Visualization of early and late molecular events associated with the development of Type I Diabetes using NMR spectroscopy

Objective: Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by the loss of the insulin-producing pancreatic β-cells. Being a complex disease, with genetics and environmental factors playing significant roles, the exact cause of T1DM remains unknown. This further emphasizes the need for extensive research in this area to gain mechanistic insights into the causation. This study aims to explore the correlation between hyperglycemia and the concurrent metabolic perturbations during T1DM development and identify biomarkers that differentiate between early and established stages of T1DM. Methods: 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 0, 1, 2, 3, 4, and 5 STZ injections and were followed for 15 (early) and 60 (late) days. The development of hyperglycemia was confirmed by performing an oral glucose tolerance and insulin tolerance test. Abundant aqueous metabolites were identified and quantified from the serum samples using ¹ H NMR spectroscopy. Results: The development of hyperglycemia was observed in 15 days for mice that received ³ 2 STZ injections. A total of 50 abundant aqueous metabolites were identified. In addition to glucose, a well-established biomarker for T1DM, a panel of 5 significantly perturbed metabolites – Diagnostic Molecular Fingerprint was identified. These metabolites include leucine, lysine, choline, mannose, and lactate. Conclusions: The proposed Diagnostic Molecular Fingerprint can differentiate between stages of T1DM and may facilitate the development of targeted therapeutic interventions with minimized side effects, ultimately enhancing patient outcomes in T1DM management.