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Purpose: Coronary microvascular dysfunction (CMVD) plays a major role in the occurrence of cardiovascular events (CVE). We recently suggested the clinical potential of myocardial perfusion entropy (MPE) quantification from SPECT myocardial perfusion images (MPI) for the prognosis of CVE occurrence. We hypothesized that the quantification of MPE from SPECT MPI would allow the assessment of CMVD-related MPE variations in a preclinical model of type 2 diabetes (T2D) including treatment with the anti-diabetic incretin liraglutide (LIR). Methods: Optimal conditions for the preclinical quantification of MPE using 201Tl SPECT MPI were determined in rats with a T2D-like condition induced by a high-fat diet and streptozotocin injection (feasibility study, n = 43). Using such conditions, echocardiography and post-mortem LV capillary density evaluation were then used in order to assess the effect of LIR and the ability of MPE to assess CMVD (therapeutic study, n = 39). Results: The feasibility study identified dobutamine stress and acute NO synthase and cyclooxygenase inhibition as optimal conditions for the quantification of MPE, with significant increases in MPE being observed in T2D animals (P < 0.01 vs controls). In the therapeutic study, T2D rats were hyperglycemic (5.5 ± 0.5 vs 1.1 ± 0.3 g/L for controls, P < 0.001) and had a significantly lower left ventricular ejection fraction (LVEF) (65 ± 4% vs 74 ± 9%, P < 0.01) and LV capillary density (2400 ± 300 vs 2800 ± 600 mm−3, P < 0.05). LIR partially restored glycemia (3.9 ± 0.6 g/L, P < 0.05 vs controls and T2D), totally prevented LVEF impairment (72 ± 7%, P = NS vs CTL), with no significant effect on capillary density. MPE was significantly increased in T2D rats (7.6 ± 0.5 vs 7.1 ± 0.5, P < 0.05), with no significant improvement in T2D-LIR rats (7.4 ± 0.4, P = NS vs controls and T2D). Conclusion: MPE quantification allowed the preclinical noninvasive assessment of CMVD. Both MPE and capillary density quantification suggested that LIR did not improve T2D-induced CMVD. The relevance of MPE for CMVD assessment warrants further clinical investigation. [ABSTRACT FROM AUTHOR]