China
Africa
Explore chapters and articles related to this topic
Neuroendocrine Interactions in the Control of Glucose- and Energy Homeostasis
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
In the last decade, strong evidence linked the WNT/β-catenin pathway to the pathogenesis of type 2 diabetes and other metabolic disorders. A 2006 genome-wide association study identified a link between polymorphisms in the TCF7l2 gene, a transcription factor of the WNT pathway, and the risk of type 2 diabetes (103). Out of all common genetic mutations implicated in T2DM, TCF7l2 is most significantly associated with disease susceptibility. Another GWAS-identified risk gene for T2DM is Cyclin-dependent Kinase 5 Regulatory Subunit-Associated Protein 1-like 1 (CDKAL1) (104). Interestingly, CDKAL1 increases protein levels of β-catenin and its active unphosphorylated form in the nucleus, thereby promoting Wnt target gene expression, suggesting that CDKAL1 activates canonical WNT signalling (105). Finally, a recent report showed that R-spondin-3 (RSPO3), which has previously been implicated by a GWAS as a risk gene for increased BMI and insulin resistance (106), regulates energy homeostasis in association with WNT signalling (107). Together, these studies strongly suggest a role for canonical WNT signalling in the regulation of energy homeostasis.
Type 2 Diabetes in Childhood
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
T2D in youth is far more common in subjects with a family history of the disease. By some estimates, 75%–100% of pediatric patients diagnosed with T2D have a first- or second-degree family member with T2D. The high concordance rate among monozygotic twins also supports the strong influence of genetic factors. Extrapolating genetic data for pediatric T2D has been challenging owing to a lack of research on the topic. With the advent of genome-wide association studies (GWAS), however, much information has been gained in recent years. GWAS data suggest that the same susceptibility genes involved in progression to T2D in adults are involved in pediatrics [26]. Currently, over 800 genes have been implicated. Progression to T2D involves genetic dysregulation in weight gain, IR, and beta-cell growth, survival, and function. GWAS have highlighted 40 loci in particular. The transcription factor 7-like 2 (TCF7L2) gene appears to be the most important T2D susceptibility gene identified to date, with linkage to all ethnicities affected by T2D, with the exception of Native Americans. TCF7L2 is thought to affect beta-cell function and insulin release. Individuals with prediabetes and a variant in TCF7L2 have up to 70% risk of progressing to T2D within 5 years [26]. Despite the improved technology involved in GWAS, much remains unknown about the genetics involved in T2D. Rare genetic variants are not picked up by GWAS and may be responsible. Epigenetic phenomena, characterized by chemical alteration of gene expression without change in gene sequence, may also contribute.
Genetics of diabetic pregnancy
Published in Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, 2018
Single-nucleotide polymorphisms (SNPs) in the TCF7L2 gene have been associated with a significantly higher risk of T2DM in several different populations.43,44 The TCF7L2 gene, located on chromosome 10q25.3, is a transcription factor that acts through regulation of pro-glucagon gene expression.45 When compared to noncarriers, the relative risk of T2DM was 1.45 for heterozygotes of the at-risk allele and 2.41 for homozygotes of the at-risk allele.44 Individuals with impaired glucose tolerance and the TCF7L2 gene variant were more likely to progress to diabetes over 3 years than those without the variant (HR 1.55, CI 1.2–2).46 Analysis in GDM also suggested an increased risk of GDM in individuals with TCF7L2 variant (OR 1.653, 95% CI 1.416–1.930).47
Single nucleotide polymorphisms in treatment of polycystic ovary syndrome: a systematic review
Published in Drug Metabolism Reviews, 2019
Ritu Deswal, Smiti Nanda, Amita Suneja Dang
Transcription factor 7-like 2 (TCF7L2) is expressed by pancreatic β-cells. Insulin secretion is reduced in those with the risk alleles suggesting a predominant role of TCF7L2 on β-cell function and risk of diabetes type 2. There is considerable interindividual variation in the hypoglycemic response to sulfonylureas used widely to treat diabetes type 2. Carriers of risk alleles at rs7903146 would have a poorer hypoglycemic response to sulfonylureas due to decreased β-cell function compared with individuals lacking these alleles (Holstein et al. 2011). A variety of medications with different mechanisms of action have been developed for controlling glycemic index in diabetes type 2 patients. There are still uncertainties about the optimal insulin treatment regimens, but long-acting insulin analogs seem beneficial. Trials showed that both insulin and insulin analogs are equally effective in lowering A1c and have comparable risk of hypoglycemia (Giugliano et al. 2016).
The Association between Genetic Variation in Wnt Transcription Factor TCF7L2 (TCF4) and Alopecia Areata
Published in Immunological Investigations, 2019
Fateme Rajabi, Mahsa M. Amoli, Reza M Robati, Mina Almasi-Nasrabadi, Navid Jabalameli, Hamideh Moravvej
The involvement of TCF7L2 in the pathogenesis of AA may also be explained by its role in regulating dendritic cells. Studies have suggested that dendritic cells are responsible for the strong IFNα signature in the lesional skin in AA (Abou Rahal et al., 2016; Ghoreishi et al., 2010), and they are probably involved in mediating the beneficial effects of contact sensitizers in the treatment of AA (Daman et al., 1978; Gupta et al., 2006). The β-catenin signaling pathway is suggested to have a prime role in phenotypic changes of dendritic cells via inducing the transcription of a set of target genes (Suryawanshi et al., 2015). Thus variation in the structure and function of the TCF7L2, perhaps due to genetic polymorphisms, could lead to a great impact on the cellular functions that ultimately affects the immune system.
TCF7L2 Expression Is Regulated by Cell Differentiation and Overfeeding in Human Adipose Tissue
Published in Endocrine Research, 2019
Louise Justesen, Rasmus Ribel-Madsen, Linn Gillberg, Ninna S. Hansen, Anne Louise Wulff, Louise G. Grunnet, Charlotte Brøns
The genetic variant rs7903146 in TCF7L2 has been shown to have the largest effect on type 2 diabetes risk as reported in genome-wide association studies.1,2 The variant is located in an intron of TCF7L2, and this genomic region was recently shown to constitute an enhancer for the neighboring ACSL5, which encodes a member of the long-chain acyl-CoA synthetases.3 The TCF7L2 protein acts as a transcription factor and is involved in the Wnt signaling pathway. The transcription factor is highly expressed in a variety of glucose sensing and metabolically important tissues including pancreatic islets, liver, brain and adipose tissue.4–6 Studies suggest that members of the Wnt signaling pathway play important roles in homeostasis of adipose tissue by inhibiting the differentiation of adipose tissue progenitor cells.7–9 The type 2 diabetes risk T-allele rs7903146 is associated with increased expression of TCF7L2 in pancreatic islets compared to the non-risk C-allele.10 The clinical phenotype of risk T-allele carriers has mostly been related to impaired insulin secretion. However, although the human literature is limited, some studies have suggested a role of rs7903146 in peripheral and hepatic insulin resistance11–14, whereas another study found no association.15 Furthermore, a recent study in adolescents who had undergone a hyperinsulinemic eugycemic clamp showed that suppression of the endogenous hepatic glucose production was lower in subjects with the TCF7L2 rs7903146 risk variant.16 Increased TCF7L2 expression in pancreatic beta cells impairs insulin processing and release, whereas increased TCF7L2 expression in hepatocytes suppresses hepatic glucose production.10,11