Exenatide blocks JAK1-STAT1 in pancreatic beta cells.
Exenatide (Ex-4) is an antidiabetic drug that acts through the glucagon-like peptide 1 receptor and has recently been approved for the treatment of type 2 diabetes mellitus. Ex-4 also has been shown to affect beta cell gene expression and increase beta cell mass in rodent models of type 1 diabetes mellitus, but the mechanisms are not fully understood. We therefore analyzed the pathways affected by Ex-4 in human islets by using oligonucleotide microarrays and the PathwayStudio software (Ariadne Genomics, Rockville, MD). We identified the JAK1-STAT1 pathway as a novel target of Ex-4 and confirmed the Ex-4-mediated down-regulation of JAK1 and STAT1 by quantitative reverse transcription-polymerase chain reaction in human islets and INS-1 cells. JAK1-STAT1 is the major signaling pathway mediating the interferon gamma effects on beta cell apoptosis in type 1 diabetes mellitus. Thus, these findings suggest that Ex-4 treatment may also be beneficial in type 1 diabetes mellitus, where it may help protect beta cells from cytokine-induced cell death by inhibiting JAK1-STAT1.
Couto
Francesca M
FM
Department of Medicine, University of Wisconsin, Madison, WI, USA.
Minn
Alexandra H
AH
Pise-Masison
Cynthia A
CA
Radonovich
Mike
M
Brady
John N
JN
Hanson
Matthew
M
Fernandez
Luis A
LA
Wang
Ping
P
Kendziorski
Christina
C
Shalev
Anath
A
D002478:Cells, Cultured; D000077270:Exenatide; D020869:Gene Expression Profiling; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D010455:Peptides / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D010455:Peptides; D050794:STAT1 Transcription Factor; D014688:Venoms; D007371:Interferon-gamma; D000077270:Exenatide; C507904:JAK1 protein, human; D053613:Janus Kinase 1