# RFX6 expression is central to the development and function of the neuroendocrine compartments of the pancreas and intestine and strongly affects diabetes risk

**Authors:** Thomas S. R. Bate, Yuanhao Huang, Xin Luo, Diane C. Saunders, John T. Walker, Vivek Rai, Stephen C. J. Parker, Jie Liu, Marcela Brissova

PMC · DOI: 10.1007/s13340-025-00867-1 · Diabetology international · 2026-02-17

## TL;DR

The RFX6 gene plays a key role in the development of pancreatic and intestinal cells and is strongly linked to diabetes risk.

## Contribution

This paper reviews RFX6's role in development and diabetes, highlighting its potential for personalized diabetes treatment.

## Key findings

- RFX6 is essential for the differentiation of islet endocrine and enteroendocrine cells.
- Variants in RFX6 are associated with syndromic neonatal diabetes, MODY, and T2D.
- Understanding RFX6's regulatory role could lead to new diabetes treatments.

## Abstract

Transcription factors are central to the developmental and functional regulation of cells through co-ordination of gene expression via interaction with the genome. RFX6 is a winged-helix transcription factor whose expression is highly specific to the pancreas and gastrointestinal tract. Recent developments have highlighted an association between RFX6 and Type 2 Diabetes (T2D), which affects over 500 million people throughout the world. RFX6 controls development in both the pancreas and the gastrointestinal tract, where it is required for the differentiation of islet endocrine and enteroendocrine cells. Coding and non-coding RFX6 variants have been associated with syndromic neonatal diabetes (Mitchell-Riley Syndrome), Maturity Onset Diabetes of the Young (MODY), and T2D. Given the central position of RFX6 in pancreatic development and diabetes, understanding in more detail the regulatory role of RFX6 in different cell types and at different stages of development may open avenues towards patient-specific diabetes treatment and prevention. In this article, we review the literature surrounding RFX6 with respect to its role in development and diabetes pathogenesis.

## Linked entities

- **Genes:** RFX6 (regulatory factor X6) [NCBI Gene 222546]
- **Diseases:** Type 2 Diabetes (MONDO:0005148), Maturity Onset Diabetes of the Young (MONDO:0018911), MODY (MONDO:0018911)

## Full-text entities

- **Genes:** CDX2 (caudal type homeobox 2) [NCBI Gene 1045] {aka CDX-3, CDX2/AS, CDX3}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, GLP1R (glucagon like peptide 1 receptor) [NCBI Gene 2740] {aka GLP-1, GLP-1-R, GLP-1R}, SOX2 (SRY-box transcription factor 2) [NCBI Gene 6657] {aka ANOP3, MCOPS3}, Hnf4a (hepatic nuclear factor 4, alpha) [NCBI Gene 15378] {aka HNF-4, Hnf4, Hnf4alpha, MODY1, Nr2a1, TCF-14}, Cacna1d (calcium channel, voltage-dependent, L type, alpha 1D subunit) [NCBI Gene 12289] {aka 8430418G19Rik, Cach3, Cacn4, Cacnl1a2, Cav1.3, Cchl1a}, Pdx1 (pancreatic and duodenal homeobox 1) [NCBI Gene 18609] {aka IDX-1, IPF-1, Ipf1, Mody4, STF-1, pdx-1}, Cacna1a (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit) [NCBI Gene 12286] {aka APCA, BI, Caca1a, Cacnl1a4, Cav2.1, Ccha1a}, Cacnb2 (calcium channel, voltage-dependent, beta 2 subunit) [NCBI Gene 12296] {aka CAB2, Cavbeta2, Cchb2}, Neurod1 (neurogenic differentiation 1) [NCBI Gene 18012] {aka BETA2, BHF-1, Nd1, Neurod, bHLHa3}, Pax4 (paired box 4) [NCBI Gene 18506] {aka Pax-4}, PDX1 (pancreatic and duodenal homeobox 1) [NCBI Gene 3651] {aka GSF, IDX-1, IPF1, IUF1, MODY4, PAGEN1}, GIP (gastric inhibitory polypeptide) [NCBI Gene 2695], RFX6 (regulatory factor X6) [NCBI Gene 524074], Gcg (glucagon) [NCBI Gene 14526] {aka GLP-1, Glu, PPG}, ins.S (insulin S homeolog) [NCBI Gene 378696] {aka ins-a, ins-b, ins1, ins1-a, xins}, Plagl1 (pleiomorphic adenoma gene-like 1) [NCBI Gene 22634] {aka 2610311E24Rik, Lot1, Zac1}, NEUROG3 (neurogenin 3) [NCBI Gene 50674] {aka Atoh5, Math4B, NGN-3, bHLHa7, ngn3}, pdx1.L (pancreatic and duodenal homeobox 1 L homeolog) [NCBI Gene 108708702] {aka STF-1, XlHbox-8, XlHbox8, ipf1, pdx-1}, Chga (chromogranin A) [NCBI Gene 12652] {aka ChrA, cgA}, LDAH (lipid droplet associated hydrolase) [NCBI Gene 60526] {aka C2orf43, hLDAH}, Sst (somatostatin) [NCBI Gene 20604] {aka SOM, SRIF, SS, Smst}, CAT (catalase) [NCBI Gene 847], Arx (aristaless related homeobox) [NCBI Gene 11878] {aka Arx1}, RFX1 (regulatory factor X1) [NCBI Gene 5989] {aka EFC, RFX}, Gck (glucokinase) [NCBI Gene 103988] {aka GLK, Gk, Gls006, HK4, HKIV, HXKP}, SOX9 (SRY-box transcription factor 9) [NCBI Gene 6662] {aka CMD1, CMPD1, ENH13, SRA1, SRXX2, SRXY10}, Hnf1a (HNF1 homeobox A) [NCBI Gene 21405] {aka HNF1, HNF1-alpha, HNF1[a], Hnf-1, Hnf1alpha, LFB1}, sst.L (somatostatin, gene 1 L homeolog) [NCBI Gene 399212] {aka smst, som, sst, sst.1, sst.1.L, sst.2}, Abcc8 (ATP-binding cassette, sub-family C member 8) [NCBI Gene 20927] {aka D930031B21Rik, SUR1, Sur}, Jun (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 16476] {aka AP-1, Junc, c-jun}, Ptf1a (pancreas specific transcription factor, 1a) [NCBI Gene 19213] {aka PTF1-p48, PTF1p48, bHLHa29}, Gip (gastric inhibitory polypeptide) [NCBI Gene 14607], RFX6 (regulatory factor X6) [NCBI Gene 222546] {aka MTCHRS, MTFS, RFXDC1, dJ955L16.1}, Cacna1c (calcium channel, voltage-dependent, L type, alpha 1C subunit) [NCBI Gene 12288] {aka Cav1.2, Cchl1a1, D930026N18Rik, MBC, MELC-CC}, gcg.L (glucagon L homeolog) [NCBI Gene 373686] {aka gcg, gcg-A, gcg1}, Cdx2 (caudal type homeobox 2) [NCBI Gene 12591] {aka Cdx-2}, Rfx6 (regulatory factor X, 6) [NCBI Gene 320995] {aka 4930572O07Rik, Rfxdc1}, NKX6-1 (NK6 homeobox 1) [NCBI Gene 4825] {aka NKX6.1, NKX6A}, Ins1 (insulin I) [NCBI Gene 16333] {aka Ins-1, Ins2-rs1}, Neurog3 (neurogenin 3) [NCBI Gene 11925] {aka Atoh5, Math4B, bHLHa7, ngn3}, ptf1a.L (pancreas associated transcription factor 1a L homeolog) [NCBI Gene 100381084] {aka Ptf1a/p48, XPtf1a, ptf1a, ptf1a-a, ptf1a-b}, Nkx6-1 (NK6 homeobox 1) [NCBI Gene 18096] {aka NKX6A, Nkx6.1}, rfx6.L (regulatory factor X6 L homeolog) [NCBI Gene 100529153] {aka rfx6}, foxa2.L (forkhead box A2 L homeolog) [NCBI Gene 100127318] {aka FoxA2-A, FoxA2a, HNF-3B, foxa2, hnf3-beta, hnf3b}
- **Diseases:** gallbladder aplasia or hypoaplasia (MESH:C536482), Diabetes (MESH:D003920), pancreatic hypoplasia (MESH:D010195), intestinal atresia (MESH:D007409), autosomal recessive condition (MESH:D020763), prostate cancer (MESH:D011471), hypoplastic pancreas (MESH:D010190), developmental abnormalities (MESH:D006130), duodenal malrotation (MESH:D004382), Maturity Onset Diabetes of the Young (MESH:C562772), duodenal atresia (MESH:C535720), Young (MESH:C536718), gestational diabetes (MESH:D016640), obesity (MESH:D009765), diarrhoea (MESH:D003967), hypoglycemia (MESH:D007003), gastrointestinal aberrations (MESH:D005767), Mitchell-Riley Syndrome (MESH:C567570), PF (MESH:D001041), intestinal malabsorption (MESH:D008286), islet dysfunction (MESH:C531777), glucose (MESH:D018149), hypoplastic or annular pancreas (MESH:C536376), pancreatic agenesis (MESH:C564908), neonatal diabetes (MESH:C563322), Maturity-Onset Diabetes (MESH:D003924), atresia (MESH:D018633), T1D (MESH:D003922)
- **Chemicals:** ADP (MESH:D000244), fat (MESH:D005223), doxycycline (MESH:D004318), blood glucose (MESH:D001786), 3-isobutyl-1-methylxanthine (MESH:D015056), Ca2+ (-), KCl (MESH:D011189), glucose (MESH:D005947), calcium (MESH:D002118), ATP (MESH:D000255)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Danio rerio (leopard danio, species) [taxon 7955], Xenopus laevis (African clawed frog, species) [taxon 8355], Bos taurus (bovine, species) [taxon 9913]
- **Mutations:** c.1129C > T, rs10090154, p.Ser217Phe, p.R652X
- **Cell lines:** STC-1 — Homo sapiens (Human), Lung small cell carcinoma, Cancer cell line (CVCL_3171), EndoC-betaH2 — Homo sapiens (Human), Conditionally immortalized cell line (CVCL_IS71), L- — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0462), K- — Clarias batrachus (Walking catfish), Spontaneously immortalized cell line (CVCL_S935), H9 — Homo sapiens (Human), Sezary syndrome, Cancer cell line (CVCL_1240)

## Full text

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## References

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Source: https://tomesphere.com/paper/PMC12913827