Human Islet MicroRNA-200c is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion

The genetics of Type 2 diabetes a complex metabolic disorder, characterized by decreased insulin secretion and insulin resistance resulting in impaired blood glucose homeostasis remains enigma for geneticists. In 2006 an important step while finding genetic causes of diabetes type 2 was identification of transcription factor 7-like 2 (TCF7L2) gene an important marker in predisposition of type 2 diabetes in almost all ethnic population. Recent genetic research identifies numerous novel type 2 diabetes susceptible genes among these genes TCF7L2 is considered as gang head and emerged as the most promising types 2 diabetes causing gene. Risk variants in TCF7L2 effects pancreatic beta cell development and insulin secretion by influencing Wnt Signaling pathway. Genetic variants in TCF7L2 confer risk for type 2 diabetes by altering expression of transcription factor (which has key role in blood glucose regulation) in pancreas. The purpose of this paper is to evaluate type 2 diabetes susceptible gene the TCF7L2 and to present a comprehensive review of studies carried out worldwide in different ethnic population on association of TCF7L2 polymorphism with type 2 diabetes.

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Evaluation of sequence variants in the pre-B cell leukemia transcription factor 1 gene: A positional and functional candidate for type 2 diabetes and impaired insulin secretion

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2005.07.008 ◽

2005 ◽

Vol 86 (3) ◽

pp. 384-391 ◽

Cited By ~ 5

Author(s):

Hua Wang ◽

Winston Chu ◽

Xiaoqin Wang ◽

Zhengxian Zhang ◽

Steven C. Elbein

Keyword(s):

Type 2 Diabetes ◽

Transcription Factor ◽

Insulin Secretion ◽

B Cell ◽

Sequence Variants ◽

Cell Leukemia ◽

Impaired Insulin ◽

B Cell Leukemia ◽

Transcription Factor 1

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Polymorphism of Transcription Factor 7-Like 2 Gene and HOMA-β Level of Individuals With and Without Type 2 Diabetes Mellitus Family History

Indonesian Journal of Biotechnology ◽

10.22146/ijbiotech.9312 ◽

2016 ◽

Vol 19 (2) ◽

pp. 176

Author(s):

Waode Astria Sahrani ◽

Indwiani Astuti ◽

Ahmad Hamim Sadewa

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Transcription Factor ◽

Insulin Secretion ◽

Family History ◽

Model Assessment ◽

Tcf7l2 Gene ◽

Type 2 Dm

Family history has considered as a risk factor of type 2 diabetes. Transcription factor-7 like 2 (TCF7L2) hasrole to regulates insulin secretion and blood glucose homeostasis. The aim of current study was to determine thers7903146 polymorphism of TCF7L2 gene and homeostatic model assessment-β (HOMA-β) level on individual withand without type 2 Diabetes Mellitus (DM) family history. This work is a case-control study. Thirty six subjectswith type 2 DM family history and 36 subjects without type 2 DM family history were recruited. HOMA-βmeasure to analyze the insulin secretion. Polymorphisms of TCF7L2 gene was analyzed by using PCR-RFLPmethod. Statistical analysis was performed by using T-test, Mann-Whitney and Chi-square with signifi cancelevel 0.05. The frequency of the T allele of the cases were 4.2% and the controls were 2.8% (p=0.500). The oddratio was 0.649 (CI;95%:0.106-4.055). The HOMA-β levels of the cases were signifi cant low (132.56±62.48)compared with the controls (266.09±1.68) with p=0.000. The subjects with type 2 DM family history have asimilar frequency of having T alleles and CT/TT genotypes. The subjects with type 2 DM family history hassignifi cantly lower HOMA-β levels than subject without DM family history.

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Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion

Diabetologia ◽

10.1007/s00125-007-0656-6 ◽

2007 ◽

Vol 50 (6) ◽

pp. 1192-1200 ◽

Cited By ~ 117

Author(s):

J. Wang ◽

J. Kuusisto ◽

M. Vänttinen ◽

T. Kuulasmaa ◽

J. Lindström ◽

...

Keyword(s):

Type 2 Diabetes ◽

Transcription Factor ◽

Insulin Secretion ◽

Diabetes Prevention ◽

Glucose Regulation ◽

Impaired Glucose Regulation ◽

Tcf7l2 Gene ◽

Prevention Study ◽

Impaired Insulin

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Human Islet MicroRNA-200c is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion

10.2337/figshare.16903927.v1 ◽

2021 ◽

Author(s):

Jones K. Ofori ◽

Alexandros Karagiannopoulos ◽

Mototsugu Nagao ◽

Efraim Westholm ◽

Shaima Ramadan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Transcription Factor ◽

Insulin Secretion ◽

Pearson Correlation ◽

Human Islets ◽

Vital Role ◽

Luciferase Assay ◽

Identify Transcription Factor ◽

Glucose Stimulated Insulin Secretion

MicroRNAs (miRNAs) are part of deregulated insulin secretion in type 2 diabetes (T2D) development. Rodent models have suggested miR-200c to be involved, but the role and potential as therapeutic target of this miRNA in human islets is not clear. Here we report increased expression of miR-200c in islets from T2D as compared with non-diabetic (ND) donors and display results showing reduced glucose-stimulated insulin secretion in EndoC-βH1 cells overexpressing miR-200c. We identify transcription factor ETV5 as the top rank target of miR-200c in human islets using TargetScan in combination with Pearson correlation analysis of miR-200c and mRNA expression data from the same human donors. Among other targets were JAZF1, as earlier shown in miR-200 knockout mice. Accordingly, linear model analysis of ETV5 and JAZF1 gene expression showed reduced expression of both genes in islets from human T2D donors. Western blot analysis confirmed the reduced expression of ETV5 on protein level in EndoC-βH1 cells overexpressing miR-200c and Luciferase assay validated ETV5 as a direct target of miR-200c. Finally, LNA knockdown of miR-200c (LNA200c) increased glucose-stimulated insulin secretion in islets from T2D donors ~3-fold. Our data reveal a vital role of the miR-200c-ETV5 axis in beta cell dysfunction and pathophysiology of T2D.

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Human Islet MicroRNA-200c is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion

10.2337/figshare.16903927 ◽

2021 ◽

Author(s):

Jones K. Ofori ◽

Alexandros Karagiannopoulos ◽

Mototsugu Nagao ◽

Efraim Westholm ◽

Shaima Ramadan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Transcription Factor ◽

Insulin Secretion ◽

Pearson Correlation ◽

Human Islets ◽

Vital Role ◽

Luciferase Assay ◽

Identify Transcription Factor ◽

Glucose Stimulated Insulin Secretion

MicroRNAs (miRNAs) are part of deregulated insulin secretion in type 2 diabetes (T2D) development. Rodent models have suggested miR-200c to be involved, but the role and potential as therapeutic target of this miRNA in human islets is not clear. Here we report increased expression of miR-200c in islets from T2D as compared with non-diabetic (ND) donors and display results showing reduced glucose-stimulated insulin secretion in EndoC-βH1 cells overexpressing miR-200c. We identify transcription factor ETV5 as the top rank target of miR-200c in human islets using TargetScan in combination with Pearson correlation analysis of miR-200c and mRNA expression data from the same human donors. Among other targets were JAZF1, as earlier shown in miR-200 knockout mice. Accordingly, linear model analysis of ETV5 and JAZF1 gene expression showed reduced expression of both genes in islets from human T2D donors. Western blot analysis confirmed the reduced expression of ETV5 on protein level in EndoC-βH1 cells overexpressing miR-200c and Luciferase assay validated ETV5 as a direct target of miR-200c. Finally, LNA knockdown of miR-200c (LNA200c) increased glucose-stimulated insulin secretion in islets from T2D donors ~3-fold. Our data reveal a vital role of the miR-200c-ETV5 axis in beta cell dysfunction and pathophysiology of T2D.

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