HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus

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.

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY)

“…Both mutations, described also as an SNP, have been shown to cause decreased transcriptional activity of HNF1A (55,56). It is known, some mutations in the HNF1A gene cause MODY3, whereas other mutations do not cause MODY3 but significantly increase the risk of type 2 diabetes, and some of them GDM (57). Confusingly, some HNF1A mutations are observed in both MODY3 and type 2 diabetes, in which case the age of onset is used for differential diagnosis.…”

Pleiotropic Influence of DNA Methylation QTLs on physiological and aging traits

“…109,110 However, direct deletion of Hnf1a in mice, or deleterious mutations in HNF1A in humans, do not appear to confer any lifespan advantage despite the mice having a form of Laron dwarfism and humans have lower BMI. [91][92][93][94][95] We suggest that HNF1A, in addition to its role as a TF for developmental and metabolic genes, also influences the epigenome early in life, and contributes to epigenomic maintenance in adulthood and aging. We present a model in which the meQTL.5a locus exerts horizontal pleiotropic effects on physiological traits and CpG methylation.…”

“…85 Some mutations in HNF1A do not cause MODY but increase the susceptibility to type 2 diabetes and lower BMI. 91,92 In mice, deletion of Hnf1a causes Laron dwarfism and hyperglycemia. [93][94][95] Although HNF1A is not a direct regulator of DNAm, there is some intriguing evidence that it contributes to the epigenetic state.…”

Leveraging the strengths of mice, human stem cells, and organoids to model pancreas development and diabetes

“…A similar example of species-specific differences can be found in the transcription factor HNF1a. Heterozygous mutations in this gene lead to MODY3, the most common form of monogenic diabetes (36,37) and while these mutations can be modeled using hPSC derived b cells (38) inducing similar mutations in mice does not affect b cell development or function (39). While both GATA6 and HNF1a are highly evolutionarily conserved, these examples highlight that there are still species-specific disease modifiers that need to be addressed.…”