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ANTIDIABETIC ACTIVITY OF Hypericum mysorense Heyne
Published in V. R. Mohan, A. Doss, P. S. Tresina, Ethnomedicinal Plants with Therapeutic Properties, 2019
V. Sornalakshmi, P. S. Tresina, K. Paulpriya, V. R. Mohan
Juvenile DM: Among several monogenic forms of DM which have been identified, maturity onset diabetes of the young (MODY) is a familial form of NIDDM with autosomal dominant inheritance, which usually develops in childhood, adolescence, or young adulthood, and presents primarily insulin secretion defects (Raffel et al., 1997). MODY is not a single entity, but involves genetic, metabolic, and clinical heterogeneity. Mutations in six genes cause most cases of MODY (MODY 1–MODY 6) (Horikawa et al., 1997; Malecki et al., 1999). The prevalence of MODY is unknown but about 2–5% of patients with type 2 diabetes may in fact have MODY (Lederman, 1995). The term juvenile onset diabetes has sometimes been used for IDDM and maturity onset for NIDDM (Bastaki, 2005).
Secondary Forms and Genetic Syndromes of Diabetes Mellitus
Published in Jack L. Leahy, Nathaniel G. Clark, William T. Cefalu, Medical Management of Diabetes Mellitus, 2000
Shirwan A. Mirza, Jack L. Leahy
The first MODY family to be extensively studied was the famous RW pedigree from the University of Michigan. The locus is on the long arm of chromosome 20 and was recently identified to be a mutation in the hepatic nuclear factor-4a (HNF-4a) gene, which is a beta-cell and liver transcription factor. MODY 1 is an uncommon form of MODY, which is characterized by severe insulin secretory dysfunction, so that patients typically end up taking insulin and may develop neuropathic and vascular diabetes complications.
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
Genome scans and linkage analysis have identified MODY 3 as the most common form of MODY worldwide. The mutated gene was recently identified as the transcription factor hepatic nuclear factor (HNF)-1α,396 which is involved in the regulation of several hepatic genes. In pancreatic cells, it is a weak transactivator of the insulin-I gene. The mutated gene in MODY 1 was identified as HNF-4α, a member of the steroid/thyroid hormone superfamily that regulates expression of HNF-1α.397 Late-onset NIDDM appears in some family members who carry the mutation.11 Homozygous transgenic mice lacking HNF-lα did not thrive and died around the time of weaning.398 However, although they suffered from phenylketonurea and renal tubular dysfunction, they had normal blood glucose levels. The response to an intravenous glucose infusion appeared normal, but since there was a massive glycosuria any diabetic state may have been masked. It is not known how mutations in the HNF-1α and HNF-4α genes result in diabetes when present on a single allele. It was postulated that partial deficiency may lead to β-cell dysfunction and diabetes, or mutations may cause diabetes by acting in a dominant-negative fashion.396 HNF-4α acts on regulatory elements and promoters of a number of genes the products of which are involved in cholesterol, fatty acid, amino acid, and glucose metabolism.399 In transgenic studies, HNF-4α+/− mice did not have diabetes or abnormal glucose tolerance, however loss of both genes resulted in early embryonic death due to dysfunction of the visceral endoderm in which it is expressed,399 preventing studies on these animals. In vitro studies by Stoffel and Duncan399 showed that mutant (Gln268X (nonsense)) HNF-4α protein does not bind to DNA-binding site as a homodimer or heterodimer. Several genes involved in glucose uptake and glycolysis were shown to be dependent upon HNF-4α, including GLUT-2, aldolase B, and glyceraldehyde-3-phosphate dehydrogenase. Deficient expression of these proteins in β-cells probably accounts for the altered insulin secretion in patients with MODY. It was also found that levels of HNF-1α mRNA were only slightly reduced by the complete absence of HNF-4α. Therefore, other pathways are presumably also involved in patients with MODY 1.
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
Hepatocyte nuclear factors (HNFs) are a class of transcription factors (TFs) of the Pit-Oct-Unc (POU) homeodomain family that regulate liver-specific gene expression. According to the different regions corresponding to functional domains of HNFs, four families are classified: namely HNF1, HNF3, HNF4, and HNF6 (Lau et al. 2018). HNF1 has two subtypes: HNF1α and HNF1β. HNF4, a member of the orphan nuclear receptor family, has two subtypes: HNF4α and HNF4γ. Both HNF4α and HNF1α can bind to DNA in the form of dimers and regulate nutrient and exogenous metabolism as well as cell homeostasis, proliferation, and apoptosis. The HNF4α and HNF1α genes were initially identified as mutated genes associated with maturity-onset diabetes of the young (MODY) 1 and MODY3; patients with both mutated genes may exhibit more severe diabetes symptoms (Forlani et al. 2010). Subsequently, the roles of HNF4α and HNF1α in various metabolic diseases, liver diseases, cancer, and other diseases and their potential as drug targets have gradually emerged.