Tirzepatide Failed to Improve Neuropathy in a Murine Nonobese Streptozotocin-Induced Type 1 Diabetes Model, Despite Alleviating Systemic Inflammation

Background/Objectives: This study aimed to assess the effect of tirzepatide on systemic inflammation in a diabetic neuropathy (DN) model in mice. Methods: Type 1 diabetes was induced with streptozotocin 180 mg/kg i.p. One month later, we injected two doses of tirzepatide (5 or 15 mcg/kg BW s.c. e3d) over the next 4 weeks, then performed a battery of neurological tests and measured blood cytokines with the Simple Plex® platform CE-IVD version. Data were compared with naïve controls with or without diabetes induction. Results: Tirzepatide treatment failed to improve both glycemia and neuropathic behavior post-streptozotocin treatment. Higher-dose tirzepatide-treated mice had significantly decreased grip strength (p = 0.013) and higher cold (p = 0.04) and mechanical (p < 0.001) sensitivity, despite substantially lower systemic inflammation, as assessed by TNF-α and IL-6. An exploratory composite inflammatory index (ECII) derived from IL-6 and TNF-α showed statistically significantly lower systemic inflammation in the group treated with a higher tirzepatide dose vs. the treatment-naïve control (p < 0.05), the diabetic group (p < 0.05), and the diabetic group treated with lower-dose tirzepatide (p < 0.05). Conclusions: Tirzepatide failed to improve DN in a streptozotocin-induced murine nonobese model of type 1 diabetes, although it substantially decreased systemic inflammation. Testing tirzepatide for potential protection against DN in non-streptozotocin-based DN animal models is warranted.