Oligonucleotide microarray analysis of intact human pancreatic islets: identification of glucose-responsive genes and a highly regulated TGFbeta signaling pathway.
Human pancreatic islets are a major focus of diabetes research due to their key role in glucose homeostasis and their potential for transplantation in the treatment of type 1 diabetes. Currently, no comprehensive analysis of baseline or glucose-stimulated islet gene expression is available. Using oligonucleotide microarrays we analyzed isolated intact human islets incubated at low and high glucose. We identified approximately 6000 islet genes, several with clinical implications, as well as a number of glucose-regulated genes. Interestingly, two transforming growth factor beta (TGFbeta) superfamily members were highly regulated by glucose. One of them, PDF, was found to have a very high expression level compared to other TGFbeta superfamily members. Quantitative reverse transcriptase polymerase chain reaction confirmed these results and demonstrated that the highly expressed PDF was approximately 10-fold down- regulated by glucose while other TGFbeta superfamily members and target genes were up-regulated. These results suggest that a highly regulated TGFbeta signaling cascade exists in human islets, and that PDF may play a central role in islet biology. Since TGFbeta is involved in differentiation and immune modulation, this novel pathway may link glucose metabolism, immune response and development of human islets. We report here the first gene expression profile of intact human islets. These and similar analyses will provide better understanding of human islet biology and enhance the development of novel diabetes therapies.
Transplantation and Autoimmunity Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20889-5603, USA.
Anath
A
Shalev
Cynthia A
CA
Pise-Masison
Michael
M
Radonovich
Steven C
SC
Hoffmann
Boaz
B
Hirshberg
John N
JN
Brady
David M
DM
Harlan
D000682:Amyloid / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000737:chemistry* / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D043484:Proprotein Convertases; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013879:Thioredoxins; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D002352:Carrier Proteins; D058228:Islet Amyloid Polypeptide; D009479:Neuropeptides; C486715:TXNIP protein, human; D016212:Transforming Growth Factor beta; D013879:Thioredoxins; D043484:Proprotein Convertases; D016282:Aspartic Acid Endopeptidases; D005947:Glucose