The Transcription Factor YY1 Is Essential for Normal DNA Repair and Cell Cycle in Human and Mouse ß-Cells.

Identifying the mechanisms behind the ß-cell adaptation to failure is important to develop strategies to manage type 2 diabetes (T2D). Using db/db mice at early stages of the disease process, we took advantage of unbiased RNA sequencing to identify genes/pathways regulated by insulin resistance in ß-cells. We demonstrate herein that islets from 4-week-old nonobese and nondiabetic leptin receptor-deficient db/db mice exhibited downregulation of several genes involved in cell cycle regulation and DNA repair. We identified the transcription factor Yin Yang 1 (YY1) as a common gene between both pathways. The expression of YY1 and its targeted genes was decreased in the db/db islets. We confirmed the reduction in YY1 expression in ß-cells from diabetic db/db mice, mice fed a high-fat diet (HFD), and individuals with T2D. Chromatin immunoprecipitation sequencing profiling in EndoC-ßH1 cells, a human pancreatic ß-cell line, indicated that YY1 binding regions regulate cell cycle control and DNA damage recognition and repair. We then generated mouse models with constitutive and inducible YY1 deficiency in ß-cells. YY1-deficient mice developed diabetes early in life due to ß-cell loss. ß-Cells from these mice exhibited higher DNA damage, cell cycle arrest, and cell death as well as decreased maturation markers. Tamoxifen-induced YY1 deficiency in mature ß-cells impaired ß-cell function and induced DNA damage. In summary, we identified YY1 as a critical factor for ß-cell DNA repair and cell cycle progression.

Thyroid states regulate subcellular glucose phosphorylation activity in male mice.

The thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), are very important in organism metabolism and regulate glucose utilization. Hexokinase (HK) is responsible for the first step of glycolysis, catalyzing the conversion of glucose to glucose 6-phosphate. HK has been found in different cellular compartments, and new functions have been attributed to this enzyme. The effects of hyperthyroidism on subcellular glucose phosphorylation in mouse tissues were examined. Tissues were removed, subcellular fractions were isolated from eu- and hyperthyroid (T3, 0.25 µg/g, i.p. during 21 days) mice and HK activity was assayed. Glucose phosphorylation was increased in the particulate fraction in soleus (312.4% ± 67.1, n = 10), gastrocnemius (369.2% ± 112.4, n = 10) and heart (142.2% ± 13.6, n = 10) muscle in the hyperthyroid group compared to the control group. Hexokinase activity was not affected in brain or liver. No relevant changes were observed in HK activity in the soluble fraction for all tissues investigated. Acute T3 administration (single dose of T3, 1.25 µg/g, i.p.) did not modulate HK activity. Interestingly, HK mRNA levels remained unchanged and HK bound to mitochondria was increased by T3 treatment, suggesting a posttranscriptional mechanism. Analysis of the AKT pathway showed a 2.5-fold increase in AKT and GSK3B phosphorylation in the gastrocnemius muscle in the hyperthyroid group compared to the euthyroid group. Taken together, we show for the first time that THs modulate HK activity specifically in particulate fractions and that this action seems to be under the control of the AKT and GSK3B pathways.