HNF1A Mutations and Beta Cell Dysfunction in Diabetes

Miyachi, Yukihisa; Miyazawa, Takashi; Ogawa, Yoshihiro

doi:10.3390/ijms23063222

Cited by 26 publications

(15 citation statements)

References 161 publications

(189 reference statements)

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“…HNF1α is a known transcriptional regulator (Miyachi et al 2022); thus, to investigate the mechanisms underlying islet phenotypes detailed above, we performed RNA sequencing (RNA-seq) to characterize the β cell transcriptome after HNF1A loss (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

HNF1α transcriptional activation and repression maintain human islet α and β cell function

Qian

Bevacqua

Nguyen

et al. 2022

Preprint

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HNF1A haploinsufficiency underlies the most common form of human monogenic diabetes (HNF1A-MODY) and hypomorphic HNF1A variants confer type 2 diabetes risk, but a lack of experimental systems has limited our understanding of how the transcription factor HNF1α regulates adult human islet function. Here, we combined human islet genetics, RNA sequencing, Cleavage Under Targets & Release Using Nuclease (CUT&RUN) chromatin mapping, patch-clamp electrophysiology and transplantation-based assays to elucidate HNF1α-regulated mechanisms in mature pancreatic α and β cells. shRNA-mediated suppression of HNF1A in primary human pseudoislets led to blunted insulin output and dysregulated glucagon secretion both in vitro and after transplantation into immunocompromised mice, recapitulating phenotypes observed in HNF1A-MODY patients. These deficits corresponded with altered expression of genes encoding factors critical for hormone secretion, including calcium channel subunits, ATP-transporters and extracellular matrix constituents. Additionally, HNF1A loss led to upregulation of transcriptional repressors, providing evidence for a mechanism of transcriptional de-repression through HNF1α. CUT&RUN mapping of HNF1α DNA-binding sites in primary human islets verified that a subset of HNF1α-regulated genes were direct targets. These data provide unprecedented mechanistic links between HNF1A loss and diabetic phenotypes in mature human α and β cells.

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Section: Resultsmentioning

confidence: 99%

HNF1α transcriptional activation and repression maintain human islet α and β cell function

Qian

Bevacqua

Nguyen

et al. 2022

Preprint

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“…This information may be useful for clarifying the molecular evolution of the hnf1 gene and also functional evolution of the vertebrate liver. Because the inactivation of Hnf1a and Hnf1b in mice results roughly in hepatic functional impairment and biliary abnormality, respectively (El‐Khairi & Vallier, 2016; Miyachi et al, 2022), hnf1 may also regulate hepatic functions in hepatocytes, and biliary epithelial integrity in biliary cells of the hagfish. The question of how hnf1 can work in hepatocytes or biliary cells having different signaling cascades to perform their respective functions is intriguing.…”

Section: Discussionmentioning

confidence: 99%

Gene expression in the liver of the hagfish (Eptatretus burgeri) belonging to the Cyclostomata is ancestral to that of mammals

Ota,

Kato,

Shiojiri

2023

The Anatomical Record

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Although the liver of the hagfish, an earliest diverged lineage among vertebrates, has a histological architecture similar to that of mammals, its gene expression has not been explored yet. The present study was undertaken to comparatively characterize gene expression in the liver of the hagfish with that of the mouse, using in situ hybridization technique. Expression of alb (albumin) was detectable in all hepatocytes of the hagfish liver, but was negative in intrahepatic bile ducts. Their expression in abundant periportal ductules was weak. The expression pattern basically resembled that in mammalian livers, indicating that the differential expression of hepatocyte markers in hepatocytes and biliary cells may have been acquired in ancestral vertebrates. alb expression was almost homogeneous in the hagfish liver, whereas that in the mouse liver lobule was zonal. The glul (glutamate–ammonia ligase) expression was also homogeneously detectable in hepatocytes without zonation, and weakly so in biliary cells of the hagfish, which contrasted with its restricted pericentral expression in mouse livers. These findings indicated that the hagfish liver did not have mammalian‐type zonation. Whereas tetrapods had Hnf (hepatocyte nuclear factor) 1a and Hnf1b genes encoding the transcription factors, the hagfish had a single gene of their orthologue hnf1. Although HNF1α and HNF1β were immunohistochemically detected in hepatocytes and biliary cells of the mouse, respectively, hnf1 was expressed in both hepatocytes and biliary cells of the hagfish. These data indicate that gene expression of hnf1 in the hagfish liver may be ancestral with that of alb and glul during vertebrate evolution.

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“…Single genes cause diabetes resulting in a decreased production of insulin hormone in the beta cells [ 1 ]. Global research on the genetics of diabetes has focused on SNPs and gene mutations in nuclear and mitochondrial DNA as well as in different ethnic groups [ 53 ]. Amanda and colleagues’ pilot study on SNPs found that 26 SNPs are linked to T2DM in Hispanic adults [ 54 ].…”

Section: Diabetes In Hispanic and Latino Communitiesmentioning

confidence: 99%

Support Provided by Caregivers for Community-Dwelling Diabetic Hispanic Adults with Intellectual Disabilities and Comorbid Conditions

Rawat

Sehar

Bisht

et al. 2023

IJMS

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Diabetes is an age-related chronic health condition and a major public health concern. Diabetes is one of the significant causes of morbidity and mortality and a major contributing factor to dementia. Recent research reveals that Hispanic Americans are at an increased risk of chronic conditions such as diabetes, dementia, and obesity. Recent research also revealed that diabetes develops at least ten years earlier in Hispanics and Latinos than in neighboring non-Hispanic whites. Furthermore, the management of diabetes and providing necessary/timely support is a challenging task for healthcare professionals. Caregiver support is an emerging area of research for people with diabetes, mainly family caregiver support work for Hispanic and Native Americans. Our article discusses several aspects of diabetes, factors associated with diabetes among Hispanics, its management, and how caregivers can support individuals with diabetes.

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HNF1A Mutations and Beta Cell Dysfunction in Diabetes

Cited by 26 publications

References 161 publications

HNF1α transcriptional activation and repression maintain human islet α and β cell function

HNF1α transcriptional activation and repression maintain human islet α and β cell function

Gene expression in the liver of the hagfish (Eptatretus burgeri) belonging to the Cyclostomata is ancestral to that of mammals

Support Provided by Caregivers for Community-Dwelling Diabetic Hispanic Adults with Intellectual Disabilities and Comorbid Conditions

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