title: BH3-Only protein bmf is required for the maintenance of glucose homeostasis in an in vivo model of HNF1α-MODY diabetes.
abstract: Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1α (HNF-1α) gene can lead to diminished amounts of functional HNF-1α, resulting in the onset of a particularly severe form of maturity-onset diabetes of the young (MODY). We have previously shown that induction of a dominant-negative mutant of HNF-1α (DNHNF-1α) results in the activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), preceding the onset of apoptosis and the induction of pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor) as a mediator of DNHNF-1α-induced apoptosis. Through the knockout of bmf in a transgenic mouse model with DNHNF-1α suppression of HNF-1α function in pancreatic beta-cells, this study aimed to examine the effect of loss-of-function of this BH3-only protein on the disease pathology and progression, and further elucidate the role of Bmf in mediating DNHNF-1α-induced beta-cell loss. Morphological analysis revealed an attenuation in beta-cell loss in bmf-deficient diabetic male mice and preserved insulin content. Surprisingly, bmf deficiency was found to exacerbate hyperglycemia in both diabetic male and hyperglycemic female mice, and ultimately resulted in a decreased glucose-stimulated insulin response, implicating a role for Bmf in glucose homeostasis regulation independent of an effect on beta-cell loss. Collectively, our data demonstrate that Bmf contributes to the decline in beta-cells in a mouse model of HNF1A-MODY but is also required for the maintenance of glucose homeostasis in vivo.
authors.affiliation: Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland , 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Pfeiffer
authors.affiliation: Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland , 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: L
authors.initials: L
authors.lastname: Halang
authors.affiliation: Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland , 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: H
authors.initials: H
authors.lastname: Düssmann
authors.affiliation: Department of Endocrinology, Mater Misericordiae University Hospital , 30 Eccles Street, Dublin 7, Ireland.
authors.forename: M M
authors.initials: MM
authors.lastname: Byrne
authors.affiliation: Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland , 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Jhm
authors.initials: J
authors.lastname: Prehn