title: Peptidergic regulation of maturation of the stimulus-secretion coupling in fetal islet beta cells.
abstract: The stimulus-secretion coupling of the insulin-producing pancreatic islet beta cell is subject to functional maturation during fetal life. We studied the maturation of a glucose-responsive insulin release from fetal rat islets and specifically investigated the impact of peptidergic regulation. To this end, islets were isolated from 21-day-old fetal rats and maintained for 7 days in tissue culture at 3.3 or 11.1 mM glucose and various supplements. In islets cultured in low glucose, acutely raising the ambient glucose concentration to 16.7 mM evoked a modest stimulation of short-term insulin release that was more pronounced in islets maintained in high glucose. Moreover, the insulin content was much higher in islets cultured in high than in low glucose. Culture with growth hormone (GH) markedly amplified both basal and stimulated short-term insulin secretion from islets maintained in either low or high glucose. Additionally, GH significantly elevated the insulin content in islets maintained in low glucose. Transforming growth factor alpha (TGF-alpha) increased basal, but not glucose-stimulated, insulin release and insulin content in islets cultured in low glucose. Gastrin, expressed in islets during fetal life, did not affect basal or glucose-stimulated insulin release, or insulin content, in islets maintained in either low or high glucose. The addition of gastrin to TGF-alpha did not affect the results obtained with the latter peptide. Gastrin-releasing peptide failed to influence basal or glucose-responsive insulin secretory rates, and insulin content, at either glucose concentration during culture. The somatostatin analog Sandostatin (octreotide acetate) neither influenced basal nor stimulated short-term insulin release at any glucose concentration present during culture, whereas the hormone significantly decreased the insulin content of islets cultured in high glucose. Pancreastatin, produced by porcine islet beta and delta cells, failed to influence basal or glucose-responsive insulin secretory rates, and islet insulin content, at either glucose concentration during culture. Culture with gastric inhibitory peptide (GIP) or glucagon-like peptide I (GLP-1), two proposed incretins, did not affect short-term insulin secretion in response to 3.3 or 16.7 mM glucose irrespective of the ambient glucose concentration during culture. To the contrary, GLP-1, but not GIP, increased the content of insulin in islets cultured in low glucose. We conclude that islet beta-cell differentiation and functional maturation of the stimulus-secretion coupling can be modulated in vitro in fetal rat pancreatic tissue by peptidergic regulation and glycemic stimulation. We suggest that GH and TGF-alpha stimulate, while somatostatin, through paracrine interaction, may inhibit, these processes. These effectors may be of regulatory significance in the in vivo development of glucose-sensitive beta cells, and defects in these mechanisms may result in glucose intolerance in adult subjects.
authors.affiliation: Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden. ake@enk.ks.se
authors.forename: A
authors.initials: A
authors.lastname: Sjöholm
authors.forename: E
authors.initials: E
authors.lastname: Sandberg
authors.forename: C G
authors.initials: CG
authors.lastname: Ostenson
authors.forename: S
authors.initials: S
authors.lastname: Efendić
mesh_terms: D000818:Animals; D053379:Chromogranin A; D046508:Culture Techniques; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D015282:Octreotide / Q000494:pharmacology; D010187:Pancreatic Hormones / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D011247:Pregnancy; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
chemical_list: D053379:Chromogranin A; D007328:Insulin; D010187:Pancreatic Hormones; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D016211:Transforming Growth Factor alpha; C050836:pancreastatin; D019382:Human Growth Hormone; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose; D015282:Octreotide