Low-Dose T3 Replacement Restores Depressed Cardiac T3 Levels, Preserves Coronary Microvasculature and Attenuates Cardiac Dysfunction in Experimental Diabetes Mellitus

Abstract

Thyroid dysfunction is common in individuals with diabetes mellitus (DM) and may contribute to the associated cardiac dysfunction. However, little is known about the extent and pathophysiological consequences of low thyroid conditions on the heart in DM. DM was induced in adult female Sprague Dawley (SD) rats by injection of nicotinamide (N; 200 mg/kg) followed by streptozotocin (STZ; 65 mg/kg). One month after STZ/N, rats were randomized to the following groups (N = 10/group): STZ/N or STZ/N + 0.03 μg/mL T 3 ; age-matched vehicle-treated rats served as nondiabetic controls (C). After 2 months of T 3 treatment (3 months post-DM induction), left ventricular (LV) function was assessed by echocardiography and LV pressure measurements. Despite normal serum thyroid hormone (TH) levels, STZ/N treatment resulted in reductions in myocardial tissue content of THs (T 3 and T 4 : 39% and 17% reduction versus C, respectively). Tissue hypothyroidism in the DM hearts was associated with increased DIO3 deiodinase (which converts THs to inactive metabolites) altered TH transporter expression, reexpression of the fetal gene phenotype, reduced arteriolar resistance vessel density, and diminished cardiac function. Low-dose T 3 replacement largely restored cardiac tissue TH levels (T 3 and T 4 : 43% and 10% increase versus STZ/N, respectively), improved cardiac function, reversed fetal gene expression and preserved the arteriolar resistance vessel network without causing overt symptoms of hyperthyroidism. We conclude that cardiac dysfunction in chronic DM may be associated with tissue hypothyroidism despite normal serum TH levels. Low-dose T 3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.

Cardiac Thyroid Hormone Metabolism and Heart Failure

“…The minimal metabolism of T4 in rodent hearts [21] furthermore indicates the importance of T3 uptake. Effects of cardiac remodeling on protein expression of TH transporters have not been reported, but in a rat model of diabetic cardiomyopathy mRNA levels of MCT8 were found to be upregulated, while those of MCT10 were downregulated [22]. …”

“…The ventricle-specific expression of DIO3 correlated with the extent of the changes in gene expression characteristic of pathological remodeling and was associated with a reduction of tissue T3 levels [24, 49, 50]. Induction of cardiac DIO3 activity has since been found in rodent models of LV pathological remodeling induced by aortic stenosis [51], MI [45, 52], isoproterenol [53], and diabetes mellitus [22]. DIO3 activity in the mouse model of MI was already maximal at 1 week after MI surgery and remained high for at least 8 weeks [45].…”

T3 supplementation affects ventilatory timing & glucose levels in type 2 diabetes mellitus model

“…Prior to STZ/N administration, body weights and resting glucose levels were similar among the three groups (Weltman et al, 2014). Mean body weights were 249 ± 10.5 g, 246 ± 24.2 g, and 245 ± 13.2 g, for the control, STZ/N, and STZ/N/T 3 , respectively.…”

“…Consequently, we expected that T 3 supplementation would help regulate blood glucose of STZ/N rats. A recent paper used this approach to study effects of the STZ/N model and T 3 supplementation on cardiovascular function and coronary vasculature (Weltman et al, 2014).…”

Causal role of oxidative stress in unfolded protein response development in the hyperthyroid state

“…In humans, readjusting thyroid hormones to normal levels is also beneficial in specific cases, as shown by (i) the improvement in mental, motor, and neurological outcomes in infants of <28 weeks' gestation [58]; (ii) the lower cognitive side effects of lithium and electroconvulsive therapy in patients with bipolar disorders [59]; and (iii) the higher number of organs from brain-dead donors that are acceptable for transplantation and exhibit better graft survival [60]. Recently, low-dose T 3 replacement was proposed as a therapy for diabetic vascular complications in humans, as it preserves coronary microvasculature and attenuates cardiac dysfunction in an experimental model [61], whereas T 3 supplementation in rats substantially recovered hypothyroidism-induced liver apoptosis [62], supporting the role of T 3 in cytoprotection and functional recovery. …”