Contribution of systemic inflammation to permanence of K_ATP-induced neonatal diabetes in mice

Abstract

Gain-of-function (GOF) mutations in ATP-sensitive potassium (K) channel cause neonatal diabetes. Despite the well-established genetic root of the disease, the pathways modulating disease severity and treatment effectiveness remain poorly understood. Patient phenotypes can vary from severe diabetes to remission, even in individuals with the same mutation and within the same family; suggesting that subtle modifiers can influence disease outcome. We have tested the underlying mechanism of transient vs permanent neonatal diabetes in K-GOF mice treated for 14-days with glibenclamide. Some K-GOF mice show remission of diabetes and enhanced insulin sensitivity long-after diabetes treatment ended, compared with severely insulin-resistant non-remitting mice. However, insulin sensitivities are not different between the two groups before or during diabetes induction, suggesting that improved sensitivity is a consequence, rather than the cause of remission; implicating other factors modulating glucose early in diabetes progression. Leptin, glucagon, insulin and GLP-1 are not different between remitters and non-remitters. However, liver glucose production is significantly reduced before transgene induction in remitter, relative to non-remitter and non-treated mice. Surprisingly, while subsequent remitter animals exhibited normal serum cytokines, non-remitter mice showed increased cytokines, which paralleled the divergence in blood glucose. Together, these results suggest that systemic inflammation may play a role in the transient vs permanent form of neonatal diabetes. Supporting this conclusion, treatment with the anti-inflammatory Meloxicam significantly increased the fraction of remitting animals. Beyond neonatal diabetes, the potential for inflammation and glucose production to exacerbate other forms of diabetes from a compensated state to a glucotoxic state should be considered.

Genetic Reduction of Glucose Metabolism Preserves Functional β-Cell Mass in KATP-Induced Neonatal Diabetes

“…Plasma insulin was assayed using rat/mouse ELISA kit (Crystal Chem, Elk Grove Village, IL). Plasma hormones (insulin, glucagon, glucagon-like peptide 1 [GLP-1], and leptin) were measured using the Luminex MILLIPLEX Mouse Metabolic Hormone panel at the Immunomonitoring Laboratory, Bursky Center for Human Immunology and Immunotherapy Programs Assay Core ( https://chiips.wustl.edu ) ( 24 ). After a 4 h fast, blood glucose was collected for triglyceride, cholesterol, and free fatty acid (FFA) measurement at the Washington University Diabetes Models Phenotyping Core ( https://diabetesresearchcenter.dom.wustl.edu/diabetes-models- phenotyping-core ) ( 25 ).…”