PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance.
Inadequate compensatory beta cell hyperplasia in insulin-resistant states triggers the development of overt diabetes. The mechanisms that underlie this crucial adaptive response are not fully defined. Here we show that the compensatory islet-growth response to insulin resistance in 2 models--insulin receptor (IR)/IR substrate-1 (IRS-1) double heterozygous mice and liver-specific IR KO (LIRKO) mice--is severely restricted by PDX-1 heterozygosity. Six-month-old IR/IRS-1 and LIRKO mice both showed up to a 10-fold increase in beta cell mass, which involved epithelial-to-mesenchymal transition. In both models, superimposition of PDX-1 haploinsufficiency upon the background of insulin resistance completely abrogated the adaptive islet hyperplastic response, and instead the beta cells showed apoptosis resulting in premature death of the mice. This study shows that, in postdevelopmental states of beta cell growth, PDX-1 is a critical regulator of beta cell replication and is required for the compensatory response to insulin resistance.
Kulkarni
Rohit N
RN
Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA. Kulkarni@joslin.harvard.edu
Jhala
Ulupi S
US
Winnay
Jonathon N
JN
Krajewski
Stan
S
Montminy
Marc
M
Kahn
C Ronald
CR
D000375:Aging / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D002455:Cell Division; D018398:Homeodomain Proteins / Q000235:genetics; D006965:Hyperplasia; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology / Q000473:pathology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
D001786:Blood Glucose; D002096:C-Peptide; D018398:Homeodomain Proteins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein