262-OR: The Transcription Factor Yin Yang 1 (YY1) Is Critical to Beta-Cell Maintenance and Glucose Homeostasis

Abstract

Diabetes is characterized by loss of β cell mass and function. mTORC1 has an important role in the control of insulin secretion, β cell proliferation and death. YY1 is important in development, apoptosis, metabolism and growth in several tissues. In muscle, mTORC1 regulates the expression of insulin signaling genes by controlling YY1 binding to the promoter region. However, YY1 role in β cells was not addressed so far. Here we observed that diabetic and diet-induced obese mice exhibited lower levels of YY1 in the β cells. To understand the role of YY1 in β cell, we developed a new β cell YY1 depleted mouse model (β-YY1KO) by crossing our floxed YY1 mouse with a Ins-cre mouse. Haploinsufficiency of YY1 (β-YY1HET) did not impair fed or fasting glycemia, blood insulin levels and glucose tolerance. Even after 10 weeks in HFD, β-YY1HET did not differ from littermate controls in terms of glucose tolerance and glucose-stimulating insulin secretion. However, β-YY1KO mice exhibited a profound diabetic phenotype. While glucose and insulin levels in newborn β-YY1KO were normal, blood glucose begun to rise in the β-YY1KO mice at 2 weeks. All β-YY1KO became diabetic at 3 weeks presenting fed hyperglycemia and lower fed insulin levels, suggesting decreased β cell function and/or β cell loss. Remarkably, β cell mass is reduced at 2 and 3 weeks. To understand the decrease in β cell mass, we assessed β cell proliferation and death by IHF for Ki67 and flow cytometry for active Casp 3, respectively. Although β cell proliferation was normal at 2 weeks, there was a reduction Ki67+ β cell at 3 weeks. However, active casp 3 was already increased at 2 weeks. One striking role of YY1 is to regulate mitochondrial function and structure, therefore, we evaluated mitochondrial morphology by electron microscopy. We found that β-YY1KO mice presented less mitochondrial area and abnormal structure. Altogether, these results show that YY1 is important for appropriate control of glucose homeostasis and β-cell maintenance. Disclosure F.M. Peçanha: None. E. Bernal-Mizrachi: None.