Loss of Serine Racemase in Pancreatic Beta Cells Enhances Obesity by Elevating Basal Insulin Level

• Published in: Obesity (Silver Spring, Md.) Md.), 2022-11, Vol.30, p.191-192
• Main Authors: Nueherberg, Xue Liu, Ruiz-Ojeda, Francisco, Onogi, Yasuhiro, Prudente, Natalia, Murat, Cahuê, Caliskan, Özüm, Yan, Xiaocheng, Isreal, Andreas, Caceres, Cristina, Krahmer, Natalie, Perocchi, Fabiana, Ussar, Siegfried
• Format: Article
• Language: English
• Subjects: Glucose; Insulin resistance; Proteomics
• ISSN: 1930-7381; 1930-739X

Background: Maintaining or restoring insulin secretion from pancreatic beta cells is one of the major objectives for the treatment of diabetes. Recently, we identified two single nucleotide polymorphisms (SNPs) associated with human insulin secretion in serine racemase (SRR), an enzyme converting L-serine to D-serine. Unlike L-serine, Dserine is not proteinogenic but acts as a co-agonist for the NMDA receptor, which is known to modulate membrane potential and thereby insulin secretion from Beta cells. However, the mechanism underlying the modulation of insulin secretion by serine racemase and a possible role of NMDARs remains to be elucidated. Methods: Established conditional knockout mice for SRR in pancreatic beta cells (SrrIns1cre) pancreatic islets isolation Glucose tolerance test In vivo/ vitro glucose stimulated insulin secretion test Seahorse experiment for testing mitochondrial function Proteomics metabolic monitoring by TSE Results: Genetic deletion of SRR in beta cells increased alpha cell numbers and impaired overall islet architecture. However, loss of SRR in beta cells did not impair glucose-stimulated insulin secretion in vivo and ex vivo and led to an overall improved glucose tolerance in chow diet fed mice. Conversely, basal insulin secretion, tested ex vivo, was significantly increased in SrrIns1cre mice. To elucidate the underlying mechanism, a combination of electrophysiology, metabolomics, proteomics and bioenergentics was applied. These experiments revealed an increased membrane potential under low glucose conditions, which was not due to altered activation of NMDARs but consequence of increased mitochondrial ATP production. Insulin is about 6 times more potent in suppressing lipolysis than inducing glucose uptake. Thus, we challenged SrrIns1cre mice with high fat diet to investigate the effects of slightly increased basal insulin secretion on body weight gain. High fat diet fed SrrIns1cre mice showed an increased fat mass gain and insulin resistance compared to controls. Proteomic of subcutaneous adipose tissue of HFD fed SrrIns1cre mice revealed downregulation of fatty acid metabolism and insulin signaling components. Conclusions: Our data unravel the role of SRR in the regulation of basal insulin secretion and underscore the pivotal role of basal insulin secretion in the regulation of body weight.