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.
Highlights
Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic, non-insulin-dependent diabetes mellitus, characterized by autosomal dominant transmission and the development of severe hyperglycemia generally before the age of 25 years.[1]
In order to examine the role of Bcl-2-modifying factor (Bmf) in the progressive beta-cell deletion of bmf did not appear to have any effect on wild-type dysfunction attributed to excessive beta-cell apoptosis observed in HNF1A-maturity-onset diabetes of the young (MODY), we introduced a bmf deficiency in a transgenic (WT) pancreatic sections that developed normally, displaying the typical islet architecture[27] in both bmf-expressing (Figure 1b) and mouse model suppressed hepatocyte nuclear factor 1α (HNF-1α) function in the pancreatic bmf-deficient (Figure 1d) wild type (WT) groups
Progressive beta-cell dysfunction and cell death, with impaired glucose-stimulated insulin secretion response and resulting hyperglycemia, is the hallmark and primary cause of diabetes and chronic related complications observed in hepatocyte nuclear factor 1α (HNF1α)-MODY patients
Summary
Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic, non-insulin-dependent diabetes mellitus, characterized by autosomal dominant transmission and the development of severe hyperglycemia generally before the age of 25 years.[1]. HNF-1α is a dimeric, homeodomain-containing transcription factor involved in the control of expression of a wide variety of tissue-specific genes in the kidney, liver, spleen, intestine and pancreas, such as glucose transporter (Glut2) and insulin in the pancreatic beta-cell.[3,4,5,6,7] Mutations the HNF-1α protein can lead to diminished amounts of functional HNF-1α through either haploinsufficiency or a dominant-negative mechanism and onset of the HNF1α-MODY phenotype.[3,8,9] Several in vitro and in vivo models of various forms of MODY have been established utilizing these mutations to further elucidate the molecular mechanisms and progressive beta-cell dysfunction attributed to excessive betacell apoptosis observed in HNF1α-MODY.[10,11,12]
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