Early diabetes treatment does not prevent sympathetic dysinnervation in the streptozotocin diabetic rat heart

Positron emission tomography (PET) studies have demonstrated reduced sympathetic neuronal integrity in high-fat diet fed streptozotocin insulin-resistant diabetic rats in parallel with abnormal early-to-atrial transmitral velocity. We hypothesized that administration of anti-glycemic drugs early after diabetes induction would prevent sympathetic neuronal dysfunction. Male Sprague-Dawley rats fed high-fat diet were administered streptozotocin (45 mg center dot kg(-1), ip, n = 23) to induce diabetes or vehicle alone (n = 6). Diabetic rats were randomized to receive insulin (4 U center dot day(-1)), metformin (650 mg center dot kg(-1)center dot day(-1)), rosiglitazone (4 mg center dot kg(-1)center dot day(-1)), or no treatment 1 week after streptozotocin. Small animal PET imaging using the norepinephrine analog [C-11]meta-hydroxyephedrine (HED) at baseline and 8 weeks of diabetes determined sympathetic neuronal integrity. Echocardiography assessed cardiac function. Plasma norepinephrine levels were determined in parallel. Ex vivo immunoblotting was performed at the end of the experiment to compare the relative expression of various proteins involved in metabolic and noradrenergic signaling. Insulin restored blood glucose and lipid levels to normal. Despite improved plasma lipid levels, neither metformin nor rosiglitazone reduced blood glucose. At 8 weeks, untreated and treated diabetics displayed a 39%-42% reduction in myocardial HED standardized uptake values (P < .05). In all diabetic groups, plasma norepinephrine was elevated (2.3- to 3.3-fold, P < .05) and norepinephrine reuptake transporter expression reduced (28%-35%, P < .05) compared to non-diabetics. Doppler echocardiography revealed delayed development of prolonged mitral valve deceleration and elevated early-to-atrial filling velocity ratio among treated diabetic rats. Early glycemic treatment of insulin-resistant diabetic rats did not prevent deterioration of sympathetic neuronal integrity though ventricular filling abnormalities were delayed.