combination with 10 nm exendin-4 or 10 mm L-arginine. Glucagon secretion was induced by 20 mm L-arginine. Basal secretion of insulin and glucagon was measured at 2.8 or 3.3 mm glucose.


RESULTS
SSTR1-, SSTR2-, and SSTR5-selective agonists inhibited insulin secretion with the following order of potency: SSTR2 (EC50, 0.08 nm) > SSTR5 (EC50, 5.3 nm) > SSTR1 (EC50, 35 nm). Glucagon secretion was inhibited by SSTR-selective agonists with the following order of potency: SSTR2 (EC50, 0.05 nm) > SSTR1 (EC50, 1.8 nm) > SSTR5 (EC50, 28 nm). DC-41-33 dose-dependently reversed the effects of the SSTR2-selective agonist on insulin and glucagon secretion.


CONCLUSIONS
Our study demonstrates that SSTR2-agonist is the most potent inhibitor of insulin and glucagon secretion from isolated human pancreatic islets. Furthermore, we identify SSTR1- and SSTR5-selective agonists as additional inhibitors of insulin and glucagon secretion from human pancreas.
Singh
Vandana
V
Medizinische Klinik m. S. Hepatologie, Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
Brendel
Mathias D
MD
Zacharias
Sylvia
S
Mergler
Stefan
S
Jahr
Henning
H
Wiedenmann
Bertram
B
Bretzel
Reinhard G
RG
Plöckinger
Ursula
U
Strowski
Mathias Z
MZ
D001120:Arginine / Q000494:pharmacology; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D008875:Middle Aged; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology
D007004:Hypoglycemic Agents; D007328:Insulin; D008565:Membrane Proteins; D010455:Peptides; D017481:Receptors, Somatostatin; D014688:Venoms; C103631:somatostatin receptor 3; C098681:somatostatin receptor subtype-4; C101130:somatostatin receptor type 1; C094573:somatostatin receptor 5; D005934:Glucagon; D001120:Arginine; D000077270:Exenatide; C093733:somatostatin receptor 2; D005947:Glucose