IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion.
Ghrelin is a newly discovered peptide and an endogenous ligand for growth hormone (GH) secretagogue (GHS) receptor. It has been shown to possess various central and peripheral effects, including GH secretion, food intake, and gastric and cardiac effects. Ghrelin and the GHS receptor are expressed also in pancreatic islets. We have identified several ghrelin-induced genes by PCR-select subtraction methods, among which is a beta-cell autoantigen for type 1 diabetes, IA-2beta. Administration of ghrelin increased IA-2beta mRNA in mouse brain, pancreas, and insulinoma cell lines (MIN6 and betaTC3). However, the expression of IA-2, another structurally related beta-cell autoantigen, was not induced by ghrelin. Administration of ghrelin or overexpression of IA-2beta, but not overexpression of IA-2, inhibited glucose-stimulated insulin secretion in MIN6 insulinoma cells and, moreover, inhibition of IA-2beta expression by the RNA interference technique ameliorated ghrelin's inhibitory effects on glucose-stimulated insulin secretion. These findings strongly suggest that inhibitory effects of ghrelin on glucose-stimulated insulin secretion are at least partly due to increased expression of IA-2beta induced by ghrelin. Our data demonstrate the link among ghrelin, IA-2beta, and glucose-stimulated insulin secretion.
Doi
Asako
A
The First Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
Shono
Takeshi
T
Nishi
Masahiro
M
Furuta
Hiroto
H
Sasaki
Hideyuki
H
Nanjo
Kishio
K
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D054439:Ghrelin; D005947:Glucose / Q000378:metabolism*; D013006:Growth Hormone / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007340:Insulinoma / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D036361:Peptide Hormones / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D001323:Autoantibodies; D054439:Ghrelin; C096322:ICA512 autoantibody; D007328:Insulin; D008024:Ligands; D008565:Membrane Proteins; D036361:Peptide Hormones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013006:Growth Hormone; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005947:Glucose