Hyperuricemia Causes Pancreatic β-Cell Death and Dysfunction through NF-κB Signaling Pathway

Abstract

Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid–treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid–treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11–7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.

Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathway

“…Pathways providing mechanistic links for modulating cytokine production (NF-κB, mTOR, FoxO, lysosome) were further investigated. Uric acid was previously reported to induce NF-κB and to promote cell death in pancreatic β cells (31). In our in vitro setup, we were unable to detect changes in phosphorylation of NF-κB component p65 in monocytes treated with uric acid (Fig.…”

Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease

“…In addition to the direct effect of urea identified here, evidence in support of other uremic toxins disrupting β cell function is emerging. Recently, uric acid was shown to affect insulin secretion by increasing oxidative stress in β cells (51). In addition, the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), at concentrations found in CKD patients, impairs insulin secretion by inducing mitochondrial dysfunction and inhibition of insulin biosynthesis in β cells (52).…”

The Role of Uric Acid in Carbohydrate Metabolism among Hypertensive Individuals

“…Moreover, there are studies verifying the causal of uric acid in direct pancreatic β-cell death through activation of NF-κΒ signaling pathways, speeding up insulin secretion and progression to diabetes [15].…”