Overexpression of UBE2E2 in mouse pancreatic β-cells leads to glucose intolerance via reduction of the β-cell mass

Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes (E2s) involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Herein, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in non-coding regions was associated with upregulation of the UBE2E2 mRNA in the human pancreas. While glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic β-cells-specific Ube2e2-transgenic (TG) mice exhibited reduced insulin secretion and decreased β-cell mass. In the TG mice, suppressed proliferation of β-cells before the weaning period and under the high-fat-diet condition was accompanied by elevated gene expression levels of p21, resulting in decreased postnatal β-cell mass expansion and compensatory β-cell hyperplasia, respectively. In the TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin-protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in the β-cells play an important role in regulating glucose homeostasis and β-cell mass.