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Congenital hyperinsulinism
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Christopher A. Behr, Stephen E. Dolgin
While mutations in the genes affecting the KATP channel are implicated in 80%–90% of the identifiable causes of CH, the other 10%–20% of cases are caused by mutations in one of six different genes affecting other processes. The GLUD1 (encoding glutamate dehydrogenase enzyme), CGK (encoding glucokinase), HADH (encoding short-chain L-3-hydroxyacyl-CoA dehydrogenase), SLC16A1 (encoding a monocarboxylate transporter), and UCP2 (encoding UCP2 protein) genes all affect the ATP/ADP ratio within the beta cells, which determines the status of the KATP channel [4, 23–26]. Likewise, a transcription factor defect in the HNF4A (hepatocyte nuclear factor 4 alpha) gene has been shown to cause neonatal hyperinsulinemia [27]. All of these mutations result in the diffuse, usually mild, form of CH, and all are diazoxide responsive (except GCK, which has variable diazoxide responsiveness) (Figure 39.2).
Embryo/fetal–maternal cross talk
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Nuria Balaguer, Francisco Dominguez, Carlos Simón, Felipe Vilella
However, genetic mutations and environmental triggers are not sufficient to explain the pathogenesis and the rising incidence of cancer, obesity, and T2D. Epigenetic mechanisms (i.e., DNA methylation, histone, and noncoding RNA modification) may permanently modulate gene expression profiles in progeny during critical developmental windows wherein adverse parental nutrition has taken place (118). Einstein et al. (119) identified epigenetic modifications that link IUGR with T2D in adulthood. Specifically, they found that IUGR subjects were distinctive for having a number of consistent differences in methylation patterns near genes involved in critical processes for stem cell function, including cell cycle and cellular maintenance. Moreover, the results indicated that variation in methylation in the HNF4A promoter region may be responsible for diabetes onset later in life.
Carbohydrate metabolism
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
Maturity-onset diabetes of the young (MODY): – MODY 1: mutation of the hepatocyte nuclear factor (HNF4A) gene,– MODY 2: mutation of the glucokinase gene,– MODY 3: mutation of the HNF1A gene.Some cases are thought to be point mutations in mitochondrial deoxyribonucleic acid (DNA) associated with diabetes mellitus and deafness and are usually autosomal dominant.
A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism
Published in Drug Metabolism Reviews, 2022
Jianxin Yang, Xue Bai, Guiqin Liu, Xiangyang Li
HNF4A mutations cause pancreatic β-cell dysfunction, induce MODY1 (Yamagata et al. 1996), and may promote the development of type 2 diabetes (Gupta and Kaestner 2004). The mechanism might be due to the mutated HNF4α protein losing its ability to bind the HNF4α binding site, consequently leading to the abnormal expression of genes during glucose transport and glycolysis, and affecting the enterohepatic circulation of glucose and uptake into liver cells and insulin secretion by pancreatic β-cell (Stoffel and Duncan 1997; Gupta et al. 2005). To date, the Human Gene Mutation Database (HGMD) has reported more than 100 HNF4A mutations, of which single amino acid mutations are directly associated with MODY1 phenotypes. Several rare phenotypes, including hyperinsulinemia, hypoglycemia, and renal Fanconi syndrome, are also associated with HNF4A mutations (Cubuk and Yalcin 2021). Moreover, alverine and benfluorex are agonists of HNF4α, and these are well-known drugs that have been used to treat irritable bowel syndrome and type 2 diabetes, respectively (Lee et al. 2013). Benfluorex has been studied in clinical trials for type 2 diabetes and was proven to be effective in reducing hemoglobin A1c (Del et al. 2003; Moulin et al. 2006). Therefore, HNF4α agonists might be potential drugs to treat some metabolic diseases, such as diabetes, dyslipidemia, and cholestasis (Chiang 2009).
Metformin for diabetes prevention: update of the evidence base
Published in Current Medical Research and Opinion, 2021
The DPP group conducted a detailed analysis of genetic variants that affected study outcomes in the DPP29. Reduced risk of diabetes on metformin, but not in other treatment groups, was seen in subjects with vs. without the single nucleotide polymorphisms (SNPs) rs2453583 in the SLC47A1 and rs8065082gene (HRs 0.68 [0.54,0.86] and 0.78 [0.64, 0.96], respectively), and rs315978 in the LC22A1 gene (HR 0.67 [0.47, 0.96]); both of these genes encode metformin transporters. The presence of rs11086926 in the ABCC8 gene, which encodes the SUR sulphonylurea receptor (HR 0.79 [0.63, 0.98]) was also associated with a reduced risk of diabetes on metformin. Increased progression to diabetes was associated with SNPs rs11086926 of the HNF4a gene (hepatocyte nuclear factor 4a; HR 1.81 [1.35, 2.43]), rs10213440 of the PPARGC1A gene (a transcriptional coactivator involved in energy metabolism; HR 1.31 [1.03, 1.66]), rs4424892 of the MEF2A gene and rs6666307 of the MEF2D gene (both transcriptional regulator involved in the physiological response to exercise; HRs 1.31 [1.14, 1.80], and 2.15 [1.22,3.80], respectively).
Therapeutic Potential of HNF4α in End-stage Liver Disease
Published in Organogenesis, 2021
Ricardo Diaz-Aragon, Michael C. Coard, Sriram Amirneni, Lanuza Faccioli, Nils Haep, Michelle R. Malizio, Takashi Motomura, Zehra N. Kocas-Kilicarslan, Alina Ostrowska, Rodrigo M. Florentino, Carla Frau
Since alternative treatment options for ESLD are urgently needed, different approaches to treat ESLD are currently under investigation.7,8 Moroni et al.8 confirmed the safety of autologous macrophage transplantation for potential treatment of cirrhosis and other fibrotic diseases. One of the most promising methods is the exploration of liver-enriched transcription factors (LETFs). LETFs, along with transactivation factors, have a great influence on the maintenance of liver-specific gene transcription.9 Liu et al.10 reported the initial hypothesis, which described the role of hepatocyte-specific transcription factors in the development of ESLD.10,11 Interestingly, the expression of hepatocyte nuclear factor 4-alpha (HNF4α) was found to be directly correlated to liver disease in humans.10,12 HNF4α is a transcription factor that plays an important role in liver morphogenesis and maintenance of proper hepatocyte function in a mature liver.13–15 Most liver diseases have been associated with altered HNF4α expression, isoform ratios, and localization.16 Therefore, many studies have indicated that HNF4α may potentially be a target gene for the regression of fibrosis and cirrhosis.17,18 This review touches upon the functions and regulation of HNF4α in a healthy mature liver, as well as the role of HNF4α in liver disease, particularly in ESLD. Implementation of HNF4α as a key therapeutic target for future ESLD treatment is discussed as well.