Discovery And Identification Of Spontaneous Type 2 Diabetes Mellitus Complicated With Diastolic Heart Failure Rhesus Monkey Model

Objectives: Diastolic heart failure is a common and deadly complication of diabetes mellitus, with diabetic cardiomyopathy as one of the key determinants. Significant advances in this area may come from studies on suitable animal models. In this study, we aim to screen out individuals with diastolic dysfunction from spontaneous T2 DM rhesus monkeys, and analyze the similarities with human being to explore a suitable animal model for prevention and treatment research of this critical disease as well as novel therapy development.Method: A total of 25 male rhesus monkeys(12-16 year, 9-13 kg) were enrolled. Fifteen of them were diagnosed as spontaneous type 2 diabetes mellitus(T2DM, FPG ≥ 104 mg/dl, Hb A1c: 4.7-5.5%, diabetes duration: 1-4 years). The other 10 monkeys were non-diabetic(ND, FPG<90 mg/dl). Echocardiography and cardiac magnetic resonance were used for evaluating the cardiac structure and function. One T2 DM monkey with impaired diastolic function and another ND monkey were sacrificed for pathology and protein expression study.Results: Six out of 15 T2 DM rhesus monkeys were diagnosed to have diastolic dysfunction(DD) by echocardiography. No abnormalities were found in ND monkeys. Those 6 monkeys all showed low e’ velocity, decreased e’/a’ ratio and increased E/e’ ratio, among which three showed decreased E/A ratio(0.8±0.1, n=3), another 3 showed elevated E/A ratio(1.5±0.2, n=3), which appears to be similar to the impaired relaxation pattern and pseudonormal pattern in patients respectively. EF and FS of monkeys with pseudonormal pattern decreased significantly compared with ND subjects. CMR study showed LVID at end systole of 5 DD monkeys were significantly longer than that of 3 ND monkeys(21.8±2.9 vs 17.5±0.1, mm, p < 0.05). Myocardium lesions and mitochondria impairment and increased expression of AGEs and caspase-3 were found in a DD subject.Conclusion: The changes in imaging and physiological markers in spontaneous T2 DM rhesus monkeys are similar to human type 2 diabetes and diastolicdysfunction. This monkey model could help us to understand the pathogenesis of the disease and serve to explore measures to prevent and treat diabetic cardiomyopathy.