Aims/hypothesis <p>This study investigated insulin sensitivity using the hyperinsulinaemic–euglycaemic clamp technique in individuals with obesity and type 2 diabetes treated with tirzepatide at the low dose of 5 mg over a 12-week treatment period.</p> Methods <p>This prospective, single-arm, open-label, single-centre study was conducted in obese individuals with type 2 diabetes<i>.</i> Participants received tirzepatide 2.5 mg once weekly for 4 weeks; the dose was then increased to 5 mg for the remaining 8 weeks. The primary outcome was change in the glucose infusion rate. Secondary outcomes were changes in HbA_1c, body weight, body composition, lipid profile, glucagon level, the HOMA2-IR and HOMA2-%β indices, and the association of these variables with the glucose infusion rate (GIR).</p> Results <p>Sixteen participants completed the study. The GIR increased from 3.21 to 5.16 mg min⁻¹ kg⁻¹ (<i>p</i>&lt;0.001). HbA_1c decreased from 63.4 to 43.6 mmol/mol (7.95% to 6.14%, <i>p</i>&lt;0.001) and body weight decreased by 4.9 kg (5.0%, <i>p</i>&lt;0.001). Muscle mass, fat mass and fat percentage significantly decreased by 1.8%, 9.1% and 4.5%, respectively. Glucagon decreased significantly from 28.8 pg/ml to 20.8 pg/ml. However, simple linear regression analysis revealed no significant relationship between changes in GIR and other clinical variables.</p> Conclusions/interpretation <p>Tirzepatide significantly improves insulin sensitivity within 12 weeks, indicating an early metabolic effect that is not solely attributable to weight loss.</p> Trial registration <p>UMIN registration number: UMIN000056862</p> Graphical Abstract <p></p>