Pdx1 restores beta cell function in Irs2 knockout mice.
The homeodomain transcription factor Pdx1 is required for pancreas development, including the differentiation and function of beta cells. Mutations in Pdx1 or upstream hepatocyte nuclear factors cause autosomal forms of early-onset diabetes (maturity-onset diabetes of the young [MODY]). In mice, the Irs2 branch of the insulin/Igf signaling system mediates peripheral insulin action and pancreatic beta cell growth and function. To investigate whether beta cell failure in Irs2(-/-) mice might be related to dysfunction of MODY-related transcription factors, we measured the expression of Pdx1 in islets from young Irs2(-/-) mice. Before the onset of diabetes, Pdx1 was reduced in islets from Irs2(-/-) mice, whereas it was expressed normally in islets from wild-type or Irs1(-/-) mice, which do not develop diabetes. Whereas male Irs2(-/-)Pdx1(+/+) mice developed diabetes between 8 and 10 weeks of age, haploinsufficiency for Pdx1 caused diabetes in newborn Irs2(-/-) mice. By contrast, transgenic expression of Pdx1 restored beta cell mass and function in Irs2(-/-) mice and promoted glucose tolerance throughout life, as these mice survived for at least 20 months without diabetes. Our results suggest that dysregulation of Pdx1 might represent a common link between ordinary type 2 diabetes and MODY.
Kushner
Jake A
JA
Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Ye
Jing
J
Schubert
Markus
M
Burks
Deborah J
DJ
Dow
Matthew A
MA
Flint
Carrie L
CL
Dutta
Sanjoy
S
Wright
Christopher V E
CV
Montminy
Marc R
MR
White
Morris F
MF
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D011972:Receptor, Insulin