Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes.
To test the hypothesis that c-Myc plays an important role in beta-cell growth and differentiation, we generated transgenic mice overexpressing c-Myc in beta-cells under control of the rat insulin II promoter. F(1) transgenic mice from two founders developed neonatal diabetes (associated with reduced plasma insulin levels) and died of hyperglycemia 3 days after birth. In pancreata of transgenic mice, marked hyperplasia of cells with an altered phenotype and amorphous islet organization was displayed: islet volume was increased threefold versus wild-type littermates. Apoptotic nuclei were increased fourfold in transgenic versus wild-type mice, suggesting an increased turnover of beta-cells. Very few cells immunostained for insulin; pancreatic insulin mRNA and content were markedly reduced. GLUT2 mRNA was decreased, but other beta-cell-associated genes (IAPP [islet amyloid pancreatic polypeptide], PDX-1 [pancreatic and duodenal homeobox-1], and BETA2/NeuroD) were expressed at near-normal levels. Immunostaining for both GLUT2 and Nkx6.1 was mainly cytoplasmic. The defect in beta-cell phenotype in transgenic embryos (embryonic days 17-18) and neonates (days 1-2) was similar and, therefore, was not secondary to overt hyperglycemia. When pancreata were transplanted under the kidney capsules of athymic mice to analyze the long-term effects of c-Myc activation, beta-cell depletion was found, suggesting that, ultimately, apoptosis predominates over proliferation. In conclusion, these studies demonstrate that activation of c-Myc in beta-cells leads to 1) increased proliferation and apoptosis, 2) initial hyperplasia with amorphous islet organization, and 3) selective downregulation of insulin gene expression and the development of overt diabetes.
Laybutt
D Ross
DR
Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, Massachusetts, USA.
Weir
Gordon C
GC
Kaneto
Hideaki
H
Lebet
Judith
J
Palmiter
Richard D
RD
Sharma
Arun
A
Bonner-Weir
Susan
S
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000235:genetics*; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000235:genetics*; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D008938:Mitosis; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000235:genetics; D016035:Pancreas Transplantation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D009004:Monosaccharide Transport Proteins; C105201:NKX6-1 protein, human; C491328:Nkx6-1 protein, mouse; C491327:Nkx6-1 protein, rat; D012333:RNA, Messenger