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The pathophysiology of diabetes
Published in Janet Titchener, Diabetes Management, 2020
Monogenic diabetes encompasses a heterogeneous group of diabetes that, as the name implies, are caused by a single gene defect or chromosomal abnormality within the β-cell resulting in impaired insulin secretion.16 Monogenic diabetes includes MODY (maturity-onset diabetes of the young), neonatal diabetes and mitochondrial diabetes. Multiple genetic mutations have now been identified resulting in many different types of monogenic diabetes. However, four types of monogenic diabetes, associated with mutations in the HNF1A, HNF1B, HNF4A and GCK genes, account for 90% of all cases.
Endocrine and reproductive disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
With insulin resistance a feature of the disorder, molecular defects in the insulin molecule or its receptor might have been expected, but these have been found only in a few individuals. The rare MODY (maturity-onset diabetes of the young) form with juvenile onset, which appears to follow autosomal dominant inheritance (although with incomplete penetrance), has been linked to the glucokinase locus in some families, with specific mutations found in this gene, and more frequently in the hepatocyte nuclear factor-1-α (HNF1A) gene, as well as less commonly in others. MODY appears to make up about 1% of all T2D, although MODY may be more accurately seen as distinct from T2D and, in any case, heterogeneous. Other susceptibility loci have so far proved too inconsistent to use in practice. Variants in the mitochondrial genome have also been found in some families showing maternal transmission.
Endocrinology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Mehul Dattani, Catherine Peters
Correct diagnosis is important. Patients with mutations in the glucokinase gene rarely require treatment and are not at increased risk of diabetic complications. Those with mutations in HNF1a and HNF4a may respond to sulphonylurea treatment.
Stereotactic radiofrequency ablation as a valid first-line treatment option for hepatocellular adenomas
Published in International Journal of Hyperthermia, 2022
Gregor Laimer, Peter Schullian, Yannick Scharll, Daniel Putzer, Gernot Eberle, Georg Oberhuber, Reto Bale
In this study, we demonstrated that SRFA is a safe and effective treatment option for large and multifocal HCAs. Hemorrhage and malignant transformation are two major potential complications of HCAs. While the risk for hemorrhage is significantly high at 27.2% per patient and 15.8% per tumor [6], the reported risk for malignant transformation is relatively low at 4.2% [26]; although the probability is 10 times more in men than in women [27]. Risk factors for hemorrhage include increasing tumor size and recent (within six months) hormonal usage [28]. In our study, we did not observe mortality, instances of malignant transformation, or adenoma-related hemorrhages during a median follow-up of 49.6 months. These findings are in line with the findings of similar studies and case reports on the thermal ablation of HCAs [11,29–32]. Histological subtypes may play an important role in the risk of malignant transformation/hemorrhage. HCA can be classified into inflammatory, HNF-1α inactivated, β-Catenin activated, and unclassified. The inflammatory and β-Catenin activated types have a higher risk of hemorrhage and malignant transformation, respectively. In contrast, the HNF1-α inactivated type is reported to have a lower risk for both complications [33,34]. However, the limited number of (or missing in the case of HNF1-α) histological subtypes in our study precludes us from analyzing their influence on patient outcomes or complication risks.
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
The HNF1 family contains HNF1α and HNF1β. HNF1α is predominantly expressed in the human liver, followed by the ileum, renal cortex, testis, renal medulla, colon, subcutaneous fat, visceral fat, adrenal gland, aorta, and other tissues (Chen et al. 2020). The HNF1A gene on chromosome 12 encodes HNF1α. The protein structure of HNF1α consists of three domains (Figure 1), including an N-terminal dimerization binding domain, a DBD, and a C-terminal transactivation domain. The DBD is a highly conserved homeodomain with a 21-amino acid peptide inserted between α-helix 2 and 3 (Begum 2020). The N-terminal is a conserved POUs domain unique to the POU family, the C-terminal is a traditional POUh homeodomain, and a peptide connects the POUs and POUh domains. Unlike other POU TFs, HNF1α and HNF1β bind to DNA only in the dimer form, thus greatly increasing the complexity and diversity of their functions.
The role of sulfonylureas in the treatment of type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2022
Brian Tomlinson, Nivritti Gajanan Patil, Manson Fok, Paul Chan, Christopher Wai Kei Lam
Maturity-onset diabetes of the young (MODY) due to dominant mutations in one of at least 13 different genes occurs in <5% of people with diabetes and usually manifests before the age of 25 years [116,117]. MODY3 caused by mutations in the gene for hepatocyte nuclear factor 1 α (HNF1A) is the most common form of MODY, accounting for more than half the cases of MODY. Patients with this condition and with MODY1 caused by mutations in HNF1A and MODY12 caused by mutations in ABCC8 are extremely sensitive to sulfonylureas, which are considered first-line therapy in these patients [117–119]. Patients with HNF1A MODY had a 5.2-fold greater reduction in fasting plasma glucose with gliclazide than with metformin and 3.9-fold greater response to gliclazide than those patients with T2D [120].