Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic beta-cells.
The hormone glucagon is secreted by the alpha-cells of the endocrine pancreas (islets of Langerhans) during fasting and is essential for the maintenance of blood glucose levels by stimulation of hepatic glucose output. Excessive production and secretion of glucagon by the alpha-cells of the islets is a common accompaniment to diabetes. The resulting hyperglucagonemia stimulates hepatic glucose production, thereby contributing to hyperglycemia of diabetes. The reduced insulin secretion in diabetes and resultant failure to suppress glucagon secretion by intra-islet paracrine mechanisms is believed to cause the hypersecretion of glucagon. Here, we report the discovery of a new mechanism by which glucagon suppresses insulin secretion. We show that glucagon, but not glucagon-like peptide 1 (GLP-1), or pituitary adenylyl cyclase-activating peptide (PACAP) specifically induces the expression of the transcriptional repressor inducible cAMP early repressor (ICER) in pancreatic beta-cells, resulting in a repression of the transcriptional expression of the insulin gene. Remarkably, glucagon, GLP-1, and PACAP all stimulate the formation of cAMP to a comparable extent in rat pancreatic islets, but only glucagon activates the expression of ICER and represses insulin gene transcription in beta-cells. These findings lead us to propose that hyperglucagonemia may additionally aggravate the diabetic phenotype via a suppression of insulin gene expression mediated by the transcriptional repressor ICER.
Hussain
M A
MA
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston 02114, USA.
Daniel
P B
PB
Habener
J F
JF
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009479:Neuropeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
C495403:Adcyap1 protein, rat; D004268:DNA-Binding Proteins; D007328:Insulin; D009479:Neuropeptides; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011498:Protein Precursors; D012333:RNA, Messenger; D012097:Repressor Proteins; D051786:Cyclic AMP Response Element Modulator; D005576:Colforsin; D052216:Glucagon-Like Peptide 1; D004247:DNA; D005934:Glucagon; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine