Metabolic actions of insulin to promote glucose disposal are augmented by nitric oxide (NO)-dependent increases in microvascular blood flow to skeletal muscle. The balance between NO-dependent vasodilator actions and endothelin-1-dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. Angiotensin II acting on AT2 receptor increases capillary blood flow to increase insulin-mediated glucose disposal. In contrast, AT1 receptor activation leads to reduced NO bioavailability, impaired insulin signaling, vasoconstriction, and insulin resistance. Insulin-resistant states are characterized by dysregulated local renin-angiotensin-aldosterone system (RAAS). Under insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Similarly, excess AT1 receptor activity in the microvasculature may selectively impair vasodilation while simultaneously potentiating the vasoconstrictor actions of insulin. Therapeutic interventions that target pathway-selective impairment in insulin signaling and the imbalance in AT1 and AT2 receptor signaling in microvascular endothelium may simultaneously ameliorate endothelial dysfunction and insulin resistance. In the present review, we discuss molecular mechanisms in the endothelium underlying microvascular and metabolic actions of insulin and Angiotensin II, the mechanistic basis for microvascular endothelial dysfunction and insulin resistance in RAAS dysregulated clinical states, and the rationale for therapeutic strategies that restore the balance in vasodilator and constrictor actions of insulin and Angiotensin II in the microvasculature.

Energy metabolism is one of the most recognized targets of thyroid hormone action, which indeed plays a critical role in modulating energy expenditure in all of its components. This is because thyroid hormone receptors are ubiquitous, and thyroid hormones interact and influence most metabolic pathways in virtually all systems throughout the entire life of the organism. The pleiotropic actions of thyroid hormone are the results of interaction between the local availability of T3 and the signal transduction machinery, which confer in physiologic conditions time and tissue specificity of the hormonal signal despite negligible variations in circulating levels. Historically, the measurement of energy expenditure has been used as the gold standard for the clinical assessment of the hormonal action until the advent of the immunoassays for TSH and thyroid hormone, which have since been used as proxy for measurement of thyroid hormone action. Although the clinical correlates between thyroid hormone action and energy expenditure in cases of extreme dysfunction (florid hyperthyroidism or hypothyroidism) are well recognized, there is still controversy on the effects of moderate, subclinical thyroid dysfunction on energy expenditure and, ultimately, on body weight trajectory. Moreover, little information is available on the effects of thyroid hormone replacement therapy on energy expenditure. This mini review is aimed to define the clinical relevance of thyroid hormone action in normal physiology and functional disorders, as well the effects of thyroid hormone therapy on energy expenditure and the effects of changes in energy status on the thyroid hormone axis.

Background: L-triiodothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer (TC) patients during the preparation for nuclear medicine procedures, and it is used in combination with LT4 in patients who do not respond to the standard treatment for hypothyroidism. This therapy is commonly done by using fixed doses, potentially resulting in supraphysiologic levels of triiodothyronine (T3). A good understanding of the LT3 pharmacokinetics (PK) is necessary to design combination treatment schemes that are able to maintain serum T3 levels within the reference range, but data on the PK of LT3 are conflicting. Here, we present a study designed to characterize the PK of LT3 in patients devoid of endogenous thyroid hormone production, and not receiving LT4 therapy. Methods: We performed an open-label, PK study in patients undergoing thyroid hormone withdrawal in preparation for nuclear medicine procedures for the evaluation and treatment of follicular-derived TC. LT3 was substituted for LT4 at a 1:3 mcg/mcg dosage ratio thrice daily for at least 30 days. PK of the last LT3 dose while at steady state and terminal elimination was assessed over 11 days. Thereafter, a PK study was performed following the nuclear medicine procedure in patients who volunteered for a second study. Results: Fourteen patients age 48.5-16.0 years completed the last dose study and five completed the second PK study. PK analysis indicates a time to maximum serum concentration of 1.8-0.32 hours and two distinct phases of linear elimination, with a fast distribution phase and slow elimination phases with half-lives of 2.3-0.11 hours and 22.9-7.7 hours, supporting a two-compartment model. PK modeling predicts that a twicedaily administration of low-dose LT3 (0.07 mcg/kg twice daily) in combination with LT4 can predictably increase the serum T3 concentration without significant peaks above the reference range. Conclusions: The PK of LT3 is well described by a two-compartment model that assumes elimination only from the sampling compartment, with a rapid distribution phase and a slow elimination phase. This information will contribute to design therapeutic strategies for LT3/LT4 combination therapies directed to maintain stable T3 serum levels.

Thyroid dysfunction, either thyrotoxicosis or hypothyroidism, represents an important cardiovascular risk factor. Heart disease is the leading cause of death for men and women in the United States. Cardiovascular disease is multifactorial and many efforts have been made to assess precipitants for optimal guideline-based, primary, and secondary prevention. Thyroid hormone receptors are present in the myocardium and endothelium, and small alterations in its levels could have significant effects in cardiac function. Specifically, overt hypothyroidism is associated with an increased risk for atherosclerotic cardiovascular disease due to metabolic and hemodynamic effects. Several concomitant factors like impaired lipid profile, low-grade chronic inflammatory state, increased oxidative stress and increased insulin resistance enforce this relationship. The last decade has seen a renewed interest on the impact of subclinical hypothyroidism on the cardiovascular system and whether or not it should be treated. The aim of this review is to provide current evidence of the effect of thyroid hormone replacement, either with levothyroxine mono-therapy or in combination with liothyronine, on specific cardiovascular parameters.