BH3-Only protein bmf is required for the maintenance of glucose homeostasis in an in vivo model of HNF1α-MODY diabetes Shona L. Pfeiffer Luise Halang Heiko Düssmann Maria M. Byrne Jochen Prehn 10779/rcsi.10792649.v1 https://repository.rcsi.com/articles/journal_contribution/BH3-Only_protein_bmf_is_required_for_the_maintenance_of_glucose_homeostasis_in_an_in_vivo_model_of_HNF1_-MODY_diabetes/10792649 <p>Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1<em>α</em> (HNF-1<em>α</em>) gene can lead to diminished amounts of functional HNF-1<em>α</em>, 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-1<em>α</em> (DNHNF-1<em>α</em>) 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-1<em>α</em>-induced apoptosis. Through the knockout of <em>bmf</em> in a transgenic mouse model with DNHNF-1<em>α</em> suppression of HNF-1<em>α</em> 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-1<em>α</em>-induced beta-cell loss. Morphological analysis revealed an attenuation in beta-cell loss in <em>bmf</em>-deficient diabetic male mice and preserved insulin content. Surprisingly, <em>bmf</em> 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 <em>in vivo</em>.</p> 2019-11-22 17:03:04 BH3-Only protein glucose homeostasis HNF1α-MODY diabetes Physiology Medical Physics