Islet Beta-Cell Specific Deletion of UBL5 Gene Associated with Mitochondrial Stress Leads to Diabetes in Mice and Beta-Cell Impairment/Death

Abstract

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 known to have a crucial role in the UPRmt in C. elegans and upregulated during the UPRmt mammals. The aim of this study was to determine whether UBL-5 has a role in maintaining β-cell mass and function through modulating the UPRmt, 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 while heterozygous mice (UBL5+/-) showed no difference. UBL5-/- had significantly reduced plasma insulin levels during IVGTT compared to control. Interestingly, UBL5+/- had significantly increased plasma insulin levels during IVGTT. Beta-cell mass was also significantly reduced in UBL5-/-, with most showing signs of frank diabetes (blood glucose >20 mM), polyuria and polydipsia, while UBL5+/- had increased β-cell mass. One week post UBL5 deletion, UBL5-/- mice had significantly increased blood glucose levels and 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. Islets taken from UBL5+/- mice had increased insulin secretion compared to control. 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, while the UBL5+/- mice showed an overall increase in most UPRmt related genes. Disclosure C. Haralambous: None. V. Ntouma: None.