Advanced glycation end products (AGEs) contribute significantly to diabetic complications, both macro- and microvascular. TRC4186 is an AGE-breaker that has been evaluated in vitro and in vivo and shown to reduce AGE burden. The aim of this study was to determine the effect of TRC4186 on diabetic cardiomyopathy and nephropathy in obese Zucker spontaneously hypertensive fatty rats (Ob-ZSF1), an animal model of diabetes with progressive cardiac and renal dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC4186, 9 or 27 mg/kg twice daily intraperitoneally or vehicle control and monitored telemetrically throughout the study. Cardiac function was assessed terminally by Millar catheter. Markers of cardiac and renal dysfunction were measured and changes evaluated histopathologically. TRC4186 at 27 mg/kg prevented rise in blood pressure (BP) and also improved cardiac output (CO) secondary to better diastolic relaxation as well as systolic emptying in association with the reduction in afterload. At 9 mg/kg, CO was improved by compensatory increase in pre-load however afterload reduction was not adequate to allow efficient systolic emptying. Brain natriuretic peptide (BNP) and interleukin-6 (IL-6) expression was reduced with treatment. Deterioration in renal function was retarded as evident from albumin to creatinine ratio and renal histopathology. TRC4186, an AGE-breaker, clearly preserved cardiac function and reduced the severity of renal dysfunction in Ob-ZSF1, an animal model with persistent severe hyperglycemia leading to diabetic heart failure and renal failure.

Background:Reduced exercise capacity in diabetics has been attributed to limitations in cardiac function and microvascular dysfunction leading to impaired oxygen supply and nutritive perfusion to exercising muscles.Objective:To study changes in cardiac function and microvascular utilisation during exercise in diabetic individuals compared to age-matched controls.Methods:Diabetics with glycosylated haemoglobin (HbA1c) <8 (n = 31), diabetics with HbA1c ⩾8 (n = 38) and age-matched non-diabetic controls (n = 32) performed exercise at 50 W for 10 minutes followed by recovery, with continuous monitoring of cardiac function by impedance cardiography and regional flow and oxygen saturation by laser Doppler and white light spectroscopy.Results:In the diabetics, cardiac reserve during exercise and cardiac overshoot during recovery are significantly reduced because of reduction in capacity to increase stroke volume. Regional flow to the exercising muscle is reduced and there is also disproportionately greater desaturation of the regional flow. Abnormalities in cardiac function and regional perfusion are related to the severity of diabetes.Conclusion:Cardiac response to exercise is attenuated significantly in diabetic individuals. Simultaneously, there is impairment in the regional distribution. These changes could be the harbinger of reduced exercise capacity in diabetics.

TRC4186 was safe and well tolerated when administered orally with either a single or multiple doses across the different ages, sexes, races and formulations studied. A dose-proportional increase in plasma TRC4186 concentration was seen, with steady state being achieved within 6 days.

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