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To date, identification of nonislet-specific transcriptional factors in the regulation of insulin gene expression has been little studied. Here, we report that the expression level of the transcription factor YY1 is increased dramatically in both human and mouse pancreatic β-cells after birth. Nevertheless, the physiological role of YY1 during β-cell development and its regulatory mechanism in β-cell function remain largely unknown. After β-cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance, and reduced β-cell mass in neonatal and adult mice. These mice also had hypoinsulinemia with normal insulin sensitivity compared with their wild-type littermates, manifesting as a type 1 diabetic phenotype. Mechanistically, genome-wide RNA sequencing has defined dysregulated insulin signaling and defective glucose responsiveness in β-cells devoid of YY1. Integrative analyses coupled with chromatin immunoprecipitation assays targeting YY1, and histone modifications, including H3K4me1, H3K27ac, and H3K27me3, have further identified Ins1 and Ins2 as direct gene targets of YY1. Luciferase reporter assays and loss- and gain-of-function experiments also demonstrated that YY1 binds to the enhancer regions in exon 2 of Ins1 and Ins2, activating insulin transcription and, therefore, proinsulin and insulin production in pancreatic β-cells. YY1 also directly interacts with RNA polymerase II, potentially stabilizing the enhancer-promoter interaction in the multiprotein-DNA complex during transcription initiation. Taken together, our findings suggest a role for YY1 as a transcriptional activator of insulin gene expression, assisting β-cell maturation and function after birth. These analyses may advance our understanding of β-cell biology and provide clinically relevant insights targeting the pathophysiological origins of diabetes.

Introduction: Currently, the impact of body mass index (BMI) on the outcomes of laparoscopic liver resections (LLR) is poorly defined. This study attempts to evaluate the impact of BMI on the peri-operative outcomes following laparoscopic left lateral sectionectomy (L-LLS). Methods: A retrospective analysis of 2183 patients who underwent pure L-LLS at 59 international centers between 2004 and 2021 was performed. Associations between BMI and selected peri-operative outcomes were analyzed using restricted cubic splines. Results: A BMI of >27kg/m2 was associated with increased in blood loss (Mean difference (MD) 21 mls, 95% CI 5–36), open conversions (Relative risk (RR) 1.13, 95% CI 1.03–1.25), operative time (MD 11 min, 95% CI 6–16), use of Pringles maneuver (RR 1.15, 95% CI 1.06–1.26) and reductions in length of stay (MD -0.2 days, 95% CI -0.3 to −0.1). The magnitude of these differences increased with each unit increase in BMI. However, there was a “U” shaped association between BMI and morbidity with the highest complication rates observed in underweight and obese patients. Conclusion: Increasing BMI resulted in increasing difficulty of L-LLS. Consideration should be given to its incorporation in future difficulty scoring systems in laparoscopic liver resections.

To date, identification of non-islet specific transcriptional factors in the regulation of insulin gene expression has been less studied. Here, we report that the expression level of the transcription factor YY1 has increased dramatically after birth in both human and mouse pancreatic beta cells. Nevertheless, the physiological role of YY1 during beta cell development, and its regulatory mechanism in beta cell function remain largely unknown. Following beta cell ablation of Yy1, we observed rapid onset of hyperglycemia, impaired glucose tolerance and reduced beta cell mass in both neonates and adult mice. These mice also displayed hypoinsulinemia with normal insulin sensitivity compared to their wildtype littermates, manifesting as a type-1 diabetic phenotype. Mechanistically, genome-wide RNA-seq has defined dysregulated insulin signalling and defective glucose responsiveness in beta cells devoid of YY1. Integrative analyses coupled with chromatin immunoprecipitation (ChIP) assays targeting YY1 and histone modifications including H3K4me1, H3K27ac and H3K27me3 have further identified Ins1 and Ins2 as direct gene targets of YY1. Further analyses through luciferase reporter assays, loss- and gain-of-function experiments demonstrate that YY1 binds to the enhancer regions in exon 2 of Ins1 and Ins2, activating insulin transcription and, therefore, proinsulin and insulin production in pancreatic beta cells. YY1 also directly interacts with RNA polymerase II, potentially stabilising the enhancer-promoter interaction in the multiprotein-DNA complex during transcription initiation. Taken together, our findings have suggested a hitherto novel role of YY1 as a transcriptional activator of insulin gene expression, assisting beta cell maturation and function after birth. These studies may advance our understanding of beta cell biology with clinically relevant insights targeting the pathophysiological origins of diabetes.