2161-P: Overexpression of UCP2 in Pancreatic Beta Cells Caused Impaired Insulin Secretion through Mitochondrial Dysfunction and Aldolase B Expression

Background. Mutations in human KLF11 may lead to the development of maturity-onset diabetes of the young 7 (MODY7). This occurs due to impaired insulin synthesis in the pancreas. To date, the clinical and functional characteristics of the novel KLF11 mutation c.1061G > T have not yet been reported. Methods. Whole-exon sequencing was used to screen the proband and family members with clinical suspicion of the KLF11 variant. Luciferase reporter assays were used to investigate whether the KLF11 variant binds to the insulin promoter. Real-time PCR, western blotting, and glucose-stimulated insulin secretion (GSIS) analysis were used to analyze the KLF11 variant that regulates insulin expression and insulin secretion activity in beta cell lines. The Freestyle Libre H (Abbott Diabetes Care Ltd) was used to dynamically monitor the proband daily blood glucose levels. Results. Mutation screening for the whole exon genes identified a heterozygous KLF11 (c.1061G > T) variant in the proband, her mother, and her maternal grandfather. Cell-based luciferase reporter assays using wild-type and mutant transgenes revealed that the KLF11 (c.1061G > T) variant had impaired insulin promoter regulation activity. Moreover, this variant was found to impair insulin expression and insulin secretion in pancreatic beta cells. The proband had better blood glucose control without staple food intake ( p < 0.05 ). Conclusions. Herein, for the first time, we report a novel KLF11 (c.1061G > T) monogenic mutation associated with MODY7. This variant has impaired insulin promoter regulation activity and impairs insulin expression and secretion in pancreatic beta cells. Therefore, administering oral antidiabetic drugs along with dietary intervention may benefit the proband.

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Mitochondrial Dysfunction Contributes to Impaired Insulin Secretion in INS-1 Cells with Dominant-negative Mutations of HNF-1α and in HNF-1α-deficient Islets

Journal of Biological Chemistry ◽

10.1074/jbc.m807723200 ◽

2009 ◽

Vol 284 (25) ◽

pp. 16808-16821 ◽

Cited By ~ 22

Author(s):

Rebecca L. Pongratz ◽

Richard G. Kibbey ◽

Clare L. Kirkpatrick ◽

Xiaojian Zhao ◽

Marco Pontoglio ◽

...

Keyword(s):

Insulin Secretion ◽

Mitochondrial Dysfunction ◽

Dominant Negative ◽

Impaired Insulin Secretion ◽

Impaired Insulin ◽

Dominant Negative Mutations

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Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes

Human Molecular Genetics ◽

10.1093/hmg/ddu288 ◽

2014 ◽

Vol 23 (21) ◽

pp. 5733-5749 ◽

Cited By ~ 27

Author(s):

Vladimir V. Sharoyko ◽

Mia Abels ◽

Jiangming Sun ◽

Lisa M. Nicholas ◽

Ines Guerra Mollet ◽

...

Keyword(s):

Insulin Secretion ◽

Mitochondrial Dysfunction ◽

Impaired Insulin Secretion ◽

Impaired Insulin

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Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

Nutrients ◽

10.3390/nu13093017 ◽

2021 ◽

Vol 13 (9) ◽

pp. 3017

Author(s):

Jingya Lyu ◽

Kensaku Fukunaga ◽

Hitomi Imachi ◽

Seisuke Sato ◽

Toshihiro Kobayashi ◽

...

Keyword(s):

Insulin Secretion ◽

Pancreatic Beta Cells ◽

Oxidized Ldl ◽

Specific Inhibitor ◽

Density Lipoprotein ◽

Dependent Manner ◽

Cholesterol Accumulation ◽

Impaired Insulin Secretion ◽

Abca1 Expression ◽

Impaired Insulin

Impaired insulin secretion is one of the main causes of type 2 diabetes. Cholesterol accumulation-induced lipotoxicity contributes to impaired insulin secretion in pancreatic beta cells. However, the detailed mechanism in this process remains unclear. In this study, we proved that oxidized low-density lipoprotein (OxLDL) reduced insulin content, decreased PDX-1 expression, and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells, which were rescued by addition of high-density lipoprotein (HDL). OxLDL receptors and cholesterol content were increased by OxLDL. Consistently, OxLDL suppressed cholesterol transporter ABCA1 expression and transcription in a dose-dependent and time-dependent manner. Inhibition of MEK by its specific inhibitor, PD98059, altered the effect of OxLDL on ABCA1 transcription and activation of ERK. Next, chromatin immunoprecipitation assay demonstrated that liver X receptor (LXR) could directly bind to ABCA1 promoter and this binding was inhibited by OxLDL. Furthermore, OxLDL decreased the nuclear LXR expression, which was prevented by HDL. LXR-enhanced ABCA1 transcription was suppressed by OxLDL, and the effect was cancelled by mutation of the LXR-binding sites. In summary, our study shows that OxLDL down-regulates ABCA1 expression by MEK/ERK/LXR pathway, leading to cholesterol accumulation in INS-1 cells, which may result in impaired insulin synthesis and GSIS.

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