Enhanced expression of PDX-1 and Ngn3 by exendin-4 during beta cell regeneration in STZ-treated mice.
Progenitor cells exist in the adult pancreas and transform to endocrine cells in pathological conditions. To address the mechanism of beta cell regeneration, mice were treated with streptozotocin (STZ group) or streptozotocin and exendin-4 (STZ + Ex-4 group), and the expression of PDX-1, Ngn3, insulin, IRS-2, and Foxo1 was investigated. PDX-1 mRNA was upregulated biphasically and induction of Ngn3 mRNA occurred shortly after the first increase of PDX-1 expression, a pattern similar to that observed during embryogenesis. PDX-1-positive cells appeared only in islet-like cell clusters (ICCs) in STZ group, but they appeared both in ducts and ICCs in STZ + Ex-4 group. Ngn3-positive cells emerged in ICCs but not in ducts. Therefore, regeneration seemed to occur mainly from intra-islet stem/progenitor cells. Exendin-4 upregulated PDX-1 expression which paralleled increased IRS-2 expression and translocation of Foxo1 from nucleus to cytoplasm. Further analysis of beta cell regeneration should help in the design of novel therapy for diabetes.
Kodama
Shoko
S
Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Toyonaga
Tetsushi
T
Kondo
Tatsuya
T
Matsumoto
Kazuya
K
Tsuruzoe
Kaku
K
Kawashima
Junji
J
Goto
Hideo
H
Kume
Kazuhiko
K
Kume
Shoen
S
Sakakida
Michiharu
M
Araki
Eiichi
E
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000077270:Exenatide; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053552:Keratin-7; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D013004:Somatostatin / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*
D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D000077270:Exenatide; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D007328:Insulin; D053552:Keratin-7; D007633:Keratins; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; D013004:Somatostatin; D013311:Streptozocin; D015534:Trans-Activators; D014157:Transcription Factors; D014688:Venoms; C467200:Foxo1 protein, mouse; C507496:Krt7 protein, mouse; C407737:Neurog3 protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein