Visualization of Early and Late Molecular Events Associated with the Development of Type 1 Diabetes Using NMR...

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by the loss of insulin-producing pancreatic β-cells. This study aims to explore the correlation between hyperglycemia and concurrent metabolic perturbations during T1DM development to help identify biomarkers that differentiate between the early and established stages. Streptozotocin (STZ), a glucosamine nitrosourea compound, induces T1DM. Dose- and time-dependent studies were conducted in 7-8-week-old male C57BL/6 mice, who were administered increasing numbers of STZ injections (N = 0-5) and were followed for 15 (early) and 60 (late) days. The development of hyperglycemia was confirmed by performing an oral glucose tolerance test and an insulin tolerance test. A total of 50 abundant aqueous serum metabolites were identified and quantified using ¹H NMR spectroscopy. In addition to glucose, a well-established biomarker for T1DM, a panel of 5 significantly perturbed metabolites (namely, leucine, choline, lactate, lysine, and mannose), Diagnostic Molecular Fingerprint (DMF), was identified. Unlike glucose levels, the proposed DMF (in combination with glucose) could differentiate not only between early and established stages of T1DM but also between young and aged healthy controls. However, these results need validation in humanized animal models and well-characterized patient cohorts of different ethnicities. In conclusion, the results obtained have contributed toward increasing the understanding of the pathophysiology and mechanism of T1DM establishment and progression that would possibly aid in accurate diagnosis, prognosis, risk prediction, defining the distinct stages of T1DM, and help in enhancing patient outcomes in the future.