UBL-5 is essential for sustaining pancreatic β-cell function and mass in mice — ASN Events

UBL-5 is essential for sustaining pancreatic β-cell function and mass in mice (#206)

Christian S Haralambous 1 , Benjamin J Lamont 1 , Viktoria Ntouma 1 , Salvatore P Mangiafico 1 , Sofianos Andrikopoulos 1
  1. Medicine, University of Melbourne, Melbourne, Victoria, Australia

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 (UPRmt). 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 UPRmt 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.

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