Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, improves weight and glycaemic outcomes in adults with type 1 diabetes¹˒². Its effects on autoimmune diabetes progression are unknown. This study examined the metabolic and pancreatic effects of tirzepatide and its impact on diabetes development in female NOD mice.
From eight weeks of age, mice received subcutaneous tirzepatide (TZP) or saline (CON) three times weekly, with tirzepatide dose-escalated to 40 nmol/kg. After six weeks, a subset (n=10/group) underwent a fasted oral glucose tolerance test with assessment of glucose-stimulated insulin secretion. Following this, they were sacrificed for pancreatic assessments. Remaining mice were monitored until diabetes onset or week 28. Fasting blood glucose was measured weekly, with diabetes defined as two consecutive readings >14 mmol/L.
After six weeks, tirzepatide-treated mice had a lower glucose area under the curve than CON (661.1±61.6 vs 958.4±52.6 mmol/min/L, p<0.01), indicating improved glucose tolerance. Fasting and glucose-stimulated insulin concentrations were also lower with tirzepatide (insulin area under the curve: 39.4±13.2 vs 190.4±48.9 ng/min/mL, p<0.01). Pancreatic histology showed greater immune infiltration in TZP-treated mice, with higher insulitis scores and a significantly lower proportion of non-infiltrated islets. Longitudinal monitoring demonstrated greater glucose variability and significantly shorter diabetes-free survival with tirzepatide (log-rank χ²=10.87, p<0.001), consistent with earlier progression to overt diabetes.
In female NOD mice, tirzepatide improved glucose tolerance at six weeks but was associated with lower insulin concentrations, greater insulitis, increased glucose variability and earlier diabetes onset. These findings highlight a disconnect between short-term metabolic improvement and autoimmune disease progression and warrant further investigation of the pancreatic effects of tirzepatide in type 1 diabetes.