Elevated systemic glutamic acid level in the non‐obese diabetic mouse is Idd linked and induces beta cell apoptosis

Abstract

Although type 1 diabetes (T1D) is a T-cell-mediated disease in the effector stage, the mechanism behind the initial beta cell assault is less understood. Metabolomic differences, including elevated levels of glutamic acid, have been observed in patients with T1D before disease onset, as well as in pre-diabetic non-obese diabetic (NOD) mice. Increased levels of glutamic acid damage both neurons and beta cells, implying that this could contribute to the initial events of T1D pathogenesis. We investigated the underlying genetic factors and consequences of the increased levels of glutamic acid in NOD mice. Serum glutamic acid levels from a (NOD×B6)F cohort (n = 182) were measured. By genome-wide and Idd region targeted microsatellite mapping, genetic association was detected for six regions including Idd2, Idd4 and Idd22. In silico analysis of potential enzymes and transporters located in and around the mapped regions that are involved in glutamic acid metabolism consisted of alanine aminotransferase, glutamic-oxaloacetic transaminase, aldehyde dehydrogenase 18 family, alutamyl-prolyl-tRNA synthetase, glutamic acid transporters GLAST and EAAC1. Increased EAAC1 protein expression was observed in lysates from livers of NOD mice compared with B6 mice. Functional consequence of the elevated glutamic acid level in NOD mice was tested by culturing NOD. Rag2 Langerhans' islets with glutamic acid. Induction of apoptosis of the islets was detected upon glutamic acid challenge using TUNEL assay. Our results support the notion that a dysregulated metabolome could contribute to the initiation of T1D. We suggest that targeting of the increased glutamic acid in pre-diabetic patients could be used as a potential therapy.

Eicosapentaenoic and docosahexaenoic acids attenuate hyperglycemia through the microbiome-gut-organs axis in db/db mice

“…Administration of glutamate has been shown to induce adiposity and impair glycemic control in rodents [ 70 , 71 ]. Mechanically, the elevated glutamic acid level was found to induce pancreatic β cell apoptosis through GLT1 [ 36 , 72 ]. Previous studies also revealed a link between gut microbiome and glutamate metabolism [ 73 , 74 ].…”

β‐Cell failure in diabetes: Common susceptibility and mechanisms shared between type 1 and type 2 diabetes

“…Susceptibility to high-sucrose induced diabetes is also mapped to chromosome 11 (Figure 6a) and genes for impaired b-cell function under a high-sucrose environment was localized to the central and distal segments of chromosome 11 (Figure 6b) 75 . In this region, a susceptibility locus for type 1 diabetes, Idd4, was mapped by genome scanning and congenic mapping in the NOD mice 71,[79][80][81] , suggesting the presence of a common susceptibility gene for both type 1 and type 2 diabetes in this region.…”

Protective Mechanism of Gandou Decoction in a Copper-Laden Hepatolenticular Degeneration Model: In Vitro Pharmacology and Cell Metabolomics

“…The results showed that the glutamate level in copper-laden HLD hepatocytes was significantly higher than that in the shNC cells. An abnormal increase in glutamate activates the signaling pathway of downstream ROS, causing oxidative damage, and can eventually lead to the death of hepatocytes ( Banday and Lejon, 2017 ). After GDD therapy, glutamate levels in cells tended to be normal, indicating that the protective effect of GDD on HLD may be associated with glutamate metabolism.…”