Selective deletion of the Hnf1beta (MODY5) gene in beta-cells leads to altered gene expression and defective insulin release.
Hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF1beta (or vHNF1) are closely related transcription factors expressed in liver, kidney, gut, and pancreatic beta-cells. Many HNF1 target genes are involved in carbohydrate metabolism. Human mutations in HNF1alpha or HNF1beta lead to maturity-onset diabetes of the young (MODY3 and MODY5, respectively), and patients present with impaired glucose-stimulated insulin secretion. The underlying defect in MODY5 is not known. Analysis of HNF1beta deficiency in mice has not been possible because HNF1beta null mice die in utero. To examine the role of HNF1beta in glucose homeostasis, viable mice deleted for HNF1beta selectively in beta-cells (beta/H1beta-KO mice) were generated using a Cre-LoxP strategy. beta/H1beta-KO mice had normal growth, fertility, fed or fasted plasma glucose and insulin levels, pancreatic insulin content, and insulin sensitivity. However, beta/H1beta-KO mice exhibited impaired glucose tolerance with reduced insulin secretion compared with wild-type mice but preserved a normal insulin secretory response to arginine. Moreover, beta/H1beta-KO islets had increased HNF1alpha and Pdx-1, decreased HNF4 mRNA levels, and reduced glucose-stimulated insulin release. These results indicate that HNF1beta is involved in regulating the beta-cell transcription factor network and is necessary for glucose sensing or glycolytic signaling.
Wang
Li
L
Pediatric Endocrine Unit, MassGeneral Hospital for Children, Boston, Massachusetts 02114-2696, USA.
Coffinier
Catherine
C
Thomas
Melissa K
MK
Gresh
Lionel
L
Eddu
Ganiu
G
Manor
Tal
T
Levitsky
Lynne L
LL
Yaniv
Moshe
M
Rhoads
David B
DB
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D005951:Glucose Tolerance Test; D051539:Hepatocyte Nuclear Factor 1-beta; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496496:Hnf1b protein, mouse; D007328:Insulin; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta; D001120:Arginine