Type 2 diabetes (T2D) is a metabolic disease characterised by hyperglycaemia brought on by the inability of pancreatic β-cells to secrete enough insulin to compensate for insulin resistance. Hyperglycaemia has been shown to cause oxidative stress in pancreatic β-cells, leading to the activation of stress responses such as the mitochondrial unfolded protein response (UPR^mt). Failure of these responses to adapt to or repair damage from stress results in the dysfunction and potential death of these β-cells. Ubiquitin-like protein 5 (UBL-5) is a protein thought to regulate post-translational modification of proteins and has a role in the UPR^mt in both mammalian cells and invertebrates. The aim of this study was to determine whether UBL-5 has a role in maintaining β-cell mass and insulin secretory function by generating and characterising tamoxifen-inducible β-cell specific UBL-5 knockout mice.

Homozygous β-cell UBL-5 knockout mice showed impaired glucose tolerance and lower plasma insulin levels during the OGTT, while heterozygous β-cell UBL-5 knockout showed no difference in glucose tolerance and plasma insulin. Plasma insulin levels of the homozygous β-cell UBL-5 knockout were significantly lower during IVGTT compared to control. In contrast, the heterozygous β-cell UBL-5 knockout showed an increase insulin secretion during IVGTT. β-cell mass was also significantly reduced in homozygous β-cell UBL-5 knockout mice, while the heterozygous β-cell UBL-5 knockout mice showed increased β-cell mass.

The significant impairments in glucose tolerance and glucose-stimulated insulin secretion (GSIS) associated with reduced β-cell mass in homozygous β-cell UBL-5 knockout mice and improvement in GSIS associated with increased β-cell mass in heterozygous β-cell UBL-5 knockout mice reveal a previously unknown but essential role for UBL-5 in pancreatic β-cells.