Abstract
Diabetes, a disease characterized by hyperglycemia, has a serious impact on the lives and families of patients as well as on society. Diabetes is a group of highly heterogeneous metabolic diseases that can be classified as type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM), or other according to the etiology. The clinical manifestations are more or less similar among the different types of diabetes, and each type is highly heterogeneous due to different pathogenic factors. Therefore, distinguishing between various types of diabetes and defining their subtypes are major challenges hindering the precise treatment of the disease. T2D is the main type of diabetes in humans as well as the most heterogeneous. Fortunately, some studies have shown that variants of certain genes involved in monogenic diabetes also increase the risk of T2D. We hope this finding will enable breakthroughs regarding the pathogenesis of T2D and facilitate personalized treatment of the disease by exploring the function of the signal genes involved. Hepatocyte nuclear factor 1 homeobox A (HNF1α) is widely expressed in pancreatic β cells, the liver, the intestines, and other organs. HNF1α is highly polymorphic, but lacks a mutation hot spot. Mutations can be found at any site of the gene. Some single nucleotide polymorphisms (SNPs) cause maturity-onset diabetes of the young type 3 (MODY3) while some others do not cause MODY3 but increase the susceptibility to T2D or GDM. The phenotypes of MODY3 caused by different SNPs also differ. MODY3 is among the most common types of MODY, which is a form of monogenic diabetes mellitus caused by a single gene mutation. Both T2D and GDM are multifactorial diseases caused by both genetic and environmental factors. Different types of diabetes mellitus have different clinical phenotypes and treatments. This review focuses on HNF1α gene polymorphisms, HNF1A-MODY3, HNF1A-associated T2D and GDM, and the related pathogenesis and treatment methods. We hope this review will provide a valuable reference for the precise and individualized treatment of diabetes caused by abnormal HNF1α by summarizing the clinical heterogeneity of blood glucose abnormalities caused by HNF1α mutation.
Highlights
According to the International Diabetes Federation (IDF), there were approximately 463 million adults with diabetes worldwide in 2019
We found that HNF1a single nucleotide polymorphisms (SNPs) related to glycosuria were mainly concentrated in the dimer domain and DNA binding domain of HNF1a (Table 3), indicating that HNF1a regulates the transcription of genes that control the renal glucose threshold along with other transcription factors, likely by forming a dimer with HNF1b to regulate the genes involved in glucose transport
The expression of high-sensitivity C-reactive protein (hsCRP) in gestational diabetes mellitus (GDM) patients is higher than that in HNF1A-MODY patients [84]. This finding indicates that GDM caused by HNF1a results in the same susceptibility to diabetes as the type 2 diabetes (T2D) variant, but insufficient penetrance leads to clinical MODY
Summary
According to the International Diabetes Federation (IDF), there were approximately 463 million adults with diabetes worldwide in 2019. A single HNF1a gene mutation is the cause of MODY3, environmental factors play a role in its pathogenesis. Two diabetic patients and one individual with normal plasma glucose levels in this family were homozygous mutation carriers.
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