Thyroid hormones and the potential for regulating glucose metabolism in cardiomyocytes during insulin resistance and T2DM

Abstract

In order for the heart to maintain its continuous mechanical work and provide the systolic movement to uphold coronary blood flow, substantial synthesis of adenosine triphosphate (ATP) is required. Under normal conditions cardiac tissue utilizes roughly 70% fatty acids (FA), and 30% glucose for the production of ATP; however, during impaired metabolic conditions like insulin resistance and diabetes glucose metabolism is dysregulated and FA account for 99% of energy production. One of the major consequences of a shift in FA metabolism in cardiac tissue is an increase in reactive oxygen species (ROS) and lipotoxicity, which ultimately lead to mitochondrial dysfunction. Thyroid hormones (TH) have direct effects on cardiac function and glucose metabolism during impaired metabolic conditions suggesting that TH may improve glucose metabolism in an insulin resistant condition. None-classical TH signaling in the heart has shown to phosphorylate protein kinase B (Akt) and increase activity of phosphoinositide-3-kinase (PI3K), which are critical mediators in the insulin-stimulated glucose uptake pathway. Studies on peripheral tissues such as skeletal muscle and adipocytes have demonstrated TH treatment improved glucose intolerance in a diabetic model and increased insulin-regulated glucose transporter (GLUT4) mRNA levels. GLUT4 is a downstream target of thyroid response element (TRE), which demonstrates that THs regulate glucose via GLUT4. Elevated 3,5,3′-triiodothyronine (T3) increased glucose oxidation rate and decreased the glycolytic intermediate, fructose 6-phosphate (F6P) in cardiomyocytes, in addition to increasing mitochondrial biogenesis and pyruvate transport across the mitochondrial membrane. These findings along with a few other studies on T3 treatment in cardiac tissue suggest TH may improve glucose metabolism in an insulin resistant model and ameliorate the effects of diabetes and metabolic syndrome. This review highlights the potential benefits of exogenous TH on ameliorating metabolic dysfunction in the heart.

Proteome-wide analysis of lysine β-hydroxybutyrylation in the myocardium of diabetic rat model with cardiomyopathy

“…Under normal conditions, fatty acids and glucose are the primary energy sources for the heart to maintain continuous systolic movement to support cardiac pumping. However, during aberrant metabolic conditions such as diabetes and insulin resistance, glucose utilization by cardiomyocytes decreases, while the utilization of fatty acids and ketone bodies increases ( 45 ). Cardiomyocytes need to adapt to these energy transitions to maintain myocardial energy metabolism.…”

Association of Mitochondrial Variants with the Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto’s Thyroiditis

“…In turn, thyroid hormones promote the entry of glucose and fatty acids into cells, increasing the supply of substrates for cellular respiration, including the TCA cycle [50]. In addition, these molecules boost the activity of enzymes involved in the TCA cycle and the electron transport chain, leading to increased ATP production [51]. In hypothyroidism, with reduced levels of thyroid hormones, the overall cellular metabolism tends to slow down.…”

Metabolomic profiling reveals altered phenylalanine metabolism in Parkinson’s disease in an Egyptian cohort

“…Based on our findings supporting the shift in phenylalanine metabolism towards transcinnamate production instead of tyrosine in PD, we assume that the lower levels of tyrosine in P lead to the production of lower levels of thyroxine, resulting in developing hypothyroidism. Since we had excluded any participant with a history of thyroid dysfunction disorder or on thyroid hormone replacement therapy and given that thyroxine regulates glucose metabolism (Mendez and Ortiz, 2021), we assessed the levels of glucose-6-phosphate between P and C. Our results showed that P have significantly lower levels of this metabolite, confirming our hypothesis that the shift in phenylalanine metabolism that led to a decrease in the levels of tyrosine has an impact on thyroxine level and its physiological TABLE 5 Represents the significant differences (p-value%) in the levels of the tackled metabolites between the different recruited groups: C vs. P, P vs. HC, and C vs. HC. The yellow shaded cells shows insignificant difference, while the orange cells represents metabolites that were significantly higher in P than in C; however, the rest of the metabolites were significantly higher in C than in P. functions as a consequence.…”