Liver cirrhosis and diabetes: they might share more “early” mechanisms than expected

Around 28 million people in the U.S. have type-2 diabetes, characterized by high blood sugar levels, a condition that can lead to many other health problems, including heart disease, stroke and kidney failure. Cirrhosis is one of the leading causes of death worldwide and is marked by liver fibrosis — a buildup of scar tissue on the liver. In a pair of related studies, a team of Yale researchers has found a way to reverse type-2 diabetes and liver fibrosis in mice and has shown that the underlying processes are conserved in humans. The studies appear in the Feb. 4 edition of Cell Reports and in the Jan. 17 edition of Nature Communications. In the earlier study, researchers found an important connection between how the body responds to fasting and type-2 diabetes. Fasting “switches on” a process in the body in which two particular proteins, TET3 and HNF4 increase in the liver, driving up production of blood glucose. In type-2 diabetes, this “switch” fails to turn off when fasting ends, as it would in a non-diabetic person. HNF-4α controls intestinal epithelium homeostasis and intestinal absorption of dietary lipids. HNF-4γ, the other HNF-4 form highly expressed in intestine.

Previously, another scientists team demonstrated that genetic ablation of this isoform in the intestine improved glucose tolerance as like the alpha isoform would be ablated in the liver. HNF-4α gene has two regions as promoters for transcription, P1 and P2. The P2 region is active during the embryonal stage, while the P1 takes over after birth. And here is where TET3 seems to intervene: this protein demethylates some regions in the HNF-4α gene and allow the expression of the embrional transcription. Researchers hypothesized that if they could “knock down” the levels of these two proteins, they could stop diabetes from developing. Dr. Huang and team injected mice with genetic material known as small interfering RNAs (siRNAs) packaged inside viruses that targeted TET3 or HNF4. They found that blood glucose and insulin dropped significantly, effectively stopping diabetes in its tracks. In the Cell Reports study, researchers looked at how TET3 contributed to the development of fibrosis in the liver, and found that the protein was involved in fibrosis on multiple levels. Almost all fibrosis in every organ starts from abnormal protein signaling.

The team discovered that TET3 plays a role in the fibrosis signaling pathway in three different locations — and acts as an important regulator in fibrosis development. TET3 associated physically with another transcription factor FoxA2, which allow the transcription of HNF-4α through the P2 promoter region, exactly as it would do in the embryo. This phenomenon is particularly active when cells are stimulated with glucagone, the antagonist of insulin. This means there are likely opportunities to develop drugs that inhibit TET3 to slow or reverse fibrosis.  Both diseases — type-2 diabetes and fibrosis of the liver and other organs — are common, but have few treatment options. Researchers noted that several drugs, such as metformin, are currently available to control blood sugar levels in patients with diabetes. But these have a range of unpleasant side effects, and patients can develop resistance to these drugs; beside, there is little medical relief for fibrosis sufferers. The next step will be to identify where to best target TET3 and HNF4 and to develop the most effective siRNAs or small molecules to treat type-2 diabetes or fibrosis.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Da Li et al., Huang Y. Nat Commun. 2020 Jan 17; 11(1):342. 

Yuan EF et al., Liu SM. Clin Epigenetics. 2019 Apr; 11(1):63. 

Zhao S et al., Chen G. Front Immunol. 2018 Dec 6; 9:2859. 

Informazioni su Dott. Gianfrancesco Cormaci 2113 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it