Trends Pharmacol Sci. 2023 May 13;S0165-6147(23)00087-1. doi: 10.1016/j.tips.2023.04.004. 

Striking a gut-liver balance for the antidiabetic effects of metformin

Emma Barroso ¹, Marta Montori-Grau ¹, Walter Wahli ², Xavier Palomer ¹, Manuel Vázquez-Carrera ³

Abstract

Metformin is the most prescribed drug for the treatment of type 2 diabetes mellitus (T2DM), but its mechanism of action has not yet been completely elucidated. Classically, the liver has been considered the major site of action of metformin. However, over the past few years, advances have unveiled the gut as an additional important target of metformin, which contributes to its glucose-lowering effect through new mechanisms of action. A better understanding of the mechanistic details of metformin action in the gut and the liver and its relevance in patients remains the challenge of present and future research and may impact drug development for the treatment of T2DM. Here, we offer a critical analysis of the current status of metformin-driven multiorgan glucose-lowering effects.

• PMID: 37188578
• DOI: 10.1016/j.tips.2023.04.004

Epigenetics Chromatin. 2023 May 19;16(1):19. doi: 10.1186/s13072-023-00493-8.

Premature ovarian insufficiency is associated with global alterations in the regulatory landscape and gene expression in balanced X-autosome translocations

Adriana Di-Battista ^# 1 2, Bianca Pereira Favilla ^# 1, Malú Zamariolli ¹, Natália Nunes ¹, Alexandre Defelicibus ³, Lucia Armelin-Correa ⁴, Israel Tojal da Silva ³, Alexandre Reymond ^# 2, Mariana Moyses-Oliveira ^# 1 5, Maria Isabel Melaragno ^# 6

Abstract

Background: Patients with balanced X-autosome translocations and premature ovarian insufficiency (POI) constitute an interesting paradigm to study the effect of chromosome repositioning. Their breakpoints are clustered within cytobands Xq13-Xq21, 80% of them in Xq21, and usually, no gene disruption can be associated with POI phenotype. As deletions within Xq21 do not cause POI, and since different breakpoints and translocations with different autosomes lead to this same gonadal phenotype, a “position effect” is hypothesized as a possible mechanism underlying POI pathogenesis.

Objective and methods: To study the effect of the balanced X-autosome translocations that result in POI, we fine-mapped the breakpoints in six patients with POI and balanced X-autosome translocations and addressed gene expression and chromatin accessibility changes in four of them.

Results: We observed differential expression in 85 coding genes, associated with protein regulation, multicellular regulation, integrin signaling, and immune response pathways, and 120 differential peaks for the three interrogated histone marks, most of which were mapped in high-activity chromatin state regions. The integrative analysis between transcriptome and chromatin data pointed to 12 peaks mapped less than 2 Mb from 11 differentially expressed genes in genomic regions not related to the patients’ chromosomal rearrangement, suggesting that translocations have broad effects on the chromatin structure.

Conclusion: Since a wide impact on gene regulation was observed in patients, our results observed in this study support the hypothesis of position effect as a pathogenic mechanism for premature ovarian insufficiency associated with X-autosome translocations. This work emphasizes the relevance of chromatin changes in structural variation, since it advances our knowledge of the impact of perturbations in the regulatory landscape within interphase nuclei, resulting in the position effect pathogenicity.

Keywords: Chromatin structure; Position effect; RNA sequencing; X-autosome translocation.

• PMID: 37202802
• PMCID: PMC10197467
• DOI: 10.1186/s13072-023-00493-8