Type 2 diabetes (T2D) is characterised by hyperglycaemia due to 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 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 dysfunction and death of 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 function, by generating and characterising tamoxifen-inducible islet β-cell specific UBL-5 knockout mice.
Homozygous β-cell UBL-5 knockout mice (UBL5-/-) showed glucose intolerance and lower plasma insulin levels during the OGTT & significantly reduced plasma insulin levels during IVGTT compared to control. β-cell mass was also significantly reduced in UBL5-/-, with most showing signs of frank diabetes (blood glucose >20 mM), polyuria & polydipsia. One week post UBL5 deletion, UBL5-/- mice had significantly increased blood glucose levels & islet cleaved caspase-3 levels compared to controls despite no difference in β-cell mass. In addition islets taken from UBL5-/- mice 1 week post UBL5 gene deletion showed significant decrease in insulin secretion, suggesting that β-cell dysfunction precedes the decrease in β-cell mass. Real time PCR data showed a decrease in UPRmt genes (Clpx, Clpp, CHOP, Lonp1, HSP10, HSP70, ATF5) with HSP60 showing increased expression in the UBL5-/- mice one week after gene deletion.
In conclusion, deletion of UBL-5 leads to β-cell dysfunction, which precedes β-cell death and diabetes in mice. This is the first demonstration that the UPRmt and UBL-5 are involved in cell function and survival in a mammalian system.