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BH3-Only protein bmf is required for the maintenance of glucose homeostasis in an in vivo model of HNF1 α -MODY diabetes

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

bmf knockout increases non-fasting blood glucose levels. Non-fasted blood glucose levels were measured at 3- (a), 6- (b) and 10-week-old (c) male and female (d) mice. Transgenic DNHNF-1α mice deficient in bmf demonstrated increased blood glucose at 10 weeks compared with matched bmf-expressing transgenic DNHNF-1α controls in both colonies. Data presented as mean±S.E.M. from n=5–10 per group. *P<0.05 compared with litter-matched controls; #P<0.05 compared with matched bmf-expressing controls (ANOVA, post hoc Tukey’s test).
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fig4: bmf knockout increases non-fasting blood glucose levels. Non-fasted blood glucose levels were measured at 3- (a), 6- (b) and 10-week-old (c) male and female (d) mice. Transgenic DNHNF-1α mice deficient in bmf demonstrated increased blood glucose at 10 weeks compared with matched bmf-expressing transgenic DNHNF-1α controls in both colonies. Data presented as mean±S.E.M. from n=5–10 per group. *P<0.05 compared with litter-matched controls; #P<0.05 compared with matched bmf-expressing controls (ANOVA, post hoc Tukey’s test).

Mentions: Non-fasted blood glucose levels were monitored over a 10-week period. While no difference was observed in 3-week males (Figure 4a), by 6 weeks a significantly increased blood glucose level was apparent in both DNHNF-1α bmf-expressing (16.9±2.8 mmol/l) and bmf-deficient (17.9±2.0 mmol/l) groups compared with WT controls (8.5±0.6 and 9.3±1.2 mmol/l, respectively); no distinguishable difference was observed between bmf-deficient and bmf-expressing control groups (Figure 4b). By 10 weeks, deletion of bmf significantly worsened already high blood glucose levels in DNHNF-1 bmf−/− mice (22.9±2.3 mmol/l) compared with DNHNF-1αbmf+/+ control group (16.5±0.8 mmol/l) despite the rescue in beta-cell mass (Figure 4c).


BH3-Only protein bmf is required for the maintenance of glucose homeostasis in an in vivo model of HNF1 α -MODY diabetes
bmf knockout increases non-fasting blood glucose levels. Non-fasted blood glucose levels were measured at 3- (a), 6- (b) and 10-week-old (c) male and female (d) mice. Transgenic DNHNF-1α mice deficient in bmf demonstrated increased blood glucose at 10 weeks compared with matched bmf-expressing transgenic DNHNF-1α controls in both colonies. Data presented as mean±S.E.M. from n=5–10 per group. *P<0.05 compared with litter-matched controls; #P<0.05 compared with matched bmf-expressing controls (ANOVA, post hoc Tukey’s test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4979461&req=5

fig4: bmf knockout increases non-fasting blood glucose levels. Non-fasted blood glucose levels were measured at 3- (a), 6- (b) and 10-week-old (c) male and female (d) mice. Transgenic DNHNF-1α mice deficient in bmf demonstrated increased blood glucose at 10 weeks compared with matched bmf-expressing transgenic DNHNF-1α controls in both colonies. Data presented as mean±S.E.M. from n=5–10 per group. *P<0.05 compared with litter-matched controls; #P<0.05 compared with matched bmf-expressing controls (ANOVA, post hoc Tukey’s test).
Mentions: Non-fasted blood glucose levels were monitored over a 10-week period. While no difference was observed in 3-week males (Figure 4a), by 6 weeks a significantly increased blood glucose level was apparent in both DNHNF-1α bmf-expressing (16.9±2.8 mmol/l) and bmf-deficient (17.9±2.0 mmol/l) groups compared with WT controls (8.5±0.6 and 9.3±1.2 mmol/l, respectively); no distinguishable difference was observed between bmf-deficient and bmf-expressing control groups (Figure 4b). By 10 weeks, deletion of bmf significantly worsened already high blood glucose levels in DNHNF-1 bmf−/− mice (22.9±2.3 mmol/l) compared with DNHNF-1αbmf+/+ control group (16.5±0.8 mmol/l) despite the rescue in beta-cell mass (Figure 4c).

View Article: PubMed Central - PubMed

ABSTRACT

Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1&alpha; (HNF-1&alpha;) gene can lead to diminished amounts of functional HNF-1&alpha;, 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&alpha; (DNHNF-1&alpha;) 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&alpha;-induced apoptosis. Through the knockout of bmf in a transgenic mouse model with DNHNF-1&alpha; suppression of HNF-1&alpha; 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&alpha;-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.

No MeSH data available.


Related in: MedlinePlus