Abstract P331: Transition From Pre-Diabetes To Diabetes Is Associated With Worsening Of Cardiac Autonomic Neuropathy: Reversal By Anti-Diabetic Drugs

Abstract

Cardiac autonomic neuropathy (CAN) occurs early in the course of diabetes leading to significant cardiovascular mortality and morbidity. Manifested as impaired heart rate variability (HRV) and baroreflex sensitivity (BRS), CAN represents an independent risk predictor of cardiac mortality. CAN development is linked to hyperglycemia; however, current understanding extends cardiovascular risk to pre-diabetic patients with slight glycemic changes. Here, we assessed the incidence and manifestation of CAN in a rat model of metabolic challenge prior to and after the development of diabetes. Rats were fed a hypercaloric (HC) diet (4.035 KCal/g vs. 3 KCal/g for control rats) composed of: weight (calories) 18.06 % fat (38.68%), 15.8% protein (15.66%), and 46.13% carbohydrates (45.73%). Stable fasting hyperglycemia developed by 16 weeks of feeding. The pre-diabetic stage was associated with signs of perivascular and epicardiac adipose inflammation (4- and 40- fold increase in IL-1β and TGF-β and 2-fold increase in NK-κB expression; and macrophage infiltration) and increased brainstem oxidative stress accompanied with impairment of HRV (total power decrease from 3098 ± 233 to 89 ± 88μs 2 ) and the parasympathetic arm of the baroreflex (slope decrease from -1.02 ± 0.12 to -0.34 ± 0.04). These abnormalities were reversed upon treatment with non-hypoglycemic doses of either metformin or pioglitazone or upon lowering the rat caloric intake. On the other hand, after progression to diabetes, the autonomic deficit progressed to the sympathetic arm of the baroreflex (Slope reduction from -0.35 ± 0.02 to -0.09 ± 0.03). The same hypoglycemic doses of metformin and pioglitazone failed to reverse the impaired HRV and BRS. Whereas, reduction of hyperglycemia to control levels by insulin was only capable of reversing the sympathetic impairment (BRS slope of -0.28 ± 0.04). Our present results outline a framework for sequential involvement of different detrimental mechanisms in the course of metabolic disease leading to differential impact on cardiac autonomic control. Furthermore, our findings emphasize the value of early intervention with antidiabetic drugs with potential protective pleiotropic effects.