Limits...
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

Deletion of bmf expression decreases serum glucose-stimulated insulin secretion. The change in serum insulin from fasting levels was determined at 0 and 15 min after i.p.GTT in male 3- (a and b) and 10-week-old mice (c and d) fasted for 16 h. Homeostasis model was used to assess insulin resistance (HOMA-IR) during intraperitoneal glucose tolerance test. Data are presented as the mean change in insulin levels±S.E.M. n=6-7 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

License
getmorefigures.php?uid=PMC4979461&req=5

fig6: Deletion of bmf expression decreases serum glucose-stimulated insulin secretion. The change in serum insulin from fasting levels was determined at 0 and 15 min after i.p.GTT in male 3- (a and b) and 10-week-old mice (c and d) fasted for 16 h. Homeostasis model was used to assess insulin resistance (HOMA-IR) during intraperitoneal glucose tolerance test. Data are presented as the mean change in insulin levels±S.E.M. n=6-7 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: Despite beta-cell preservation, the observed lack of corollary effect on glucose homeostasis led us to examine whether deletion of bmf in beta-cells leads to a specific insulin secretion defect. Basal and secreted insulin at 15 min was therefore also assessed in response to glucose challenge. Although no difference in fasted insulin levels was observed at 3 weeks, deletion of bmf did not confer any improvement in DNHNF-1α-decreased insulin response levels in DNHNF-1αbmf−/− or WTbmf−/− mice (P=1.0 compared with DNHNF-1αbmf+/+; Figures 6a and b). By 10 weeks, bmf deficiency remained ineffectual in having an impact on decreased insulin secretion observed in DNHNF-1αbmf+/+ (1.1±0.02 μg/l) and DNHNF-1αbmf−/− (1.1±0.03 μg/l) and was also observed to decrease glucose-stimulated insulin secretion in WTbmf−/− (1.1±0.04 μg/l) compared with WTbmf+/+control (1.3±0.06 μg/l; P=0.01 for all groups compared with WTbmf+/+; Figure 6c). Calculation of the HOMA index of degree of insulin resistance (HOMA-IR) demonstrated decreased insulin sensitivity in transgenic DNHNF-1αbmf+/+ mice (13.2±3.2) compared with WTbmf+/+ (7.3±1.5), not rescued by deletion of bmf (DNHNF-1αbmf−/−P=1.0, WTbmf−/−P=0.7).


BH3-Only protein bmf is required for the maintenance of glucose homeostasis in an in vivo model of HNF1 α -MODY diabetes
Deletion of bmf expression decreases serum glucose-stimulated insulin secretion. The change in serum insulin from fasting levels was determined at 0 and 15 min after i.p.GTT in male 3- (a and b) and 10-week-old mice (c and d) fasted for 16 h. Homeostasis model was used to assess insulin resistance (HOMA-IR) during intraperitoneal glucose tolerance test. Data are presented as the mean change in insulin levels±S.E.M. n=6-7 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

License
Show All Figures
getmorefigures.php?uid=PMC4979461&req=5

fig6: Deletion of bmf expression decreases serum glucose-stimulated insulin secretion. The change in serum insulin from fasting levels was determined at 0 and 15 min after i.p.GTT in male 3- (a and b) and 10-week-old mice (c and d) fasted for 16 h. Homeostasis model was used to assess insulin resistance (HOMA-IR) during intraperitoneal glucose tolerance test. Data are presented as the mean change in insulin levels±S.E.M. n=6-7 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: Despite beta-cell preservation, the observed lack of corollary effect on glucose homeostasis led us to examine whether deletion of bmf in beta-cells leads to a specific insulin secretion defect. Basal and secreted insulin at 15 min was therefore also assessed in response to glucose challenge. Although no difference in fasted insulin levels was observed at 3 weeks, deletion of bmf did not confer any improvement in DNHNF-1α-decreased insulin response levels in DNHNF-1αbmf−/− or WTbmf−/− mice (P=1.0 compared with DNHNF-1αbmf+/+; Figures 6a and b). By 10 weeks, bmf deficiency remained ineffectual in having an impact on decreased insulin secretion observed in DNHNF-1αbmf+/+ (1.1±0.02 μg/l) and DNHNF-1αbmf−/− (1.1±0.03 μg/l) and was also observed to decrease glucose-stimulated insulin secretion in WTbmf−/− (1.1±0.04 μg/l) compared with WTbmf+/+control (1.3±0.06 μg/l; P=0.01 for all groups compared with WTbmf+/+; Figure 6c). Calculation of the HOMA index of degree of insulin resistance (HOMA-IR) demonstrated decreased insulin sensitivity in transgenic DNHNF-1αbmf+/+ mice (13.2±3.2) compared with WTbmf+/+ (7.3±1.5), not rescued by deletion of bmf (DNHNF-1αbmf−/−P=1.0, WTbmf−/−P=0.7).

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