scholarly journals Transcription factor 7-like 2 (TCF7L2): a culprit gene in Type 2 Diabetes Mellitus

2021 ◽  
Vol 24 (4) ◽  
pp. 371-376
Author(s):  
A. Jan ◽  
H. Jan ◽  
Z. Ullah
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Insulin Secretion ◽  
Blood Glucose ◽  
Pancreatic Beta Cell ◽  
Genetic Research ◽  
Wnt Signaling Pathway ◽  
Diabetes Type 2 ◽  
Ethnic Population

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.

scholarly journals The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis

2012 ◽  
Vol 303 (9) ◽  
pp. E1166-E1176 ◽  
Author(s):  
Wilfred Ip ◽  
Weijuan Shao ◽  
Yu-ting Alex Chiang ◽  
Tianru Jin
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Wnt Signaling ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Hepatic Gluconeogenesis

Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and β-catenin (β-cat) form the bipartite transcription factor cat/TCF in stimulating Wnt target gene expression. cat/TCF may also mediate the effect of other signaling cascades, including that of cAMP and insulin in cell-type specific manners. As carriers of TCF7L2 type 2 diabetes risk SNPs demonstrated increased hepatic glucose production, we aimed to determine whether TCF7L2 expression is regulated by nutrient availability and whether TCF7L2 and Wnt regulate hepatic gluconeogenesis. We examined hepatic Wnt activity in the TOPGAL transgenic mouse, assessed hepatic TCF7L2 expression in mice upon feeding, determined the effect of insulin on TCF7L2 expression and β-cat Ser675 phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepatocytes. Wnt activity was observed in pericentral hepatocytes in the TOPGAL mouse, whereas TCF7L2 expression was detected in human and mouse hepatocytes. Insulin and feeding stimulated hepatic TCF7L2 expression in vitro and in vivo, respectively. In addition, insulin activated β-cat Ser675 phosphorylation. Wnt activation by intraperitoneal lithium injection repressed hepatic gluconeogenic gene expression in vivo, whereas lithium or Wnt-3a reduced gluconeogenic gene expression and glucose production in hepatic cells in vitro. Small interfering RNA-mediated TCF7L2 knockdown increased glucose production and gluconeogenic gene expression in cultured hepatocytes. These observations suggest that Wnt signaling and TCF7L2 are negative regulators of hepatic gluconeogenesis, and TCF7L2 is among the downstream effectors of insulin in hepatocytes.

scholarly journals Role of standard test meal in initiation of insulin therapy in type 2 diabetes

2009 ◽  
Vol 137 (9-10) ◽  
pp. 490-496
Author(s):  
Branka Koprivica ◽  
Teodora Beljic-Zivkovic ◽  
Tatjana Ille
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Insulin Secretion ◽  
Glycaemic Control ◽  
Combination Therapy ◽  
Diabetes Type 2 ◽  
Diabetes Type ◽  
Standard Meal ◽  
Target Values

Introduction Secondary monotherapy failure in diabetes mellitus type 2 occurs early in the course of disease. Choosing the optimal combination therapy depends on the primary pathogenic mechanism. Evaluation of the residual beta cell function is of primary importance in deciding whether insulin should be included in the combination therapy. Objective To investigate the influence of standard meal test and homeostasis model assessment (HOMA-B) index, as markers of residual insulin secretion, on the efficacy of two different therapeutic strategies in secondary sulphonylurea (SU) failure. Methods In the group of thirty subjects with diabetes type 2, metabolic syndrome and secondary SU failure, metformin (MET) was added for the following six months. In the group of 30 subjects with diabetes type 2, secondary SU failure, with no metabolic syndrome, insulin (INS) was added for the same period. During the six-month follow-up period, fasting, postprandial, mean daily blood glucose and glycosylated haemoglobin (HbA1C) were evaluated. Fasting and meal stimulated C-peptide (CP) and insulin levels were measured at the beginning; absolute and relative increase of CP (delta CP, delta CP%), and HOMA-B were calculated. Correlation between CP secretion and HOMA-B at the beginning and glycaemic control after six months of therapy were evaluated by using Pearson correlation coefficient. Results Glycaemic control after six months was significantly improved in both therapeutic combinations (p<0.01). However, target values were not met in either group. Stimulated CP levels correlated best with all the parameters of glycaemic control in the group SU+MET (r -0.479 to -0.791; p<0.01), and in the group SU+INS (r 0.382 to 0.635; p<0.01). HOMA-B correlated only with HbA1C in the SU+MET group (r=-0.382; p<0.05). Conclusion Clinical diagnosis of metabolic syndrome and evaluation of residual insulin secretion are necessary in choosing the best combination therapy in secondary SU failure in subjects with type 2 diabetes. Stimulated standard meal CP level is a clinically useful marker of residual insulin secretion.

scholarly journals L-Tryptophan Suppresses Rise in Blood Glucose and Preserves Insulin Secretion in Type-2 Diabetes Mellitus Rats

2012 ◽  
Vol 58 (6) ◽  
pp. 415-422 ◽  
Author(s):  
Tomoko INUBUSHI ◽  
Norio KAMEMURA ◽  
Masataka ODA ◽  
Jun SAKURAI ◽  
Yutaka NAKAYA ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Blood Glucose

scholarly journals Sorcin stimulates Activation Transcription Factor 6α (ATF6) transcriptional activity

2020 ◽  
Author(s):  
Steven Parks ◽  
Tian Gao ◽  
Natalia Jimenez Awuapura ◽  
Joseph Ayathamattam ◽  
Pauline L. Chabosseau ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Beta Cell ◽  
Er Stress ◽  
Transcriptional Activity ◽  
Pancreatic Beta Cell ◽  
Mrna Levels ◽  
High Fat ◽  
Insulin Promoter

ABSTRACTLevels of the transcription factor ATF6α, a key mediator of the unfolded protein response, that provides cellular protection during the progression endoplasmic reticulum (ER) stress, are markedly reduced in the pancreatic islet of patients with type 2 diabetes and in rodent models of the disease, including ob/ob and high fat-fed mice. Sorcin (gene name SRI) is a calcium (Ca2+) binding protein involved in maintaining ER Ca2+ homeostasis.We have previously shown that overexpressing sorcin under the rat insulin promoter in transgenic mice was protective against high fat diet-induced pancreatic beta cell dysfunction, namely preserving intracellular Ca2+ homeostasis and glucose-stimulated insulin secretion during lipotoxic stress. Additionally, sorcin overexpression was apparently activating ATF6 signalling in MIN6 cells despite lowering ER stress.Here, in order to investigate further the relationship between sorcin and ATF6, we describe changes in sorcin expression during ER and lipotoxic stress and changes in ATF6 signalling after sorcin overexpression or inactivation, both in excitable and non-excitable cells.Sorcin mRNA levels were significantly increased in response to the ER stress-inducing agents thapsigargin and tunicamycin, but not by palmitate. On the contrary, palmitate caused a significant decrease in sorcin expression as assessed by both qRT-PCR and Western blotting despite inducing ER stress. Moreover, palmitate prevented the increase in sorcin expression induced by thapsigargin. In addition, sorcin overexpression significantly increased ATF6 transcriptional activity, whereas sorcin inactivation decreased ATF6 signalling. Finally, sorcin overexpression increased levels of ATF6 immunoreactivity and FRET imaging experiments following ER stress induction by thapsigargin showed a direct sorcin-ATF6 interaction.Altogether, our data suggest that sorcin down-regulation during lipotoxicity may prevent full ATF6 activation and a normal UPR during the progression of obesity and insulin resistance, contributing to beta cell failure and type 2 diabetes.

scholarly journals Two decades since the fetal insulin hypothesis: what have we learned from genetics?

Diabetologia ◽  
2021 ◽  
Author(s):  
Alice E. Hughes ◽  
Andrew T. Hattersley ◽  
Sarah E. Flanagan ◽  
Rachel M. Freathy
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Later Life ◽  
Fat Distribution ◽  
Ample Evidence ◽  
Lower Birthweight

AbstractIn 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease. Graphical abstract

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

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.

scholarly journals Saliva 1,5-anhydroglucitol is associated with early-phase insulin secretion in Chinese patients with type 2 diabetes

2021 ◽  
Vol 9 (1) ◽  
pp. e002199
Author(s):  
Lingwen Ying ◽  
Chaohui Jian ◽  
Xiaojing Ma ◽  
Kun Ge ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Area Under The Curve ◽  
Chinese Patients ◽  
Model Assessment ◽  
Homeostasis Model Assessment ◽  
C Peptide

IntroductionSaliva collection is a non-invasive test and is convenient. 1,5-anhydroglucitol (1,5-AG) is a new indicator reflecting short-term blood glucose levels. This study aimed to explore the relationship between saliva 1,5-AG and insulin secretion function and insulin sensitivity.Research design and methodsAdult patients with type 2 diabetes who were hospitalized were enrolled. Based on blood glucose and C-peptide, homeostasis model assessment 2 for β cell secretion function, C-peptidogenic index (CGI), △2-hour C-peptide (2hCP)/△2-hour postprandial glucose (2hPG), ratio of 0–30 min area under the curve for C-peptide and area under the curve for glucose (AUCCP30/AUCPG30), and AUC2hCP/AUC2hPG were calculated to evaluate insulin secretion function, while indicators such as homeostasis model assessment 2 for insulin resistance were used to assess insulin sensitivity.ResultsWe included 284 subjects (178 men and 106 women) with type 2 diabetes aged 20–70 years. The saliva 1,5-AG level was 0.133 (0.089–0.204) µg/mL. Spearman’s correlation analysis revealed a significantly negative correlation between saliva 1,5-AG and 0, 30, and 120 min blood glucose, glycated hemoglobin A1c, and glycated albumin (all p<0.05), and a significantly positive association between saliva 1,5-AG and CGI (r=0.171, p=0.004) and AUCCP30/AUCPG30 (r=0.174, p=0.003). The above correlations still existed after adjusting for age, sex, body mass index, and diabetes duration. In multiple linear regression, saliva 1,5-AG was an independent factor of CGI (standardized β=0.135, p=0.015) and AUCCP30/AUCPG30 (standardized β=0.110, p=0.020).ConclusionsSaliva 1,5-AG was related to CGI and AUCCP30/AUCPG30 in patients with type 2 diabetes.Trial registration numberChiCTR-SOC-17011356.

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